WO2009092032A1 - Genetic markers of mental illness - Google Patents

Genetic markers of mental illness Download PDF

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Publication number
WO2009092032A1
WO2009092032A1 PCT/US2009/031322 US2009031322W WO2009092032A1 WO 2009092032 A1 WO2009092032 A1 WO 2009092032A1 US 2009031322 W US2009031322 W US 2009031322W WO 2009092032 A1 WO2009092032 A1 WO 2009092032A1
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rsl
test
subject
haplotype
marker
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PCT/US2009/031322
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French (fr)
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Mark David Brennan
Timothy Lynn Ramsey
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Suregene Llc
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Priority to EP09702855.9A priority Critical patent/EP2231872B1/en
Priority to CA2712075A priority patent/CA2712075A1/en
Priority to AU2009205920A priority patent/AU2009205920A1/en
Priority to US12/523,262 priority patent/US8586308B2/en
Publication of WO2009092032A1 publication Critical patent/WO2009092032A1/en
Priority to IL207075A priority patent/IL207075A0/en
Priority to US14/066,120 priority patent/US9040241B2/en
Priority to US14/703,753 priority patent/US20160168637A1/en
Priority to US14/968,333 priority patent/US9738934B2/en

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Definitions

  • This invention was made with an award from the Kentucky Cabinet for Economic Development, Department of Commercialization and Innovation, under Grant Agreement KSTC-184-512-07-007 with the Kentucky Science and Technology Corporation.
  • This invention relates to genetic markers of mental illness, e.g., schizophrenia (SZ), and methods of use thereof, e.g., for determining a subject's risk of developing a mental illness, e.g., SZ.
  • SZ schizophrenia
  • Schizophrenia is a severe and persistent debilitating psychiatric illness that is generally associated with considerable morbidity and extreme disability. Due to the severity of this disorder, especially the negative impact of a psychotic episode on a patient, and the diminishing recovery after each psychotic episode, there is a need to more conclusively identify individuals who have or are at risk of developing SZ, for example, to confirm clinical diagnoses, to allow for prophylactic therapies, to determine appropriate therapies based on their genotypic subtype, and to provide genetic counseling for prospective parents with a history of the disorder.
  • Psychiatry 7:689-694 (2002)Fallin et al., Am. J. Hum. Genet. 73:601-611 (2003)Ginns et al., Proc. Natl. Acad. Sci. U. S. A 95: 15531-15536 (1998)Jablensky, MoI. Psychiatry (2006)Kirov et al., J. Clin. Invest 115:1440-1448 (2005)Norton et al., Curr. Opin. Psychiatry 19:158-164 (2006)Owen et al., MoI. Psychiatry 9:14-27 (2004)).
  • the invention includes methods for assessing genetic risk, aiding in diagnosis, and/or stratifying patient populations in order to select optimal treatments based on evaluation of single nucleotide polymorphisms (SNPs) for a number of bioinformatically identified genes on chromosomes 1, 3, 6, 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, and 20 relating to SZ (which herein is broadly defined to include SZ-spectrum disorders, e.g., including schizophrenia (SZ), schizotypal personality disorder (SPD) and schizoaffective disorder (SD)).
  • SZ single nucleotide polymorphisms
  • SZ single nucleotide polymorphisms
  • SZ single nucleotide polymorphisms
  • exemplary SNPs delimiting each gene region are given along with exemplary test SNPs that can be used to capture significant haplotype variation in these genes.
  • Important variants can be identified via TDT using families with multiple affected individuals (such as those collected CCGS) and verified by Case/Control comparisons using the SNP markers presented herein. Using SNP markers lying between the delimiting SNPs, inclusive, and identical to or in linkage disequilibrium with the exemplary SNPs, one can determine the haplotypes in these genes relating to genetic risk of developing SZ. These haplotypes can then be used to determine risk of developing SZ by Case/Control studies as shown in Example 1. The allelic and genotypic variants thus identified can be used for assessing genetic risk, to aid in diagnosis, and/or to stratify patient population in order to select optimal treatments (atypical antipsychotic, typical antipsychotic, and/or psychosocial intervention) for patients.
  • genes identified as associated with increased risk of SZ are involved in a number of pathways including: glutamate signaling and metabolism, cell adhesion, cytoskeletal architecture, vesicle formation and trafficking, G-protein coupled receptors, carrier proteins and transporters, ion channels (e.g., potassium channels), and potassium current signaling molecules, cell cycle modulators, neuronal development, calcium/calmodulin signaling, neuropeptide signaling, inositol signaling (e.g., phosphatidylinositol kinases), insulin signaling, diacylglycerol signaling, and several additional genes identified by virtue of their interaction with genes in high impact pathways and their expression in the central nervous system.
  • glutamate signaling and metabolism including: glutamate signaling and metabolism, cell adhesion, cytoskeletal architecture, vesicle formation and trafficking, G-protein coupled receptors, carrier proteins and transporters, ion channels (e.g., potassium channels), and potassium current signaling molecules, cell cycle modulators, neuronal
  • Table A lists gene names and delimiting SNPs for bioinformatically identified genes relating to SZ-spectrum disorders. All of the genes are human.
  • Table A Delimiting SNPs for Novel SZ Genes (NCBI Genome Build 36.2) Delimiting SNPs for Potassium Channel and Related Genes
  • VAMP4 1 rsl0913508 169,935,102 rs7556644 169,979,491
  • the invention includes methods for obtaining information regarding a subject's risk for developing SZ, i.e., determining the subject's risk of developing SZ.
  • the methods include obtaining a test haplotype associated with schizophrenia as described herein.
  • the methods can also include obtaining a sample comprising genomic DNA (gDNA) from the subject, and determining the identity, absence or presence of a test haplotype associated with SZ as described herein.
  • gDNA genomic DNA
  • the methods include obtaining a test haplotype for the subject comprising at least one test SNP marker that is found within the region delimited by SNPl and SNP2, inclusive, for a given gene as specified in Table A, or comprising one or more of the exemplary SNP markers for each gene, as specified in the Examples and/or SNP markers in linkage disequilibrium with these markers, wherein the haplotype provides information regarding the subject's risk of developing SZ, SD, or SPD.
  • the test marker is a marker listed in one or more genes of Table A that is in linkage disequilibrium (defined by correlation, [r 2 ] > 0.5) with a marker listed in Table A in Table B as shown in the Examples, wherein the haplotype provides information regarding the subject's risk of developing SZ, e.g., markers lying between the exemplary SNPs for a gene listed in Table A, but not explicitly listed in the Examples.
  • the test haplotype includes at least one marker lying between delimiting SNPs (SNPl and SNP2), inclusive, for a given gene as specified in Table A, e.g., the exemplary delimiting SNPs listed in Table A; other delimiting SNPs can be chosen from other SNPs known in the art, e.g., the exemplary test SNPs described herein.
  • the test haplotype includes two or more markers from one gene.
  • the test genotype includes at least two markers, each from a different gene listed in Table A.
  • the test haplotype includes at least one marker lying between the SNPl and SNP2, inclusive, for a given gene as specified in Table A and provides information regarding a subject's risk of developing SZ under a narrower (DSM III/DSM IV) disease definition.
  • the methods include obtaining a test haplotype for the subject by determining the genotype of at least one test marker listed in Table B, or a test marker that lies between the delimiting markers listed in Table A and that is in linkage disequilibrium (LD, defined by correlation, [r 2 ] > 0.5) with markers listed in Table B, wherein the test haplotype indicates the subject's risk of developing SZ.
  • the at least one test marker is in the KIAAO 182 gene or the KIAA0427 gene.
  • the test marker is selected from the group consisting rs736845; rs994060; rs381579; rs217556; rs8095199; or is a test marker in LD with these markers.
  • the methods described herein can be used for predicting a human subject's likely response to an antipsychotic medication.
  • the methods include obtaining a test haplotype for the subject by determining the genotype for at least one test marker listed in Table B, or at least one test marker that lies between the delimiting markers in Table A and that is in linkage disequilibrium (LD) (defined by correlation, [r2] > 0.5) with a marker listed in Table B, wherein the test haplotype indicates the subject's likely response, e.g., likelihood of responding positively (i.e., an improvement in one or more symptoms of the disease) or negatively (i.e., with no improvement, or even a worsening, of one or more symptoms of the disease, or with excessive side effects) to an antipsychotic medication.
  • a number of antipsychotic medications are known in the art and can include, for example, olanzapine, risperidone, quetiapine, perphenazine, and ziprasidone.
  • the treatment is administration of olanzapine
  • the at least one test marker is in a gene selected from the group consisting of C16orf74, synaptic vesicle glycoprotein 2B (SV2B), calmodulin binding transcription activator 1 (CAMTAl), otogelin (OTOG), ras homolog gene family, member G (RHOG).
  • the test marker is selected from the group consisting of rs230535; rs373835; rs386061; rs449250; rs657739; rs657740; rs755475; rs755475; rsl41798; rsl 10300; rsl45172; rsl00349; rslO8328; rs202348; rsl 10243; rsl 1024358; or is a test markers in LD with one of these markers, and the test haplotype indicates the subject's likely response to administration of olanzapine.
  • the treatment is administration of risperidone
  • the at least one test marker is in a gene selected from the group consisting of neural precursor cell expressed, developmentally down-regulated 4 (NEDD4), cadherin 8, type 2 (CDH8), deformed epidermal autoregulatory factor 1 (DEAFl), hect domain and RLD 2 (HERC2).
  • the test marker is selected from the group consisting of rs230357; rs230358; rsl39713; rs805733; rs930254; rsllO754; rsl36991; rsl97879; rs649880; rs993999; rs496314; rs659799; rs936465; rs659799; rsl 10743; rsl63516; rs223828; rs7495174; or is a test marker that is in linkage disequilibrium with one of these markers.
  • the test haplotype indicates the subject's likely response to administration of risperidone.
  • the treatment is administration of quetiapine
  • the at least one test marker is in a gene selected from the group consisting of catenin (cadherin- associated protein), delta 1 (CTNNDl), reticulon 1 (RTNl), A kinase (PRKA) anchor protein 13 (AKAP 13), potassium voltage-gated channel, shaker-related subfamily, member 10 (KCNAlO), solute carrier family 17 (sodium-dependent inorganic phosphate cotransporter), member 6 (SLC 17 A6).
  • the test marker further is selected from the group consisting of: rs207835; rsllO265; rsll5582; rs207835; rs224671; rs376845; rs708228; rslO8966; rsll5701; rs215663; rs652908; rslO5399; rs206182; rs206182; rs206182; rs338523; rs407525; rs407525; rs484289; rs484307; rs484307; rs716216; rsl 10735; rsl01450; rsl27174; rsl7310036; or is a test marker that is in linkage disequilibrium with one of these markers.
  • the test haplotype indicates the subject's likely response to administration of quetiapine.
  • the treatment is administration of perphenazine
  • the at least one test marker is in a gene selected from the group consisting of secretion regulating guanine nucleotide exchange factor (SERGEF) potassium voltage-gated channel, subfamily H (eag-related), member 1 (KCNHl), functional smad suppressing element 18 (FUSSELl 8).
  • SEGEF secretion regulating guanine nucleotide exchange factor
  • the test marker is selected from the group consisting of: rsl 77022; rsl39302; rsl528; rsl72424; rs211130; rs211137; rs211146; rs228323; rsl05028; rsl77854; rs266877; rs723610; rs892583; or is a test marker that is in linkage disequilibrium with one of these markers.
  • the test haplotype indicates the subject's likely response to perphenazine.
  • the treatment is administration of ziprasidone
  • the at least one test marker is in a gene selected from the group consisting of unc-13 homo log C (C. elegans) (UNC13C), cerebellin 1 precurso (CBLNl), checkpoint with forkhead and ring finger domains (CHFR).
  • the test marker is selected from the group consisting of: rsl29109; rsllO764; rs993537; rsl25945; rsll6390; rs802519; rs930218; rs230653; rs4758954; or is a test marker that is in linkage disequilibrium with one of these markers.
  • the test haplotype indicates the subject's likely response to administration of ziprasidone.
  • the treatment is administration of an antipsychotic drug
  • the at least one test marker is in a gene selected from the group consisting of cadherin 11 , type 2, OB-cadherin (osteoblast) (CDHIl), deleted in colorectal carcinoma (DCC), Usher syndrome 1C (autosomal recessive, severe) (USHlC).
  • the test marker is selected from the group consisting of: rs35144 ; rs35148 ; rs35186 ; rs35195 ; rs35144 ; rs222908; rs950278; rsl43174; rsl24574; rs494025; rs750690; rs650823; rsl39333; rsl52023; rslO5557; rslO5557; rs207222; rs475689; rsl6770, or is a test marker that is in linkage disequilibrium with one of these markers.
  • the test haplotype indicates the subject's likely response to administration of an antipsychotic.
  • the test haplotype provides information regarding a subject's risk (or likelihood) of having a particular endophenotype, and/or a higher or lower level (e.g., severity) of the endophenotype, e.g., of one or more specific parameters of the PANSS scale, e.g., one or more symptoms, e.g., hallucinations, paranoia, anxiety, depression, or grandiosity, as well as response or lack of response to drugs and comorbidity for substance and alcohol abuse.
  • a subject's risk or likelihood
  • a higher or lower level e.g., severity
  • symptoms e.g., hallucinations, paranoia, anxiety, depression, or grandiosity
  • the invention provides methods for predicting the degree of severity of a psychiatric endophenotype in a human subject.
  • the methods include obtaining a test haplotype for the subject by determining the genotype for at least one test marker listed in Table B, or at least one test markers that lies between the delimiting markers listed in Table A and that is in linkage disequilibrium (LD) defined by correlation, [r 2 ] > 0.5) with a marker in Table B, wherein the test haplotype indicates the likely degree of severity of a psychiatric endophenotype in the subject.
  • the psychiatric endophenotype is a quantitative trait that can be measured using one or more of PANSS Total composite score, PANSS Positive composite score, PANSS Negative composite score, and PANSS General Psychopathology composite score.
  • the one or more test markers are from calcium channel, voltage-dependent, R type, alpha IE subunit (CACNAlE), echinoderm microtubule associated protein like 1 (EMLl), katanin p60 subunit A- like 2 (KATNAL2) genes.
  • CACNAlE alpha IE subunit
  • EMLl echinoderm microtubule associated protein like 1
  • KATNAL2 katanin p60 subunit A- like 2
  • the test marker is selected from the group consisting of rs 174946; rs 199960; rs385609; rs465267; rs704326; rs218709; rs224722; rs257103; rs257604; rs723351; rs930434; rs996138; rs225071; rslll605; rsll l605; rsl24336; rs657575; rs746698; rs227370; rs2273704; or is a test marker in linkage disequilibrium with one of these markers.
  • the test haplotype indicates the likely degree of severity of a psychiatric endophenotype in the subject.
  • the psychiatric endophenotype comprises one or more of: a Positive Symptom selected from the group consisting of Pl -delusions, P2-conceptual disorganization, P3 -hallucinatory behavior, P4-exitement, P5 -grandiosity, P6-suspiciousness, P7-hostility; a Negative Symptom selected from the group consisting of Nl -blunted affect, N2-emotional withdrawal, N3-poor rapport, N4-passive/appathetic social withdrawal, N5- difficultiy in abstract thinking, N60 lack of spontaneity and flow of conversation, N7- steryotyped thinking; or a general psychopathology symptom selected from the group consisting of Gl-somatic concern, G2-anxiety, G3-guilt feelings, G4-tension, G5-mannerisms and posturing,
  • the at least one test marker is from a gene selected from the group consisting of DPH3, KTIIl homo log (DPH3), insulin- like growth factor I receptor (IGFlR), calcium/calmodulin-dependent protein kinase IG (CAMKlG), neuron navigator 2 (NAV2), bone morphogenetic protein 7 (BMP7).
  • DPH3 DPH3, KTIIl homo log
  • IGFlR insulin-like growth factor I receptor
  • CAMKlG calcium/calmodulin-dependent protein kinase IG
  • NAV2 neuron navigator 2
  • BMP7 bone morphogenetic protein 7
  • the test marker is selected from the group consisting of rs224572; rs842257; rs859703; rs224570; rs496543; rsll2473; rsl 87961; rs268479; rslO8332; rs712564; rslO375 ; rs601494; rs230198; or is a test marker that is in linkage disequilibrium with one of these markers.
  • the test haplotype indicates the likely severity of a psychiatric endophenotype in the subject.
  • the methods described herein can include obtaining a haplotype that includes two or more, e.g., two, three, four, five, or six markers.
  • the methods can include determining the presence or absence of other markers known to be associated with SZ, SD, or SPD, e.g., outside of a region identified herein.
  • markers known to be associated with SZ, SD, or SPD, e.g., outside of a region identified herein.
  • a number of other such markers are known in the art, e.g., as described herein.
  • the subject can be a human (e.g., a patient having, or at risk of, SZ).
  • the subject is a patient having previously diagnosed SZ, SD, or SPD (e.g., a patient suffering from early, intermediate or aggressive SZ, SD, or SPD).
  • the methods described herein are used to obtain information regarding a subject's risk of developing SZ wherein the disorder is other than catatonic schizophrenia.
  • the subject is of Caucasian (CA) descent, i.e., has one or more ancestors who are CA.
  • CA Caucasian
  • a subject to be evaluated by a method described herein is a subject having one or more risk factors associated with SZ, SD, or SPD.
  • the subject may have a relative afflicted with SZ, e.g., one or more of a grandparent, parent, uncle or aunt, sibling, or child who has or had SZ, SD, or SPD; the subject may have a genetically based phenotypic trait associated with risk for SZ, SD, or SPD (e.g., eye tracking dysfunction); deficits in working (short-term) memory; and/or mixed-handedness (the use of different hands for different tasks), particularly in females.
  • SZ e.g., one or more of a grandparent, parent, uncle or aunt, sibling, or child who has or had SZ, SD, or SPD
  • the subject may have a genetically based phenotypic trait associated with risk for SZ, SD, or SPD (e.g., eye tracking dysfunction); deficits in working (short-term) memory; and/or
  • the subject is a child, fetus, or embryo, and one of the subject's relatives, e.g., a parent or sibling, of the child, fetus, or embryo has SZ, SD, or SPD.
  • the subject has no overt or clinical signs of SZ, SD, or SPD.
  • obtaining a test haplotype includes obtaining a sample comprising DNA from the subject; and determining the identity, presence or absence of at least one test marker that is SNP marker that is found within the region delimited by SNPl and SNP2, inclusive, for a given as specified in Table A, or comprising one or more of the exemplary SNP markers for each gene, as specified in the Table B and/or SNP markers in linkage disequilibrium with these markers (in the particular population) in the DNA .
  • the sample can be obtained, e.g., from the subject by a health care provider, or provided by the subject without the assistance of a health care provider.
  • obtaining a test haplotype includes reviewing a subject's medical history, wherein the medical history includes information regarding the presence or absence of at least one test SNP marker that is found within the region delimited by SNPl and SNP2, inclusive, for a given gene as specified in Table A, or comprising one or more of the exemplary SNP markers for each gene, as specified in Table B, and/or SNP markers in linkage disequilibrium with these markers, in the subject.
  • the methods described herein include obtaining a reference haplotype including a reference marker that corresponds to a test marker, and comparing the test haplotype to the reference haplotype.
  • a reference marker that "corresponds to" a test marker is the same marker. For example, if the test haplotype includes rs 10766410 in the OTOG gene, then the reference haplotype should also include rs 10766410 for comparison purposes; or if the test haplotype includes rs553042 in the CACNAlE gene, then the reference haplotype should also include rs553042 for comparison purposes.
  • the sharing of a haplotype (e.g., of some or all of the marker alleles) between the test haplotype and a reference haplotype is indicative of whether there is an increased likelihood that the subject will develop SZ.
  • the reference haplotype can be from a relative, e.g., a first or second degree relative, or from an unrelated individual (or population), that has been identified as either having or not having SZ, SD, or SPD.
  • a reference haplotype is also obtained from an unaffected person, e.g., an unaffected relative, and lack of sharing of a haplotype of a haplotype between the test haplotype and the reference haplotype indicates that the subject has an increased risk of developing SZ.
  • the sharing of a haplotype (e.g., of some or all of the marker alleles) between the test haplotype and a reference haplotype is indicative of whether there is an increased likelihood that the subject will have an elevated (high) or low value for that specific endophenotype.
  • the reference haplotype can be from a relative, e.g., a first or second degree relative, or from an unrelated individual (or population), e.g., a person that has been diagnosed with SZ, and further identified as either having or not having an elevated value for the specific endophenotype.
  • the presence of the haplotype does not indicate the presence or absence of a specific phenotype, but rather the degree to which the phenotype occurs, e.g., on the PANSS scale; as one example, alleles of the marker rsl 1030008 can impact the severity of delusions and suspiciousness/persecution not necessarily its presence or absence of these symptoms.
  • the sharing of a haplotype (e.g., of some or all of the marker alleles) between the test haplotype and a reference haplotype is indicative of how the subject is likely to respond to the treatment.
  • the reference haplotype can be from a relative, e.g., a first or second degree relative, or from an unrelated individual (or population), that has been diagnosed with SZ and further identified as responding positively (i.e., with an improvement in one or more symptoms of the disease) or negatively (i.e., with no improvement, or even a worsening, of one or more symptoms of the disease, or with excessive side effects).
  • the methods include administering a treatment to a subject identified as being at increased risk for developing SZ, e.g., a pharmacological treatment as described herein.
  • a treatment e.g., a pharmacological treatment as described herein.
  • the subject has no overt or clinical signs of SZ, SD, or SPD, and the treatment is administrated before any such signs appear.
  • Information obtained using a method described herein can be used, e.g., to select a subject population for a clinical trial, to stratify a subject population in a clinical trial, and/or to stratify subjects that respond to a treatment from those who do not respond to a treatment, or subjects that have negative side effects from those who do not.
  • the invention provides methods for selecting a subject for inclusion in a clinical trial, e.g., a trial of a treatment for SZ, SD, or SPD.
  • the methods include obtaining a haplotype for the subject including at least one marker that is found within the region delimited by SNPl and SNP2, inclusive, for a given gene as specified in Table A, or comprising one or more of the exemplary SNP markers for each gene, as specified in the Table B and/or SNP markers in linkage disequilibrium with these markers e.g.
  • haplotype is associated with an increased risk of developing SZ; and including the subject in the trial or excluding the subject from the trial if the haplotype indicates that the subject has altered drug response for patients with SZ, SD, or SPD.
  • the invention provides methods for selecting a subject for administration of a treatment for schizophrenia (SZ).
  • the methods include obtaining a haplotype for the subject, wherein the haplotype comprises at least one marker that is listed in Table B, or is in linkage disequilibrium with a marker listed in Table B, as exemplified by the Markers listed in Table C; determining whether the haplotype is associated with altered (e.g., positive or negative) treatment response for patients with SZ; and administering the treatment to the subject if the haplotype indicates that the subject has an improved response to the treatment.
  • the invention provides methods for selecting a treatment for administration to a subject.
  • the methods include obtaining a haplotype for the subject, wherein the haplotype comprises at least one marker that is listed in Table B, or is in linkage disequilibrium unit with a marker listed in Table B; determining whether the haplotype is associated with altered (e.g., positive or negative) treatment response for patients with schizophrenia (SZ); and administering the treatment for SZ to the subject if the haplotype indicates that the subject has an improved response to the treatment.
  • altered e.g., positive or negative
  • the invention provides methods for evaluating the effect of a haplotype on the outcome of a treatment for schizophrenia (SZ).
  • the methods include obtaining information regarding outcome of the treatment, wherein the information comprises a parameter relating to the treatment of each subject in a population of subjects; obtaining haplotypes for each subject in the population, wherein the haplotype comprises at least one marker that is listed in Table B, or is in linkage disequilibrium with a marker listed in Table B; and correlating the information regarding outcome with the haplotypes; thereby evaluating the effect of the haplotype on the outcome of the treatment.
  • the method includes selecting a treatment for administration to a subject who has a selected haplotype, based on the effect of the haplotype on the outcome of the treatment.
  • the information regarding outcome of the treatment is from a completed clinical trial, and the analysis is retrospective.
  • the invention features methods for detecting the presence of a haplotype associated with susceptibility to SZ (broadly defined as including, in addition to narrowly defined SZ, SD or SPD) in a subject, by analyzing a sample of DNA from the subject.
  • a haplotype associated with susceptibility to SZ broadly defined as including, in addition to narrowly defined SZ, SD or SPD
  • the invention features methods of predicting a test subject's risk of developing SZ.
  • the methods include obtaining a reference haplotype of a reference subject, wherein the reference subject has SZ, SD, or SPD; determining a test haplotype of the test subject in the same region; and comparing the test haplotype to the reference haplotype, wherein the sharing of a haplotype in this region between the test subject and the reference subject is an indication of an increased likelihood that the test subject will develop SZ.
  • the method further includes comparing the subject's haplotype to a reference subject who does not have SZ, SD, or SPD.
  • the invention features methods for predicting a test subject's risk of developing SZ.
  • the methods include obtaining a reference haplotype of a reference subject in a region described herein, wherein the reference subject has SZ; obtaining a test haplotype of the test subject in the same region; and comparing the test haplotype to the reference haplotype.
  • the sharing of a haplotype in this region between the test subject and the reference subject is an indication of an increased likelihood that the test subject will develop SZ.
  • the method also includes comparing the test subject's haplotype to a reference subject who does not have SZ.
  • kits for use in detection of haplotypes associated with SZ including at least one nucleic acid probe that hybridizes to a sequence that includes a polymorphism described herein, or can be used to amplify a sequence that includes a polymorphism described herein.
  • arrays that include a substrate having a plurality of addressable areas, wherein one or more of the addressable areas includes one or more probes that can be used to detect a polymorphism described herein.
  • the invention provides methods for providing information regarding a subject's risk of developing schizophrenia (SZ).
  • the methods include obtaining a sample from the subject at a first site; transferring the sample to a second site for analysis, wherein the analysis provides data regarding the identity, presence or absence of at least one test marker that is that is found within the region delimited by SNPl and SNP2, inclusive, for a given gene as specified in Table A, or comprising one or more of the exemplary SNP markers for each gene, as specified in the Examples and/or SNP markers in linkage disequilibrium with these markers; and transferring the data to one or more of a health care provider, the subject, or a healthcare payer.
  • the first site is a health care provider's place of business, or is not a health care provider's place of business, e.g., the subject's home.
  • the data is transferred to a healthcare payer and used to decide whether to reimburse a health care provider.
  • SZ Schizophrenia
  • SPD Schizotypal Personality Disorder
  • SD Schizoaffective Disorder
  • haplotype is one or a set of signature genetic changes (polymorphisms) that are normally grouped closely together on the DNA strand, and are usually inherited as a group; the polymorphisms are also referred to herein as "markers.”
  • a “haplotype” as used herein is information regarding the presence or absence of one or more contiguous genetic markers on a given chromosome in a subject.
  • a haplotype can consist of a variety of genetic markers, including indels (insertions or deletions of the DNA at particular locations on the chromosome); single nucleotide polymorphisms (SNPs) in which a particular nucleotide is changed; microsatellites; and minisatellites.
  • Microsatellites (sometimes referred to as a variable number of tandem repeats or VNTRs) are short segments of DNA that have a repeated sequence, usually about 2 to 5 nucleotides long (e.g., CACACA), that tend to occur in non-coding DNA. Changes in the microsatellites sometimes occur during the genetic recombination of sexual reproduction, increasing or decreasing the number of repeats found at an allele, changing the length of the allele. Microsatellite markers are stable, polymorphic, easily analyzed and occur regularly throughout the genome, making them especially suitable for genetic analysis.
  • chromosome refers to a gene carrier of a cell that is derived from chromatin and comprises DNA and protein components (e.g., histones).
  • the conventional internationally recognized individual human genome chromosome numbering identification system is employed herein.
  • the size of an individual chromosome can vary from one type to another with a given multi-chromosomal genome and from one genome to another. In the case of the human genome, the entire DNA mass of a given chromosome is usually greater than about 100,000,000 base pairs. For example, the size of the entire human genome is about 3 X 10 9 base pairs.
  • gene refers to a DNA sequence in a chromosome that codes for a product (either RNA or its translation product, a polypeptide).
  • a gene contains a coding region and includes regions preceding and following the coding region (termed respectively "leader” and “trailer”).
  • the coding region is comprised of a plurality of coding segments ("exons") and intervening sequences ("introns") between individual coding segments.
  • probe refers to an oligonucleotide.
  • a probe can be single stranded at the time of hybridization to a target.
  • probes include primers, i.e., oligonucleotides that can be used to prime a reaction, e.g., a PCR reaction.
  • label or "label containing moiety” refers in a moiety capable of detection, such as a radioactive isotope or group containing same, and nonisotopic labels, such as enzymes, biotin, avidin, streptavidin, digoxygenin, luminescent agents, dyes, haptens, and the like.
  • Luminescent agents depending upon the source of exciting energy, can be classified as radioluminescent, chemiluminescent, bioluminescent, and photoluminescent (including fluorescent and phosphorescent).
  • a probe described herein can be bound, e.g., chemically bound to label-containing moieties or can be suitable to be so bound. The probe can be directly or indirectly labeled.
  • direct label probe refers to a nucleic acid probe whose label after hybrid formation with a target is detectable without further reactive processing of hybrid.
  • indirect label probe refers to a nucleic acid probe whose label after hybrid formation with a target is further reacted in subsequent processing with one or more reagents to associate therewith one or more moieties that finally result in a detectable entity.
  • target refers to a nucleotide sequence that occurs at a specific chromosomal location. Each such sequence or portion is preferably at least partially, single stranded (e.g., denatured) at the time of hybridization. When the target nucleotide sequences are located only in a single region or fraction of a given chromosome, the term “target region” is sometimes used.
  • Targets for hybridization can be derived from specimens which include, but are not limited to, chromosomes or regions of chromosomes in normal, diseased or malignant human cells, either interphase or at any state of meiosis or mitosis, and either extracted or derived from living or postmortem tissues, organs or fluids; germinal cells including sperm and egg cells, or cells from zygotes, fetuses, or embryos, or chorionic or amniotic cells, or cells from any other germinating body; cells grown in vitro, from either long-term or short-term culture, and either normal, immortalized or transformed; inter- or intraspecific hybrids of different types of cells or differentiation states of these cells; individual chromosomes or portions of chromosomes, or translocated, deleted or other damaged chromosomes, isolated by any of a number of means known to those with skill in the art, including libraries of such chromosomes cloned and propagated in prokaryotic or other
  • hybrid refers to the product of a hybridization procedure between a probe and a target.
  • hybridizing conditions has general reference to the combinations of conditions that are employable in a given hybridization procedure to produce hybrids, such conditions typically involving controlled temperature, liquid phase, and contact between a probe (or probe composition) and a target. Conveniently and preferably, at least one denaturation step precedes a step wherein a probe or probe composition is contacted with a target.
  • Guidance for performing hybridization reactions can be found in Ausubel et al., Current Protocols in Molecular Biology. John Wiley & Sons, N. Y. (2003), 6.3.1-6.3.6. Aqueous and nonaqueous methods are described in that reference and either can be used.
  • Hybridization conditions referred to herein are a 50% formamide, 2X SSC wash for 10 minutes at 45°C followed by a 2X SSC wash for 10 minutes at 37°C.
  • Calculations of "identity" between two sequences can be performed as follows.
  • the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second nucleic acid sequence for optimal alignment and non-identical sequences can be disregarded for comparison purposes).
  • the length of a sequence aligned for comparison purposes is at least 30%, e.g., at least 40%, 50%, 60%, 70%, 80%, 90% or 100%, of the length of the reference sequence.
  • the nucleotides at corresponding nucleotide positions are then compared. When a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position.
  • the percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.
  • the comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm.
  • the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package, using a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.
  • nucleotide sequences that are substantially identical are at least 80%, e.g., 85%, 90%, 95%, 97% or more, identical.
  • nonspecific binding DNA refers to DNA which is complementary to DNA segments of a probe, which DNA occurs in at least one other position in a genome, outside of a selected chromosomal target region within that genome.
  • An example of nonspecific binding DNA comprises a class of DNA repeated segments whose members commonly occur in more than one chromosome or chromosome region. Such common repetitive segments tend to hybridize to a greater extent than other DNA segments that are present in probe composition.
  • stratification refers to the creation of a distinction between subjects on the basis of a characteristic or characteristics of the subjects. Generally, in the context of clinical trials, the distinction is used to distinguish responses or effects in different sets of patients distinguished according to the stratification parameters. In some embodiments, stratification includes distinction of subject groups based on the presence or absence of particular markers or haplotypes described herein. The stratification can be performed, e.g., in the course of analysis, or can be used in creation of distinct groups or in other ways.
  • FIG. 1 is a list of exemplary genes useful in the methods described herein, with the sequence identifiers from the GenBank database for their genomic sequences.
  • the present inventors have used bioinformatics and genetic linkages for related neuropsychiatric endophenotypes and DSM disease definitions to define genes in common cellular pathways across various chromosomes as high priority targets for TDT and Case/Control analysis.
  • Resources of the International HapMap project (hapmap.org) were used to define SNPs in these loci, whose pattern of transmission in families and disease association in the population captures extant genetic variation (including important coding variation if present) contributing to genetic susceptibility to SZ-spectrum disorders.
  • the invention includes methods for assessing genetic risk, aiding in diagnosis, and/or stratifying patient populations in order to select optimal treatments based on evaluation of single nucleotide polymorphisms (SNPs) for a number of bioinformatically identified genes on chromosomes 1, 3, 6, 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, and/or 20 relating to SZ- spectrum disorders including narrowly defined schizophrenia, schizotypal personality disorder (SPD) and schizoaffective disorder (SD) (collectively referred to herein as "SZ").
  • SNPs single nucleotide polymorphisms
  • SPD schizotypal personality disorder
  • SD schizoaffective disorder
  • Important variants can be verified via TDT using families with multiple affected individuals (such as those collected CCGS) and by Case/Control comparisons using the SNP markers presented herein.
  • SNP markers lying between the delimiting SNPs, inclusive, and identical to or in linkage disequilibrium with the exemplary SNPs one can determine the haplotypes in these genes relating to genetic risk of developing SZ-spectrum disorders via family-based association analyses. These haplotypes can then be used to determine risk of developing these disorders by Case/Control studies.
  • the allelic and genotypic variants thus identified can be used for assessing genetic risk, to aid in diagnosis, and/or to stratify patient population in order to select optimal treatments (atypical antipsychotic, typical antipsychotic, and/or psychosocial intervention) for patients.
  • Described herein are a variety of methods for the determination of a subject's risk of developing SZ (which can also be considered susceptibility to SZ) and related clinical phenotypes, likelihood or risk of having an specific endophenotype or severity of an endophenotype, and for predicting a subject's response to a treatment for SZ.
  • susceptibility to SZ does not necessarily mean that the subject will develop SZ, but rather that the subject is, in a statistical sense, more likely to develop SZ than an average member of the population, i.e., has an increased risk of developing SZ.
  • susceptibility to SZ exists if the subject has a haplotype associated with an increased risk of SZ as described herein. Ascertaining whether the subject has such a haplotype is included in the concept of diagnosing susceptibility to SZ as used herein.
  • susceptibility to displaying a particular clinical phenotype does not mean that the subject will have the phenotype, but rather that the subject is, in a statistical sense, more likely to display the phenotype.
  • the methods described herein can include obtaining a haplotype associated with an increased risk of having a specific clinical phenotype as described herein for the subject.
  • a prediction of response may not provide 100% certainty, but simply a statistical likelihood that the subject will respond in a particular way to a particular treatment. Such determinations are useful, for example, for purposes of diagnosis, treatment selection, and genetic counseling.
  • obtaining a haplotype includes obtaining information regarding the identity, presence or absence of one or more genetic markers in a subject.
  • Obtaining a haplotype can, but need not, include obtaining a sample comprising DNA from a subject, and/or assessing the identity, presence or absence of one or more genetic markers in the sample.
  • the individual or organization who obtains the haplotype need not actually carry out the physical analysis of a sample from a subject; the haplotype can include information obtained by analysis of the sample by a third party.
  • the methods can include steps that occur at more than one site.
  • a sample can be obtained from a subject at a first site, such as at a health care provider, or at the subject's home in the case of a self-testing kit.
  • the sample can be analyzed at the same or a second site, e.g., at a laboratory or other testing facility.
  • Obtaining a haplotype can also include or consist of reviewing a subject's medical history, where the medical history includes information regarding the identity, presence or absence of one or more genetic markers in the subject, e.g., results of a genetic test.
  • haplotypes associated with SZ include specific alleles for markers in Tables B and C, and makers in linkage disequilibrium with these, as exemplified by the Case/Control results in Table 1.
  • haplotypes associated with pharmacological response include one or more markers in Tables B and C and/or markers in linkage disequilibrium with these markers as exemplified by the Examples in Tables 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13.
  • Haplotypes associated with response to olanzapine can include one or more markers listed in Tables 2 and 3 and/or markers in linkage disequilibrium with these markers.
  • Haplotypes associated with response to risperidone can include one or more markers listed in Tables 4 and 5 and/or markers linkage disequilibrium with these markers.
  • Haplotypes associated with response to quetiapine can include one or more markers listed in Tables 6 and 7 and/or markers linkage disequilibrium with these markers.
  • Haplotypes associated with response to perphenazine can include one or more markers listed in Tables 8 and 9 and/or markers linkage disequilibrium with these markers.
  • Haplotypes associated with response to ziprasidone can include one or more markers listed in Tables 10 and 11 and/or markers linkage disequilibrium with these markers.
  • Haplotypes associated with response to antipsychotic medications, as a group can include one or more markers listed in Tables 12 and 13 and/or markers linkage disequilibrium with these markers.
  • the haplotype includes one or more of the markers listed in Tables 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13.
  • haplotypes associated with specific psychiatric endophenotypes include one or more markers in Tables B and C and/or markers in linkage disequilibrium with these markers as exemplified by the Examples in Tables 14 and 15 and/or markers linkage disequilibrium with these markers.
  • Haplotypes associated with altered scores for the main subscales of the Positive and Negative Syndrome Scale (PANSS) can include one or more markers listed in Table 14.
  • Haplotypes associated with altered scores for specific subscales of the PANSS can include one or more markers listed in Table 15 and/or markers in linkage disequilibrium with these markers.
  • the haplotype includes one or more of the markers listed in Tables 14 and 15.
  • a biological sample that includes nucleated cells is prepared and analyzed for the presence or absence of preselected markers.
  • nucleated cells such as blood, a cheek swab or mouthwash
  • diagnostic kits can be manufactured and sold to health care providers or to private individuals for self-diagnosis. Diagnostic or prognostic tests can be performed as described herein or using well known techniques, such as described in U.S. Pat. No. 5,800,998.
  • Results of these tests, and optionally interpretive information can be returned to the subject, the health care provider or to a third party payor.
  • the results can be used in a number of ways.
  • the information can be, e.g., communicated to the tested subject, e.g., with a prognosis and optionally interpretive materials that help the subject understand the test results and prognosis.
  • the information can be used, e.g., by a health care provider, to determine whether to administer a specific drug, or whether a subject should be assigned to a specific category, e.g., a category associated with a specific disease endophenotype, or with drug response or non-response.
  • the information can be used, e.g., by a third party payor such as a healthcare payer (e.g., insurance company or HMO) or other agency, to determine whether or not to reimburse a health care provider for services to the subject, or whether to approve the provision of services to the subject.
  • a healthcare payer e.g., insurance company or HMO
  • the healthcare payer may decide to reimburse a health care provider for treatments for SZ, SPD, or SD if the subject has an increased risk of developing SZ.
  • a drug or treatment may be indicated for individuals with a certain haplotype, and the insurance company would only reimburse the health care provider (or the insured individual) for prescription or purchase of the drug if the insured individual has that haplotype.
  • the presence or absence of the haplotype in a patient may be ascertained by using any of the methods described herein.
  • Information obtained from the methods described herein can also be used to select or stratify subjects for a clinical trial.
  • the presence of a selected haplotype described herein can be used to select a subject for a trial.
  • the information can optionally be correlated with clinical information about the subject, e.g., diagnostic, therapeutic, or endophenotypic information.
  • the methods described herein include the analysis of genotypic information for exemplary SNPs described herein as being associated with increased risk of developing SZ, pharmacological response, and having specific psychiatric endophenotypes.
  • the methods can also (or alternatively) include the evaluation of SNPs that are in linkage disequilibrium with the exemplary SNPs (as one of skill in the art will appreciate, those SNPs that are in linkage disequilibrium will provide essentially the same information as the exemplary SNPs).
  • the methods include the use of SNPs that are in linkage disequilibrium and are within a specified region of the gene.
  • Table B includes exemplary delimiting SNPs and exemplary test SNPs that can be used in capturing significant haplotype variation in these genes.
  • exemplary delimiting SNPs are provided, in some embodiments the region can be delimited by one of the other SNPs listed herein, e.g., an exemplary test SNP that is in LD with the primary SNP.
  • the specific region of the gene is between and excluding the delimiting SNPs; in some embodiments, the specific region is between and including the delimiting SNPs.
  • RP1-21O18.1 1 rs9663010 to rs2235789 rs7546786, rs6663699, rsl316257, rs938249, rs6674129, rs2073091, rs2076563, rsl2057431, rs4661572 CTNNDl 11 rs558653 to rs652908 rs2156638, rsl 1570176, rsl0896644, rsl 1570194, rs483030, rsl 1570199, rs612688, rsl 1570222, rs708228
  • VAMP4 rsl0913508 to rs7556644 rsl5655, rsl5655, rsl0913530, rs2073484, rs6672082, rs12096984
  • BRSK2 11 rs7395835 to rsl554857 rsl0833086, rs7932863, rs9651643, rs34893167,rsl881504, rsl 1029039, rs3829225, rsl574122
  • GOT2 16 rs2042445 to rs4238801 rs30839, rs6993, rs30842, rsl 1076256, rs257636, rs257620
  • GPR135 14 rsl7255731 to rs4898989 rsl612112, rsl253181, rsl0138199, rs9323348, rsl752427, rsl752428, rsl0136708
  • SNPs for Hormone, Inositol, and Diacylglyceride Related Genes Gene CHR Delimiting SNPs Exemplary SNPS
  • HSDl7Bl2 11 rsl2364003 to rsl 1037691 rs4573669, rsl0838160, rs4755744, rs7129046, rs3802891, rsl 1555762, rsl061810
  • TMEM55B 14 rsl 130409 to rsl760941 rsl7112002, rsl760943, rs35567022 IGFlR 15 rs35554027 to rs702497 rs8028620, rs7170035, rs7174918, rs8038015, rs4966020, rs4965436, rs8030950, rsl879613, rsl 1247380, rs45445894, rs34516635, rs33958176, , rs33958176, rs45553041, rs2684808, rs3743262, rsl546713, rs2229765, rs2684792, rsl7847203, rs3833015
  • SLCO3A1 15 rsl 1858120 to rsl060206 rsl2907294, rs4294800, rs2176452, rsl2912997, rsl878556, rs2286355, rsl517618, rs6496893, rs2074887, rs2302085, rs8174 Cell Cycle and Tumor Suppressor/Promoter Related Genes Gene CHR Delimiting SNPs Exemplary SNPS
  • HCCA2 11 rsl2786504 to rs2334652 rs7945160, rs9440, rsl0219175, rs7396514, rs7945160, rslO742185
  • PTPN5 11 rs873670 to rs7932938 rs7946105, rsl550871, rsl550870, rs6483524, rs4757707, rsl0766500, rs4272766, rs4274187, rs4345940
  • TTC5 14 rsl0130942 to rsl0873395 rslO147548, rs3737220, rsl953552, rs3742945, rs34675160, rs2318864
  • SMAD2 18 rs1792666 to rs2000709 rs7228393, rsl792682, rsl7340985, rsl787176, rsl942158, rsl2457664
  • SMAD4 18 rs620898 to rsl2456284 rs3764465, rsl2958604, rs2276163, rsl2458752,rs2298617
  • NDRG2 14 rsl263871 to rsl243451 rsl0196, rsl243444, rsl243446, rsl243446, rsl243450, rsl0138807
  • DAAMl 14 rsl7095965 to rs4127823 rsl7095965, rsl7833769, rsl252989, rsl268579, rs4901909, rsl253005, rs4898983, rslO143918, rsl2147707, rs8022614, rs941884, rsl958180, rs941886, rsl 1626926, rsl0083442
  • NEDD4 15 rs4424863 to rsl509408 rs3088077, rsl7238461, rs8028559, r s 34478706, rsl2232351, rs2303579, rs2303580, rsl912402, rsl6976618, rs2271289, rsl553739, rsl1632974
  • DCC 18 rs 17753970 to rs2270954 49311296, rsl 1875475, rsl 145245, rsl465943, rs6508145, rs8089980, rsl3381333, rsl893572, rsl431748, rs2229080, rs950278, rs8096519, rs7506904, rsl 2457407, rs4940251, rs8097413, rs2278339, rsl393331, rs984274, rs984274, rs6508235
  • CAMKlG 1 rs 17014820 to rs926387 rs2356933, rs6690557, rs9430004, rs35618105, rsl 1119314, rs 11119315, rs2272879, rs2206107, rs4140599, rs2076230
  • RIMBP2 12 rsl496858 to rs7963990 rsl 0848094, rs756186, rs749093, rsl 1060869, rs7303240, rs2277356, rs2292663, rs2292664, rs7952756, rs2277361, rs871568, rs4237817, rs4759708
  • RABGAPlL 1 rs6681627 to rsl2126129 rs6425302, rs6425305, rsl6847624 PHACS 11 rsl78512 to rs2285029 rsl6937817, rs2074038, rs33952257, rs2018795, rsl78521, rs35514614, rs2074043, rs7950395, rsl78529, rs3107275
  • YPEL4 11 rsl798177 to rsl647394 rs7947357, rs890036, rsl2793139, rs7947357, rsl2294735
  • TEPl 14 rsl713418 to rsl760890 rs2104978, rs938886, rsl713449, rs34811735,rs35929175, rs35165628, rs7150689, rs34895824, rs2297615, rs35517499, rs938887, rs34401320, rsl713456, rsl713457, rs2229100, rsl 760904, rs2228041, rsl713458, rsl760903, rs34179031, rsl7111188, rs2228035, rs34770935, rsl760898, rsl760897
  • WDR25 14 rs2273802 to rsl0151709 , rs2273801, , , rs34007610, rs34331240, rs2273800, rs3742387, rs941924, rs4905966, rsl 0873518, rs4905969, rs4905969
  • HERC2 15 rs7495174 to rsl 614575 rsl 129038, rsl 1074322, rsl 1636232, rsl 133496, rsl 133496, rs4073541, rs2238289, rs3940272, rsl 1631797, rs916977, rsl635168, rsl635163
  • Linkage disequilibrium is a measure of the degree of association between alleles in a population.
  • haplotypes involving markers in LD with the polymorphisms described herein can also be used in a similar manner to those described herein.
  • the methods include analysis of polymorphisms that are in LD with a polymorphism described herein.
  • Methods are known in the art for identifying such polymorphisms; for example, the International HapMap Project provides a public database that can be used, see hapmap.org, as well as The International HapMap Consortium, Nature 426:789-796 (2003), and The International HapMap Consortium, Nature 437:1299- 1320 (2005).
  • it will be desirable to use a HapMap constructed using data from individuals who share ethnicity with the subject e.g., a HapMap for African Americans would ideally be used to identify markers in LD with an exemplary marker described herein for use in genotyping a subject of African American descent.
  • methods described herein can include analysis of polymorphisms that show a correlation coefficient (r 2 ) of value > 0.5 with the markers described herein.
  • Results can be obtained, e.g., from on line public resources such as HapMap.org.
  • the correlation coefficient is a measure of LD, and reflects the degree to which alleles at two loci (for example two SNPs) occur together, such that an allele at one SNP position can predict the correlated allele at a second SNP position, in the case where r 2 is > 0.
  • the methods described herein can include determining the presence of a haplotype that includes one or more additional polymorphisms associated with SZ, pharmacological response, and psychiatric endophenotypes.
  • the methods described herein can include determining the presence of a haplotype that includes one or more polymorphisms near D22S526 and/or the polymorphisms in the Sult4al gene and/or polymorphisms within 1 LDU of these markers, e.g., as described in U.S. Pat. Pub. No. 2006-0177851, incorporated herein in its entirety.
  • the methods described herein can include determining the presence of a haplotype that includes one or more polymorphisms in the PI4K2B gene and/or polymorphisms in the KCNIP4 gene and/or polymorphisms in the CERK gene and/or polymorphisms in the SHANK3 gene and/or polymorphisms within 1 LDU of these markers, e.g., as described in International Pat. Application No. PCT/US2007/078399 and US Pat. Pub. No. 2009-0012371, incorporated herein in its entirety.
  • the methods described herein can include determining the presence of a haplotype that includes one or more polymorphisms in the HPCALl gene and/or the polymorphisms in the SV2C gene and/or polymorphisms in linkage disequilibrium with these markers, e.g., as described in International Pat. Application No. PCT/US2008/088061, incorporated herein in its entirety.
  • the methods include determining the presence of a haplotype that includes one or more polymorphisms in the novel SZ-spectrum genes and/or the polymorphisms in linkage disequilibrium with specific markers in these genes, e.g., as described in PCT/US2009/030057, incorporated herein in its entirety.
  • genetic markers can be identified using any of a number of methods well known in the art. For example, numerous polymorphisms in the regions described herein are known to exist and are available in public databases, which can be searched using methods and algorithms known in the art. Alternately, polymorphisms can be identified by sequencing either genomic DNA or cDNA in the region in which it is desired to find a polymorphism. According to one approach, primers are designed to amplify such a region, and DNA from a subject is obtained and amplified. The DNA is sequenced, and the sequence (referred to as a "subject sequence" or "test sequence") is compared with a reference sequence, which can represent the "normal” or "wild type” sequence, or the "affected” sequence. In some embodiments, a reference sequence can be from, for example, the human draft genome sequence, publicly available in various databases, or a sequence deposited in a database such as GenBank. In some embodiments, the reference sequence is a composite of ethnically diverse individuals.
  • a polymorphism has been identified.
  • only two polymorphic variants will exist at any location.
  • up to four variants may exist since there are four naturally occurring nucleotides in DNA.
  • Other polymorphisms such as insertions and deletions, may have more than four alleles.
  • the methods described herein can also include determining the presence or absence of other markers known or suspected to be associated with SZ, or with SD, or SPD, e.g., markers outside of a region identified herein, see, e.g., Harrison and Owen, Lancet, 361(9355):417-419 (2003), including, for example, markers on chromosome 22 and other chromosomes, e.g., in the region of 22ql2.3 (e.g., near D22S283), 22qll.2, 22qll.2, 22ql l- ql3, Iq42.1, Iq42.1, Iq21-q22, 2p, 2q, 3p25, 4p, 4q, 5qll.2-ql3.3, 6p22.3, 6p23, 6ql3-q26, 7q, 8pl2-21, 8q, 9p, 10pl5-pl3 (e.g., near D10S189), 10q22.3, Ilql4-q21, 12q
  • the methods include determining the presence or absence of one or more other markers that are or may be associated with SZ, or with SZ, SD or SPD, e.g., in one or more genes, e.g., ACE (IHi et al, Eur Neuropsychopharmacol 13:147-151 (2003));ADRAl A (Clark et al., Biol Psychiatry. 58(6):435-9 (2005)); ADHlB (Xu et al., MoI Psychiatry. 9(5):510-21 (2004); Vawter et al., Hum Genet.
  • ACE IHi et al, Eur Neuropsychopharmacol 13:147-151 (2003)
  • ADRAl A Clark et al., Biol Psychiatry. 58(6):435-9 (2005)
  • ADHlB Xu et al., MoI Psychiatry. 9(5):510-21 (2004); Vawter et al., Hum Genet.
  • CCKAR Zhang et al., MoI Psychiatry 5:239-240 (2000); Sanjuan et al., Eur Psychiatry 19:349-353 (2004)); CHGB (Kitao et al., Psychiatr Genet 10:139-143 (2000); Zhang et al., Neurosci Lett 323:229-233 (2002)); CHI3L1 (Zhao et al., Am J Hum Genet. 80(1): 12-8 (2007)); CHRNA2 (Blaveri et al., Europ. J. Hum. Genet. 9: 469-472 (2001)); CHRNA7 (Leonard et al.
  • DGCR8 Jacquet et al., Hum MoI Genet. ll(19):2243-9 (2002)
  • DISCI Olet al., 2005, supra; see, e.g., the D1S2709 marker (Ekelend et al., Hum. Molec. Genet. 10:1611-1617 (2001), DDRl (Roig et al., MoI Psychiatry.
  • DTNBPl (Owen et al., 2005, supra); EGR3 (Yamada et al., Proc Natl Acad Sci 104(8):2815-20 (2007)); EPSIN4 (Am J Hum Genet. 76(5):902-7 (2005)); ErbB; EGF (Futamura et al., Am. J. Hum. Genet.
  • GRIK3 Shibata et al., Psychiatry Res. 30: 141(1): 39-51 (2006)
  • GRIK4 Pieris et al., MoI Psychiatry ll(9):847-57(2006)
  • GRINl Qin et al., Eur J Hum Genet. 13(7):807-14 (2005)
  • GRIN2A, GRIN2B Abdolmaleky et al., Am J Pharmacogenomics. 5(3): 149-60 (2005)
  • GRIN2D Mikino et al., Psychiatr Genet.
  • GRM3 Egan et al., Proc Natl Acad Sci U S A. 101(34): 12604-9 (2004)
  • GRM4 Ohtsuki et al., Psychiatr Genet. ll(2):79-83 (2001)
  • GRM5 Devon et al., MoI Psychiatry. 6(3):311-4 (2001)
  • GSTMl Harada et al., Biochem Biophys Res Commun 281 :267-271 (2001); Pae et al., Psychiatr Genet 14:147-150 (2004)
  • G30/G72 Schoulze et al., Am J Psychiatry.
  • HTR2A Baritaki et al., Eur J Hum Genet. 12(7):535-41 (2004)); HLA-DRBl (Schwab et al., Am J Med Genet. 114(3):315-20 (2002)); HLA-BRB3 (Yu et al., Zhonghua Liu Xing Bing Xue Za Zhi. 24(9):815-8 (2003)); HTR5 A (Abdolmaleky et al., Schizophr Res 67:53-62 (2004)); HTR6 (Tsai et al., Neurosci Lett.
  • ILlB Keratila et al., MoI Psychiatry 4:179-181(1999); Meisenzahal et al., Am J Psychiatry 158:1316-1319 (2001); Zanardini et al., J Psychiatr Res 37:457-462 (2003)); ILlRN (Zanardini et al., J Psychiatr Res 37:457-462 (2003); Kim et al., Psychiatr Genet 14:165-167 (2004); Papiol et al., Neuroimage 27:1002- 1006 (2005)); ILlO (Chiavetto et al., Biol Psychiatry 51 :480-484 (2002); Jun et al., Psychiatry Clin Neurosci 56:177-180 (2002)); IL2RB (Schwab et al., Am J Med Genet.
  • KCNN3 Ujike et al., Psychiatry Res. 101(3):203-7 (2001)); KIF13A (Jamain et al., Genomics. 74(l):36-44 (2001)); KIF2A (Li et al., Neurosci Letters 407(2) 151- 5 (2006)); KPNA3 (Wei and Hemmings, Neurosci Res. 52(4):342-6 (2005)); LGIl (Fallin et al. A J Hum Genet. 77:918-36 (2005)); MAG (Wan et al, Neurosci Lett.
  • NTNGl Fluorescence N-Field et al.
  • PDE4B Millar et al., Science 310:1187-1191 (2005)); PDLIM5 (Horiuchi et al., Biol Psychiatry 59(5):434-9 (2005)); PICKl (Hong et al., Neuroreport 15:1965-1967 (2004); Fujii et al., Molecular Psychiatry 11 :150-157 (2005)); PIK3C3 ( Stopkova et al., Biol Psychiatry 55:981-988 (2004); Duan et al., Neurosci Lett.,379:32-36 (2005)); PIK4CA (Saito et al., Am J Med Genet B Neuropsychiatr Genet.
  • PIP5K2A (Stopkova et al., Psychiatr Genet.l5(3): 223-7 (2005)); PLA2G4A, PLA2G4C (Yu et al., Prostaglandins Leukot Essent Fatty Acids. 73(5):351-4 (2005)); PLA2G4B (Tao et al., Am J Med Genet B Neuropsychiatr Genet 137:56-58 (2005)); PLXNA2 (Mah et al., Molecular Psychiatry 11 :471-478 (2006)); PTGS2 ( Wei and Hemmings.
  • the methods described herein include determining the presence or absence of haplotypes associated with SZ, pharmacological response, and psychiatric endophenotypes.
  • an association with SZ is determined by the presence of a shared haplotype between the subject and an affected reference individual, e.g., a first or second- degree relation of the subject, or population of affected individuals, and the absence of the haplotype in an unaffected reference individual.
  • an association with a pharmacological response is determined by the presence of a shared haplotype between the subject and a reference individual (or population) who had an identified response to a pharmacological treatment.
  • an association with a specific psychiatric endophenotype is determined by the presence of a shared haplotype between the subject and a reference subject or population with (or without) the specific endophenotype.
  • the methods can also include obtaining and analyzing a sample from a suitable reference individual.
  • Samples that are suitable for use in the methods described herein contain genetic material, e.g., genomic DNA (gDNA).
  • sources of samples include urine, blood, and tissue.
  • the sample itself will typically consist of nucleated cells (e.g., blood or buccal cells), tissue, etc., removed from the subject.
  • the subject can be an adult, child, fetus, or embryo.
  • the sample is obtained prenatally, either from a fetus or embryo or from the mother (e.g., from fetal or embryonic cells in the maternal circulation).
  • Methods and reagents are known in the art for obtaining, processing, and analyzing samples.
  • the sample is obtained with the assistance of a health care provider, e.g., to draw blood.
  • the sample is obtained without the assistance of a health care provider, e.g., where the sample is obtained non- invasively, such as a sample comprising buccal cells that is obtained using a buccal swab or brush, or a mouthwash sample.
  • the sample may be further processed before the detecting step.
  • DNA in a cell or tissue sample can be separated from other components of the sample.
  • the sample can be concentrated and/or purified to isolate DNA.
  • Cells can be harvested from a biological sample using standard techniques known in the art. For example, cells can be harvested by centrifuging a cell sample and resuspending the pelleted cells. The cells can be resuspended in a buffered solution such as phosphate -buffered saline (PBS). After centrifuging the cell suspension to obtain a cell pellet, the cells can be lysed to extract DNA, e.g., gDNA. See, e.g., Ausubel et al, 2003, supra. All samples obtained from a subject, including those subjected to any sort of further processing, are considered to be obtained from the subject.
  • PBS phosphate -buffered saline
  • the absence or presence of a haplotype associated with SZ, pharmacological response, and/or psychiatric endophenotypes, as described herein can be determined using methods known in the art, e.g., gel electrophoresis, capillary electrophoresis, size exclusion chromatography, sequencing, and/or arrays to detect the presence or absence of the marker(s) of the haplotype.
  • Amplification of nucleic acids where desirable, can be accomplished using methods known in the art, e.g., PCR.
  • Methods of nucleic acid analysis to detect polymorphisms and/or polymorphic variants include, e.g., microarray analysis.
  • Hybridization methods such as Southern analysis, Northern analysis, or in situ hybridizations, can also be used (see Current Protocols in Molecular Biology, Ausubel, F. et al, eds., John Wiley & Sons 2003).
  • FISH fluorescence in situ hybridization
  • probes that detect all or a part of a microsatellite marker can be used to detect microdeletions in the region that contains that marker.
  • the methods described herein include determining the sequence of the entire region of the genes listed in Tables A and B e.g. between and including the delimiting SNPs for the particular gene. In some embodiments, the sequence is determined on both strands of DNA.
  • genomic DNA a portion of genomic DNA (gDNA) encompassing the polymorphic site.
  • gDNA genomic DNA
  • Such regions can be amplified and isolated by PCR using oligonucleotide primers designed based on genomic and/or cDNA sequences that flank the site.
  • LCR ligase chain reaction
  • NASBA nucleic acid based sequence amplification
  • a sample e.g., a sample comprising genomic DNA
  • the DNA in the sample is then examined to determine a haplotype as described herein.
  • the haplotype can be determined by any method described herein, e.g., by sequencing or by hybridization of the gene in the genomic DNA, RNA, or cDNA to a nucleic acid probe, e.g., a DNA probe (which includes cDNA and oligonucleotide probes) or an RNA probe.
  • the nucleic acid probe can be designed to specifically or preferentially hybridize with a particular polymorphic variant.
  • a peptide nucleic acid (PNA) probe can be used instead of a nucleic acid probe in the hybridization methods described above.
  • PNA is a DNA mimetic with a peptide-like, inorganic backbone, e.g., N-(2-aminoethyl)glycine units, with an organic base (A, G, C, T or U) attached to the glycine nitrogen via a methylene carbonyl linker (see, e.g., Nielsen et al., Bioconjugate Chemistry, The American Chemical Society, 5:1 (1994)).
  • the PNA probe can be designed to specifically hybridize to a nucleic acid comprising a polymorphic variant conferring susceptibility to or indicative of the presence of SZ.
  • restriction digest analysis can be used to detect the existence of a polymorphic variant of a polymorphism, if alternate polymorphic variants of the polymorphism result in the creation or elimination of a restriction site.
  • a sample containing genomic DNA is obtained from the individual.
  • Polymerase chain reaction (PCR) can be used to amplify a region comprising the polymorphic site, and restriction fragment length polymorphism analysis is conducted (see Ausubel et al., Current Protocols in Molecular Biology, supra).
  • the digestion pattern of the relevant DNA fragment indicates the presence or absence of a particular polymorphic variant of the polymorphism and is therefore indicative of the presence or absence of susceptibility to SZ.
  • Sequence analysis can also be used to detect specific polymorphic variants.
  • a sample comprising DNA or RNA is obtained from the subject.
  • PCR or other appropriate methods can be used to amplify a portion encompassing the polymorphic site, if desired.
  • the sequence is then ascertained, using any standard method, and the presence of a polymorphic variant is determined.
  • Allele-specif ⁇ c oligonucleotides can also be used to detect the presence of a polymorphic variant, e.g., through the use of dot-blot hybridization of amplified oligonucleotides with allele-specific oligonucleotide (ASO) probes (see, for example, Saiki et al, Nature (London) 324:163-166 (1986)).
  • ASO allele-specific oligonucleotide
  • an “allele-specif ⁇ c oligonucleotide” (also referred to herein as an “allele-specif ⁇ c oligonucleotide probe”) is typically an oligonucleotide of approximately 10-50 base pairs, preferably approximately 15-30 base pairs, that specifically hybridizes to a nucleic acid region that contains a polymorphism.
  • An allele-specif ⁇ c oligonucleotide probe that is specific for particular a polymorphism can be prepared using standard methods (see Ausubel et al., Current Protocols in Molecular Biology, supra).
  • a sample comprising DNA is obtained from the individual.
  • PCR can be used to amplify a portion encompassing the polymorphic site.
  • DNA containing the amplified portion may be dot-blotted, using standard methods (see Ausubel et al., Current Protocols in Molecular Biology, supra), and the blot contacted with the oligonucleotide probe.
  • the presence of specific hybridization of the probe to the DNA is then detected.
  • Specific hybridization of an allele-specif ⁇ c oligonucleotide probe (specific for a polymorphic variant indicative of susceptibility to SZ) to DNA from the subject is indicative of susceptibility to SZ.
  • fluorescence polarization template-directed dye-terminator incorporation is used to determine which of multiple polymorphic variants of a polymorphism is present in a subject (Chen et al., (1999) Genome Research, 9(5):492-498). Rather than involving use of allele-specif ⁇ c probes or primers, this method employs primers that terminate adjacent to a polymorphic site, so that extension of the primer by a single nucleotide results in incorporation of a nucleotide complementary to the polymorphic variant at the polymorphic site.
  • FP-TDI fluorescence polarization template-directed dye-terminator incorporation
  • Real-time pyrophosphate DNA sequencing is yet another approach to detection of polymorphisms and polymorphic variants (Alderborn et al., (2000) Genome Research, 10(8): 1249-1258). Additional methods include, for example, PCR amplification in combination with denaturing high performance liquid chromatography (dHPLC) (Underhill, P. A., et al., Genome Research, Vol. 7, No. 10, pp. 996-1005, 1997). The methods can include determining the genotype of a subject with respect to both copies of the polymorphic site present in the genome.
  • dHPLC denaturing high performance liquid chromatography
  • the complete genotype may be characterized as -/-, as -/+, or as +/+, where a minus sign indicates the presence of the reference or wild type sequence at the polymorphic site, and the plus sign indicates the presence of a polymorphic variant other than the reference sequence. If multiple polymorphic variants exist at a site, this can be appropriately indicated by specifying which ones are present in the subject. Any of the detection means described herein can be used to determine the genotype of a subject with respect to one or both copies of the polymorphism present in the subject's genome.
  • oligonucleotide arrays represent one suitable means for doing so.
  • Other methods including methods in which reactions (e.g., amplification, hybridization) are performed in individual vessels, e.g., within individual wells of a multi- well plate or other vessel may also be performed so as to detect the presence of multiple polymorphic variants (e.g., polymorphic variants at a plurality of polymorphic sites) in parallel or substantially simultaneously according to certain embodiments of the invention.
  • Nucleic acid probes can be used to detect and/or quantify the presence of a particular target nucleic acid sequence within a sample of nucleic acid sequences, e.g., as hybridization probes, or to amplify a particular target sequence within a sample, e.g., as a primer.
  • Probes have a complimentary nucleic acid sequence that selectively hybridizes to the target nucleic acid sequence. In order for a probe to hybridize to a target sequence, the hybridization probe must have sufficient identity with the target sequence, i.e., at least 70%, e.g., 80%, 90%, 95%, 98% or more identity to the target sequence.
  • the probe sequence must also be sufficiently long so that the probe exhibits selectivity for the target sequence over non-target sequences.
  • the probe will be at least 20, e.g., 25, 30, 35, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900 or more, nucleotides in length.
  • the probes are not more than 30, 50, 100, 200, 300, 500, 750, or 1000 nucleotides in length. Probes are typically about 20 to about I X lO 6 nucleotides in length.
  • Probes include primers, which generally refers to a single-stranded oligonucleotide probe that can act as a point of initiation of template-directed DNA synthesis using methods such as PCR (polymerase chain reaction), LCR (ligase chain reaction), etc., for amplification of a target sequence.
  • the probe is a test probe, e.g., a probe that can be used to detect polymorphisms in a region described herein, e.g., polymorphisms as described herein.
  • the probe can hybridize to a target sequence within a region delimited by delimiting SNPs, SNPl and SNP2, inclusive as specified for the particular genes in Tables A and B.
  • the probe can bind to another marker sequence associated with SZ as described herein.
  • Control probes can also be used.
  • a probe that binds a less variable sequence e.g., repetitive DNA associated with a centromere of a chromosome
  • Probes that hybridize with various centromeric DNA and locus-specific DNA are available commercially, for example, from Vysis, Inc. (Downers Grove, 111.), Molecular Probes, Inc. (Eugene, Oreg.), or from Cytocell (Oxfordshire, UK).
  • Probe sets are available commercially, e.g., from Applied Biosystems, e.g., the Assays-on-Demand SNP kits Alternatively, probes can be synthesized, e.g., chemically or in vitro, or made from chromosomal or genomic DNA through standard techniques.
  • sources of DNA that can be used include genomic DNA, cloned DNA sequences, somatic cell hybrids that contain one, or a part of one, human chromosome along with the normal chromosome complement of the host, and chromosomes purified by flow cytometry or microdissection.
  • the region of interest can be isolated through cloning, or by site-specific amplification via the polymerase chain reaction (PCR).
  • the probes are labeled, e.g., by direct labeling, with a fluorophore, an organic molecule that fluoresces after absorbing light of lower wavelength/higher energy.
  • a fluorophore an organic molecule that fluoresces after absorbing light of lower wavelength/higher energy.
  • a directly labeled fluorophore allows the probe to be visualized without a secondary detection molecule.
  • the nucleotide can be directly incorporated into the probe with standard techniques such as nick translation, random priming, and PCR labeling.
  • deoxycytidine nucleotides within the probe can be transaminated with a linker. The fluorophore then is covalently attached to the transaminated deoxycytidine nucleotides. See, e.g., U.S. Pat. No. 5,491,224.
  • Fluorophores of different colors can be chosen such that each probe in a set can be distinctly visualized.
  • a combination of the following fluorophores can be used: 7-amino-4-methylcoumarin-3-acetic acid (AMCA), Texas RedTM (Molecular Probes, Inc., Eugene, Oreg.), 5-(and-6)-carboxy-X-rhodamine, lissamine rhodamine B, 5-(and-6)- carboxyfluorescein, fluorescein-5-isothiocyanate (FITC), 7-diethylaminocoumarin-3- carboxylic acid, tetramethylrhodamine-5-(and-6)-isothiocyanate, 5-(and-6)- carboxytetramethylrhodamine, 7-hydroxycoumarin-3-carboxylic acid, 6-[fluorescein 5-(and- 6)-carboxamido]hexanoic acid, N-(4,4-difluoro-5,7-di
  • Fluorescently labeled probes can be viewed with a fluorescence microscope and an appropriate filter for each fluorophore, or by using dual or triple band-pass filter sets to observe multiple fluorophores. See, for example, U.S. Pat. No. 5,776,688. Alternatively, techniques such as flow cytometry can be used to examine the hybridization pattern of the probes. Fluorescence-based arrays are also known in the art.
  • the probes can be indirectly labeled with, e.g., biotin or digoxygenin, or labeled with radioactive isotopes such as 32 P and 3 H.
  • a probe indirectly labeled with biotin can be detected by avidin conjugated to a detectable marker.
  • avidin can be conjugated to an enzymatic marker such as alkaline phosphatase or horseradish peroxidase.
  • Enzymatic markers can be detected in standard colorimetric reactions using a substrate and/or a catalyst for the enzyme.
  • Catalysts for alkaline phosphatase include 5-bromo-4-chloro-3-indolylphosphate and nitro blue tetrazolium.
  • Diaminobenzoate can be used as a catalyst for horseradish peroxidase.
  • Oligonucleotide probes that exhibit differential or selective binding to polymorphic sites may readily be designed by one of ordinary skill in the art.
  • an oligonucleotide that is perfectly complementary to a sequence that encompasses a polymorphic site i.e., a sequence that includes the polymorphic site, within it or at one end
  • the invention features arrays that include a substrate having a plurality of addressable areas, and methods of using them. At least one area of the plurality includes a nucleic acid probe that binds specifically to a sequence comprising a polymorphism listed in Table B, and can be used to detect the absence or presence of said polymorphism, e.g., one or more SNPs, microsatellites, minisatellites, or indels, as described herein, to determine a haplotype.
  • the array can include one or more nucleic acid probes that can be used to detect a polymorphism listed in Table B.
  • the array further includes at least one area that includes a nucleic acid probe that can be used to specifically detect another marker associated with SZ as described herein.
  • the substrate can be, e.g., a two-dimensional substrate known in the art such as a glass slide, a wafer (e.g., silica or plastic), a mass spectroscopy plate, or a three-dimensional substrate such as a gel pad.
  • the probes are nucleic acid capture probes.
  • Methods for generating arrays include, e.g., photolithographic methods (see, e.g., U.S. Patent Nos. 5,143,854; 5,510,270; and 5,527,681), mechanical methods (e.g., directed-flow methods as described in U.S. Patent No. 5,384,261), pin-based methods (e.g., as described in U.S. Pat. No. 5,288,514), and bead-based techniques (e.g., as described in PCT US/93/04145).
  • the array typically includes oligonucleotide probes capable of specifically hybridizing to different polymorphic variants.
  • a nucleic acid of interest e.g., a nucleic acid encompassing a polymorphic site
  • Hybridization and scanning are generally carried out according to standard methods. See, e.g., Published PCT Application Nos. WO 92/10092 and WO 95/11995, and U.S. Pat. No. 5,424,186.
  • the array is scanned to determine the position on the array to which the nucleic acid hybridizes.
  • the hybridization data obtained from the scan is typically in the form of fluorescence intensities as a function of location on the array.
  • Arrays can include multiple detection blocks (i.e., multiple groups of probes designed for detection of particular polymorphisms). Such arrays can be used to analyze multiple different polymorphisms. Detection blocks may be grouped within a single array or in multiple, separate arrays so that varying conditions (e.g., conditions optimized for particular polymorphisms) may be used during the hybridization. For example, it may be desirable to provide for the detection of those polymorphisms that fall within G-C rich stretches of a genomic sequence, separately from those falling in A-T rich segments.
  • oligonucleotide arrays for detection of polymorphisms can be found, for example, in U.S. Pat. Nos. 5,858,659 and 5,837,832.
  • cDNA arrays may be used similarly in certain embodiments of the invention.
  • the methods described herein can include providing an array as described herein; contacting the array with a sample, e.g., a portion of genomic DNA that includes at least a portion of human chromosome 1, 3, 6, 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, and/or 20, e.g., a region between delimiting SNPs, SNPl and SNP2 for each of the genes listed in Tables A and B, and/or optionally, a different portion of genomic DNA, e.g., a portion that includes a different portion of human chromosomes 1, 3, 6, 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, and/or 20, or another chromosome, e.g., including another region associated with SZ, pharmacological response, and/or psychiatric endophenotypes, and detecting binding of a nucleic acid from the sample to the array.
  • a sample e.g., a portion of genomic DNA that includes at least a portion of human chromosome 1, 3, 6, 10, 11, 12, 13, 14, 15,
  • the method includes amplifying nucleic acid from the sample, e.g., genomic DNA that includes a portion of a human chromosome described herein, and, optionally, a region that includes another region associated with SZ, pharmacological response, and/or psychiatric endophenotypes, prior to or during contact with the array.
  • nucleic acid from the sample e.g., genomic DNA that includes a portion of a human chromosome described herein, and, optionally, a region that includes another region associated with SZ, pharmacological response, and/or psychiatric endophenotypes
  • the methods described herein can include using an array that can ascertain differential expression patterns or copy numbers of one or more genes in samples from normal and affected individuals (see, e.g., Redon et al., Nature. 444(7118):444-54 (2006)).
  • arrays of probes to a marker described herein can be used to measure polymorphisms between DNA from a subject having SZ and control DNA, e.g., DNA obtained from an individual that does not have SZ and has no familial risk factors for SZ. Since the clones on the array contain sequence tags, their positions on the array are accurately known relative to the genomic sequence.
  • the invention features methods of determining the absence or presence of a haplotype associated with SZ, pharmacological response, and/or psychiatric endophenotypes, as described herein, using an array described above.
  • the methods include providing a two dimensional array having a plurality of addresses, each address of the plurality being positionally distinguishable from each other address of the plurality having a unique nucleic acid capture probe, contacting the array with a first sample from a test subject who is suspected of having or being at risk for SZ, and comparing the binding of the first sample with one or more references, e.g., binding of a sample from a subject who is known to have SZ and/or binding of a sample from a subject who is unaffected, e.g., a control sample from a subject that does not have SZ.
  • the methods include contacting the array with a second sample from a subject who has SZ; and comparing the binding of the first sample with the binding of the second sample. In some embodiments, the methods include contacting the array with a third sample from a subject that does not have SZ; and comparing the binding of the first sample with the binding of the third sample. In some embodiments, the second and third samples are from first or second-degree relatives of the test subject. Binding, e.g., in the case of a nucleic acid hybridization, with a capture probe at an address of the plurality, can be detected by any method known in the art, e.g., by detection of a signal generated from a label attached to the nucleic acid.
  • SZ schizotypal personality disorder
  • SD schizoaffective disorder
  • SZ is considered a clinical syndrome, and is probably a constellation of several pathologies. Substantial heterogeneity is seen between cases; this is thought to reflect multiple overlapping etiologic factors, including both genetic and environmental contributions.
  • a diagnosis of SZ is typically indicated by chronic psychotic symptoms, e.g., hallucinations and delusions. Disorganization of thought and behavior are common and are considered distinguishing factors in the diagnosis of SZ. Patients typically have some subtle impairments in cognition. Reduced emotional experience and expression, low drive, and impaired speech are observed in a subgroup of patients. Cognitive, emotional and social impairments often appear early in life, while the psychotic symptoms typically manifest in late adolescence or early adulthood in men, a little later in women.
  • DSM-IV Diagnostic Criteria for SZ
  • Characteristic symptoms Two (or more) of the following, each present for a significant portion of time during a one month period (or less if successfully treated):
  • negative symptoms e.g., affective flattening, alogia, or avolition
  • delusions are playful or hallucinations consist of a voice keeping up a running commentary on the person's behavior or thoughts, or two or more voices conversing with each other.
  • D. Schizoaffective and Mood Disorder Exclusion Schizoaffective Disorder and Mood Disorder With Psychotic Features have been ruled out because either (1) no major depressive, manic, or mixed episodes have occurred concurrently with the active-phase symptoms; or (2) if mood episodes have occurred during active-phase symptoms, their total duration has been brief relative to the duration of the active and residual periods.
  • the disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.
  • SD is characterized by the presence of affective (depressive or manic) symptoms and schizophrenic symptoms within the same, uninterrupted episode of illness.
  • the DSM-IV Criteria for a diagnosis of schizoaffective disorder is as follows:
  • At least five of the following symptoms must be present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.
  • recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide
  • the symptoms do not meet criteria for a Mixed Episode.
  • the symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
  • the symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism) .
  • the symptoms are not better accounted for by Bereavement, i.e., after the loss of a loved one, the symptoms persist for longer than 2 months, or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.
  • a manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least one week (or any duration, if hospitalization is necessary).
  • the symptoms do not meet criteria for a Mixed Episode.
  • the mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.
  • the symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism).
  • Criteria for Mixed Episode A mixed episode occurs when the criteria are met both for a Manic Episode and for a Major Depressive Episode (except for duration) nearly every day during at least a 1-week period.
  • the mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.
  • the symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism) .
  • a substance e.g., a drug of abuse, a medication, or other treatment
  • a general medical condition e.g., hyperthyroidism
  • the type of SD may be may be specifiable, as either Bipolar Type, if the disturbance includes a Manic or a Mixed Episode (or a Manic or a Mixed Episode and Major Depressive Episodes), or Depressive Type, if the disturbance only includes Major Depressive Episodes.
  • SD Learning Problems, Hypoactivity, Psychotic, Euphoric Mood, Depressed Mood, Somatic/Sexual Dysfunction, Hyperactivity, Guilt/Obsession, Odd/Eccentric/Suspicious Personality, Anxious/Fearful/Dependent Personality, and Dramatic/Erratic/ Antisocial Personality.
  • a diagnosis of SPD under the criteria of the DSM-IV is generally based on a pervasive pattern of social and interpersonal deficits marked by acute discomfort with, and reduced capacity for, close relationships as well as by cognitive or perceptual distortions and eccentricities of behavior, beginning by early adulthood and present in a variety of contexts, as indicated by five (or more) of the following:
  • SPD is diagnosed if the symptoms do not occur exclusively during the course of SZ, a Mood Disorder With Psychotic Features, another Psychotic Disorder, or a Pervasive Developmental Disorder, and the disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.
  • a substance e.g., a drug of abuse, a medication
  • Associated features of SPD include Depressed Mood and Odd/Eccentric/ Suspicious Personality.
  • endophenotypes i.e., intermediate phenotypes
  • endophenotypes that may more closely reflect biological mechanisms behind SZ
  • prepulse inhibition e.g., prepulse inhibition
  • structural abnormalities evident in MRI scans e.g., structural abnormalities evident in MRI scans
  • specific domains of cognition e.g., executive function
  • fine motor performance e.g., working memory, etc.
  • Endophenotypes can also include clinical manifestations such as hallucinations, paranoia, mania, depression, obsessive-compulsive symptoms, etc., as well as response or lack of response to drugs and comorbidity for substance and alcohol abuse. See, e.g., Kendler et al, Am J Psychiatry 152(5):749-54 (1995); Gottesman and Gould, Am J Psychiatry 160(4):636-45 (2003); Cadenhead, Psychiatric Clinics of North America. 25(4):837-53 (2002); Gottesman and Gould, American Journal of Psychiatry. 160(4):636-45 (2003); Heinrichs, Neuroscience & Biobehavioral Reviews.
  • the Positive and Negative Syndrome Scale is a comprehensive psychometric scale used to classify psychopathology for severe neuropsychiatric diseases, including SZ. It measures a number of psychiatric endophenotypes or dimensions using quantitative scales based on the scoring of patients by clinicians. It is widely used to classify patients into specific subtypes, and is commonly used for measuring the improvement of symptoms in response to clinical interventions (Kay et al., Schizophr. Bull. 13:261-276 (1987); Kay et al., Br. J. Psychiatry Suppl 59-67 (1989); Leucht et al., Schizophr. Res. 79:231-238 (2005)).
  • PANSS comprises 30 individual subscales. Seven constitute a Positive Symptom Scale, seven the Negative Symptom Scale, and the remaining 16 items make up a General Psychopathology Scale. The scores for these scales are arrived at by summation of ratings across component items. Therefore, the potential ranges are 7 to 49 for the Positive and Negative Scales, and 16 to 112 for the General Psychopathology Scale (Source: The PANSS Institute).
  • Each of the 30 items is accompanied by a specific definition as well as detailed anchoring criteria for all seven rating points. These seven points represent increasing levels of psychopathology, as follows:
  • HOSTILITY Verbal and nonverbal expressions of anger and resentment, including sarcasm, passive-aggressive behavior, verbal abuse and assualtiveness.
  • N6 LACK OF SPONTANEITY AND FLOW OF CONVERSATION - Reduction in the normal flow of communication associated with apathy, avolition, defensiveness or cognitive deficit. This is manifested by diminished fluidity and productivity of the verbal interactional process.
  • N7 STEREOTYPED THINKING - Decreased fluidity, spontaneity and flexibility of thinking, as evidenced in rigid, repetitious or barren thought content.
  • ANXIETY Subjective experience of nervousness, worry, apprehension or restlessness, ranging from excessive concern about the present or future to feelings of panic.
  • TENSION -Overt physical manifestations of fear, anxiety, and agitation, such as stiffness, tremor, profuse sweating and restlessness.
  • MOTOR RETARDATION Reduction in motor activity as reflected in slowing or lessening or movements and speech, diminished responsiveness of stimuli, and reduced body tone.
  • GlO. DISORIENTATION Lack of awareness of one's relationship to the milieu, including persons, place and time, which may be due to confusion or withdrawal.
  • PANSS provides a structured, objective way of describing the various aspects of psychopathology of a given patient.
  • proper implementation of the PANSS requires highly trained personnel to conduct the assessment and to interpret the results, and there is potential for site to site variability, especially outside the research setting.
  • Each of the PANSS composite scales and subscales can be considered a clinical endophenotype.
  • the ability to link genetic profiles to these clinical endophenotypes, as described in the examples, will enable clinicians to refine a patient's diagnosis and develop a personalized therapeutic strategy for each patient.
  • the "A" allele of rs4832524, located in the KCNS3 gene is associated with lower Negative Symptom burden as shown in the regression analysis in Table 14.
  • Another example is the "A" allele of rs9823803, located in the GADLl gene, which is significantly associated with lower scores on the Grandiosity Subscale as shown in the regression analysis in Table 15.
  • Subjects with SZ typically require acute treatment for psychotic exacerbations, and long-term treatment including maintenance and prophylactic strategies to sustain symptom improvement and prevent recurrence of psychosis.
  • Subjects with schizoaffective disorder experience the symptoms of both SZ and affective disorder (manic and/or depressive), thus require the specific treatments for each disorder.
  • Subjects with SPD sometimes require medication for acute psychotic episodes but are often treated using psychosocial methods.
  • the methods described herein can include the administration of one or more accepted or experimental treatment modalities to a person identified as at risk of developing SZ, SPD, or a SD, based on the presence of a haplotype associated with SZ, SPD, or SD.
  • accepted treatments presently include both pharmacologic and psychosocial management, and occasionally electroconvulsive therapy (ECT).
  • Standard pharmacologic therapies for SZ and SD include the administration of one or more antipsychotic medications, which are typically antagonists acting at postsynaptic D 2 dopamine receptors in the brain.
  • Antipsychotic medications include conventional, or first generation, antipsychotic agents, which are sometimes referred to as neuroleptics because of their neurologic side effects, and second generation antipsychotic agents, which are less likely to exhibit neuroleptic effects and have been termed atypical antipsychotics.
  • the methods described herein include the administration of one or more antipsychotic medications to a person identified by a method described herein as being at risk of developing SZ. Antipsychotic medications substantially reduce the risk of relapse in the stable phase of illness.
  • the methods include the administration of a first generation antipsychotic medication at a dose that is around the "extrapyramidal symptom (EPS) threshold" (i.e., the dose that will induce extrapyramidal side effects, e.g., bradykinesia, rigidity, or dyskinesia, with minimal rigidity detectable on physical examination, and/or a second-generation antipsychotics at a dose that is therapeutic, yet below the EPS threshold.
  • EPS extrapyramidal symptom
  • Standard pharmacologic therapies for SD also include the administration of a combination of antidepressant, and anti-anxiety medication.
  • Suitable antidepressants include serotonergic antidepressants, e.g., fluoxetine or trazodone.
  • Suitable anxiolytics include benzodiazepines, e.g., lorazepam, clonazepam. Lithium can also be administered.
  • the methods can include the administration of one or more antidepressant and/or anti-anxiety medications to a person identified as at risk of developing SZ.
  • the methods can also include psychosocial and rehabilitation interventions, e.g., interventions that are generally accepted as therapeutically beneficial, e.g., cognitive- behavioral therapy for treatment-resistant positive psychotic symptoms; supportive, problem- solving, educationally oriented psychotherapy; family therapy and education programs aimed at helping patients and their families understand the patient's illness, reduce stress, and enhance coping capabilities; social and living skills training; supported employment programs; and/or the provision of supervised residential living arrangements.
  • psychosocial and rehabilitation interventions e.g., interventions that are generally accepted as therapeutically beneficial, e.g., cognitive- behavioral therapy for treatment-resistant positive psychotic symptoms; supportive, problem- solving, educationally oriented psychotherapy; family therapy and education programs aimed at helping patients and their families understand the patient's illness, reduce stress, and enhance coping capabilities; social and living skills training; supported employment programs; and/or the provision of supervised residential living arrangements.
  • haplotypes described herein have been correlated with an increased risk of developing or having SZ; in addition, haplotypes are described herein that are correlated with altered response to a treatment, e.g., a pharmacological treatment.
  • An altered response can be, for example, a positive response (i.e., an improvement in one or more symptoms of the disease), negative response (worsening of one or more symptoms of the disease), no response, or the presence or absence of side effects.
  • the new methods can also include selecting a treatment regimen for a subject determined to have SZ or to be at risk for developing SZ, based upon the absence or presence of a haplotype described herein.
  • the determination of a treatment regimen can also be based upon the absence or presence of other risk factors associated with SZ, e.g., as described herein. Therefore, the methods of the invention can include selecting a treatment regimen for a subject having one or more risk factors for SZ, and having a haplotype described herein. The methods can also include administering a selected treatment regimen to a subject having, or at risk for developing, SZ, to thereby treat, prevent or delay further progression of the disease.
  • a treatment regimen can include the administration of a selected antipsychotic medications to a subject identified as at risk of developing SZ, before the onset of any psychotic episodes. The medications can be selected based on the presence of a haplotype that is associated with, for example, positive response, or the absence of significant side effects.
  • the term "treat” or “treatment” is defined as the application or administration of a treatment regimen, e.g., a therapeutic agent or modality, to a subject, e.g., a patient.
  • the subject can be a patient having SZ a symptom of SZ or at risk of developing (i.e., a predisposition toward) SZ.
  • the treatment can be to cure, heal, alleviate, relieve, alter, remedy, ameliorate, palliate, improve or affect SZ, the symptoms of SZ or the predisposition toward SZ.
  • the methods described herein can further include the step of monitoring the subject, e.g., for a change (e.g., an increase or decrease) in one or more of the diagnostic criteria for SZ listed herein, or any other parameter related to clinical outcome.
  • the subject can be monitored in one or more of the following periods: prior to beginning of treatment; during the treatment; or after one or more elements of the treatment have been administered. Monitoring can be used to evaluate the need for further treatment with the same or a different therapeutic agent or modality.
  • a decrease in one or more of the parameters described above is indicative of the improved condition of the subject, although with red blood cell and platelet levels, an increase can be associated with the improved condition of the subject.
  • the methods can be used, e.g., to evaluate the suitability of, or to choose between alternative treatments, e.g., a particular dosage, mode of delivery, time of delivery, inclusion of adjunctive therapy, e.g., administration in combination with a second agent, or generally to determine the subject's probable drug response genotype.
  • a treatment for SZ can be evaluated by administering the same treatment or combinations or treatments to a subject having SZ and a haplotype as described herein and to a subject that has SZ but does not have a haplotype as described herein.
  • the effects of the treatment or combination of treatments on each of these subjects can be used to determine if a treatment or combination of treatments is particularly effective on a sub-group of subjects having SZ.
  • various treatments or combinations of treatments can be evaluated by administering two different treatments or combinations of treatments to at least two different subjects having SZ, and a haplotype as described herein. Such methods can be used to determine if a particular treatment or combination of treatments is more effective than others in treating this subset of SZ patients.
  • “Pharmacogenomics,” as used herein, refers to the application of genomics technologies such as structural chromosomal analysis, to drugs in clinical development and on the market. See, for example, Eichelbaum et al., Clin. Exp. Pharmacol. Physiol. 23:983-985 (1996) and Linder et al., Clin. Chem. 43:254-266 (1997).
  • the term refers the study of how a patient's genes determine his or her response to a drug (e.g., a patient's "drug response phenotype,” or “drug response genotype”).
  • a drug response genotype e.g., a patient's "drug response phenotype," or "drug response genotype”
  • another aspect of the invention provides methods for tailoring an individual's prophylactic or therapeutic treatment according to that individual's drug response genotype.
  • Information generated from pharmacogenomic research using a method described herein can be used to determine appropriate dosage and treatment regimens for prophylactic or therapeutic treatment of an individual. This knowledge, when applied to dosing or drug selection, can avoid adverse reactions or therapeutic failure and thus enhance therapeutic or prophylactic efficiency when administering a therapeutic composition, e.g., a cytotoxic agent or combination of cytotoxic agents, to a patient, as a means of treating or preventing SZ.
  • a therapeutic composition e.g., a cytotoxic agent or combination of cytotoxic agents
  • a physician or clinician may consider applying knowledge obtained in relevant pharmacogenomics studies, e.g., using a method described herein, when determining whether to administer a pharmaceutical composition, e.g., an antipsychotic agent or a combination of antipsychotic agents, to a subject.
  • a physician or clinician may consider applying such knowledge when determining the dosage, e.g., amount per treatment or frequency of treatments, of a treatment, e.g., a antipsychotic agent or combination of antipsychotic agents, administered to a patient.
  • a physician or clinician may determine (or have determined, e.g., by a laboratory) the haplotype of a subject as described herein, and optionally one or more other markers associated with SZ of one or a group of subjects who may be participating in a clinical trial, wherein the subjects have SZ, and the clinical trial is designed to test the efficacy of a pharmaceutical composition, e.g., an antipsychotic or combination of antipsychotic agents, and wherein the physician or clinician attempts to correlate the genotypes of the subjects with their response to the pharmaceutical composition.
  • a pharmaceutical composition e.g., an antipsychotic or combination of antipsychotic agents
  • information regarding a haplotype associated with an altered pharmacogenomic response for SZ as described herein can be used to stratify or select a subject population for a clinical trial.
  • the information can, in some embodiments, be used to stratify individuals that may exhibit a toxic response to a treatment from those that will not. In other cases, the information can be used to separate those that are more likely to be non- responders from those who will be responders.
  • the haplotypes described herein can be used in pharmacogenomics-based design and to manage the conduct of a clinical trial, e.g., as described in U.S. Pat. Pub. No. 2003/0108938.
  • information regarding a haplotype associated with an increased risk of SZ, or with altered pharmacogenomic response for SZ, as described herein can be used to stratify or select human cells or cell lines for drug testing purposes.
  • Human cells are useful for studying the effect of a polymorphism on physiological function, and for identifying and/or evaluating potential therapeutic agents for the treatment of SZ e.g., antipsychotics.
  • the methods can include performing the present methods on genetic material from a cell line.
  • the information can, in some embodiments, be used to separate cells that respond particular drugs from those that do not respond, e.g. which cells show altered second messenger signaling.
  • compositions and methods for the identification and treatment of subjects who have an increased risk of SZ, or altered clinical presentation of SZ such that a theranostic approach can be taken to test such individuals to determine the effectiveness of a particular therapeutic intervention (e.g., a pharmaceutical or non- pharmaceutical intervention as described herein) and to alter the intervention to 1) reduce the risk of developing adverse outcomes and 2) enhance the effectiveness of the intervention.
  • a therapeutic intervention e.g., a pharmaceutical or non- pharmaceutical intervention as described herein
  • the methods and compositions described herein also provide a means of optimizing the treatment of a subject having SZ.
  • a theranostic approach to treating and preventing SZ by integrating diagnostics and therapeutics to improve the real-time treatment of a subject. Practically, this means creating tests that can identify which patients are most suited to a particular therapy, and providing feedback on how well a drug is working to optimize treatment regimens.
  • a theranostic method or composition of the invention can provide key information to optimize trial design, monitor efficacy, and enhance drug safety.
  • "trial design” theranostics can be used for patient stratification, determination of patient eligibility (inclusion/exclusion), creation of homogeneous treatment groups, and selection of patient samples that are representative of the general population. Such theranostic tests can therefore provide the means for patient efficacy enrichment, thereby minimizing the number of individuals needed for trial recruitment.
  • "Efficacy” theranostics are useful for monitoring therapy and assessing efficacy criteria.
  • safety theranostics can be used to prevent adverse drug reactions or avoid medication error.
  • the methods described herein can include retrospective analysis of clinical trial data as well, both at the subject level and for the entire trial, to detect correlations between a haplotype as described herein and any measurable or quantifiable parameter relating to the outcome of the treatment, e.g., efficacy (the results of which may be binary (i.e., yes and no) as well as along a continuum), side-effect profile (e.g., weight gain, metabolic dysfunction, lipid dysfunction, movement disorders, or extrapyramidal symptoms), treatment maintenance and discontinuation rates, return to work status, hospitalizations, suicidality, total healthcare cost, social functioning scales, response to non-pharmacological treatments, and/or dose response curves.
  • efficacy the results of which may be binary (i.e., yes and no) as well as along a continuum
  • side-effect profile e.g., weight gain, metabolic dysfunction, lipid dysfunction, movement disorders, or extrapyramidal symptoms
  • treatment maintenance and discontinuation rates return to work status, hospitalizations, su
  • a correlation between a positive outcome parameter e.g., high efficacy, low side effect profile, high treatment maintenance/low discontinuation rates, good return to work status, low hospitalizations, low suicidality, low total healthcare cost, high social function scale, favorable response to non-pharmacological treatments, and/or acceptable dose response curves
  • a positive outcome parameter e.g., high efficacy, low side effect profile, high treatment maintenance/low discontinuation rates, good return to work status, low hospitalizations, low suicidality, low total healthcare cost, high social function scale, favorable response to non-pharmacological treatments, and/or acceptable dose response curves
  • a selected haplotype can influence treatment such that the treatment is recommended or selected for a subject having the selected haplotype.
  • kits comprising a probe that hybridizes with a region of human chromosome as described herein and can be used to detect a polymorphism described herein.
  • the kit can include one or more other elements including: instructions for use; and other reagents, e.g., a label, or an agent useful for attaching a label to the probe.
  • Instructions for use can include instructions for diagnostic applications of the probe for assessing risk of SZ in a method described herein.
  • Other instructions can include instructions for attaching a label to the probe, instructions for performing in situ analysis with the probe, and/or instructions for obtaining a sample to be analyzed from a subject.
  • the kit can include a label, e.g., any of the labels described herein.
  • the kit includes a labeled probe that hybridizes to a region of human chromosome as described herein, e.g., a labeled probe as described herein.
  • the kit can also include one or more additional probes that hybridize to the same chromosome, e.g., chromosome 1, 3, 6, 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, or 20, or another chromosome or portion thereof that can have an abnormality associated with risk for SZ.
  • additional probes that hybridize to the same chromosome, e.g., chromosome 1, 3, 6, 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, or 20, or another chromosome or portion thereof that can have an abnormality associated with risk for SZ.
  • the additional probe or probes can be: a probe that hybridizes to human chromosome 22ql 1-12 or a portion thereof, (e.g., a probe that detects a sequence associated with SZ or BD in this region of chromosome 22), or probes that hybridize to all or a portion of 22ql2.3 (e.g., near D22S283), 22qll.2, 22qll.2, 22qll-ql3, Iq42.1, Iq42.1, Iq21-q22, 2p, 2q, 3p25, 4p, 4q, 5qll.2-ql3.3, 6p22.3, 6p23, 6ql3-q26, 7q, 8pl2-21, 8q, 9p, 10pl5-pl3 (e.g., near D10S189), 10q22.3, I lql4-q21, 12q24, 13q34, 13q32, 14q32.3, 15ql5, 16p, 17q , 18p, 18
  • kits that includes additional probes can further include labels, e.g., one or more of the same or different labels for the probes.
  • the additional probe or probes provided with the kit can be a labeled probe or probes.
  • the kit can further provide instructions for the use of the additional probe or probes.
  • Kits for use in self-testing can also be provided.
  • test kits can include devices and instructions that a subject can use to obtain a sample, e.g., of buccal cells or blood, without the aid of a health care provider.
  • buccal cells can be obtained using a buccal swab or brush, or using mouthwash.
  • Kits as provided herein can also include a mailer, e.g., a postage paid envelope or mailing pack, that can be used to return the sample for analysis, e.g., to a laboratory.
  • the kit can include one or more containers for the sample, or the sample can be in a standard blood collection vial.
  • the kit can also include one or more of an informed consent form, a test requisition form, and instructions on how to use the kit in a method described herein. Methods for using such kits are also included herein.
  • One or more of the forms, e.g., the test requisition form, and the container holding the sample can be coded, e.g., with a bar code, for identifying the subject who provided the sample.
  • databases that include a list of polymorphisms as described herein, and wherein the list is largely or entirely limited to polymorphisms identified as useful in performing genetic diagnosis of or determination of susceptibility to SZ as described herein.
  • the list is stored, e.g., on a flat file or computer-readable medium.
  • the databases can further include information regarding one or more subjects, e.g., whether a subject is affected or unaffected, clinical information such as endophenotype, age of onset of symptoms, any treatments administered and outcomes (e.g., data relevant to pharmacogenomics, diagnostics or theranostics), and other details, e.g., about the disorder in the subject, or environmental or other genetic factors.
  • the databases can be used to detect correlations between a particular haplotype and the information regarding the subject, e.g., to detect correlations between a haplotype and a particular endophenotype, or treatment response.
  • engineered cells that harbor one or more polymorphism described herein, e.g., one or more polymorphisms that constitute a haplotype associated with SZ, altered drug response or a specific endophenotype. Such cells are useful for studying the effect of a polymorphism on physiological function, and for identifying and/or evaluating potential therapeutic agents for the treatment of SZ-spectrum disorders e.g., anti-psychotics.
  • cells in which one of the various alleles of the genes described herein has be re-created that is associated with an increased risk of SZ are included herein.
  • Methods are known in the art for generating cells, e.g., by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell, e.g., a cell of an animal.
  • the cells can be used to generate transgenic animals using methods known in the art.
  • the cells are preferably mammalian cells, e.g., neuronal type cells, in which an endogenous gene has been altered to include a polymorphism as described herein.
  • Techniques such as targeted homologous recombinations, can be used to insert the heterologous DNA as described in, e.g., Chappel, US 5,272,071; WO 91/06667, published in May 16, 1991.
  • the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), a large federally funded clinical trial designed to assess the efficacy of antipsychotics in a real world setting, is a valuable resource for determining the role of genes in drug response (Stroup et al, Schizophr. Bull. 29:15-31 (2003); Lieberman et al, N. Engl. J. Med. 353:1209-1223 (2005)).
  • SNP genotyping was performed for roughly half of the trial participants (Sullivan et al., MoI. Psychiatry 13:570-584 (2008)).
  • the genotyping data allows the identification of genetic variants (e.g., SNPs) that are statistically associated with increased risk of developing SZ.
  • Genotype and phenotype data for the CATIE trial were made available to qualified researchers through the NIMH Center for Collaborative Genetic Studies on Mental Disorders. Data for 417 patients with schizophrenia and 419 unaffected controls self reported as having exclusively European ancestry were evaluated. This same patient population was described in a recent study by Sullivan and co workers, which confirmed that there is no hidden stratification in the sample (Sullivan et al., MoI. Psychiatry 13:570-584 (2008)).
  • genotyping and phenotype data were obtained from the Genetic Analysis Information Network (GAIN)Database found at ncbi.nlm.nih.gov through dbGaP, at accession number PHSOOOO 17.vl .pi .
  • GAIN Genetic Analysis Information Network
  • Genotypes and associated phenotype data for the GAIN Genome- Wide Association Study of Schizophrenia were provided by P. Gejman, and genotyping of these samples was provided through the Genetic Association Information Network (GAIN). Data for 1172 cases and 1378 controls with Caucasian ancestry were evaluated for the GAIN sample.
  • PLINK calculates P values for the allele-specific chi-squared test and the odds ratio (OR; or relative risk) associated with the minor allele.
  • Table 1 provides numerous examples of SNP-based alleles that influence SZ risk.
  • Table 1 reports the minor allele frequencies, P values, and ORs for numerous SNPs, in Tables B and C, that affect SZ risk. ORs of > 1.0 indicate that the minor SNP allele is associated with greater susceptibility, and ORs of ⁇ 1.0 indicate that the minor SNP allele is associated with decreased susceptibility to SZ.
  • haplotype blocks result in the same Test SNP being in linkage disequilibrium with multiple SNPs in Table B.
  • haplotype blocks result in multiple Test SNPs that can be used for each SNP listed in Table B, though such redundant examples are not presented in Table 1 , unless the test SNP was evaluated in both the CATIE and GAIN samples.
  • PLINK calculates P values for the allele-specific chi-squared test and the odds ratio (OR; or relative risk) associated with the minor allele.
  • Tables 2 and 3 report the minor allele frequencies, P values, and ORs for SNPs in Tables B and C, that affect olanzapine response and side effect rates, respectively. Note in Tables 2 and 3 that haplotype blocks result in the same Test SNP being in linkage disequilibrium with multiple SNPs in Table B. Similarly, haplotype blocks result in multiple Test SNPs that can be used for each SNP listed in Table B, though such redundant examples are not presented in Tables 2 and 3. Tables 2 and 3, provide numerous examples of SNP-based alleles that predict altered response to olanzapine.
  • ORs of > 1.0 indicate that the minor SNP allele is associated with greater clinical improvement, and ORs of ⁇ 1.0 indicate that the minor SNP allele is associated with decreased susceptibility.
  • ORs of > 1.0 indicate that the minor SNP allele is associated with an increase in study ending side effects, and ORs of ⁇ 1.0 indicate that the minor SNP allele is associated a decrease in study ending side effects.
  • PLINK calculates P values for the allele-specific chi-squared test and the odds ratio (OR; or relative risk) associated with the minor allele.
  • Tables 4 and 5 report the minor allele frequencies, P values, and ORs for SNPs, in Tables B and C that affect risperidone response and side effect rates, respectively. Note in Tables 4 and 5 that haplotype blocks result in the same Test SNP being in linkage disequilibrium with multiple SNPs in Table B. Similarly, haplotype blocks result in multiple Test SNPs that can be used for each SNP listed in Table B, though such redundant examples are not presented in Tables 4 and 5.
  • Tables 4 and 5 provide numerous examples of SNP-based alleles that predict altered response to risperidone.
  • ORs of > 1.0 indicate that the minor SNP allele is associated with greater clinical improvement
  • ORs of ⁇ 1.0 indicate that the minor SNP allele is associated with lesser clinical improvement.
  • ORs of > 1.0 indicate that the minor SNP allele is associated with an increase in study ending side effects
  • ORs of ⁇ 1.0 indicate that the minor SNP allele is associated a decrease in study ending side effects.

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Abstract

This invention relates to genetic markers of mental illness, e.g., schizophrenia (SZ), and methods of use thereof.

Description

GENETIC MARKERS OF MENTAL ILLNESS
CLAIM OF PRIORITY
This application claims the benefit of U.S. Provisional Patent Application Serial No. 61/021,756, filed on January 17, 2008, the entire contents of which are hereby incorporated by reference.
FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
This invention was made with Government support under Grant Nos. R43 MH078437, NOl MH900001, and MH074027, awarded by the National Institutes of Health. The Government has certain rights in the invention.
ACKNOWLEDGEMENT
This invention was made with an award from the Kentucky Cabinet for Economic Development, Department of Commercialization and Innovation, under Grant Agreement KSTC-184-512-07-007 with the Kentucky Science and Technology Corporation.
TECHNICAL FIELD
This invention relates to genetic markers of mental illness, e.g., schizophrenia (SZ), and methods of use thereof, e.g., for determining a subject's risk of developing a mental illness, e.g., SZ.
BACKGROUND
Schizophrenia (SZ) is a severe and persistent debilitating psychiatric illness that is generally associated with considerable morbidity and extreme disability. Due to the severity of this disorder, especially the negative impact of a psychotic episode on a patient, and the diminishing recovery after each psychotic episode, there is a need to more conclusively identify individuals who have or are at risk of developing SZ, for example, to confirm clinical diagnoses, to allow for prophylactic therapies, to determine appropriate therapies based on their genotypic subtype, and to provide genetic counseling for prospective parents with a history of the disorder.
Various genes and chromosomes have been implicated in etiology of SZ. Whole genome scans for genes involved in SZ and related SZ-spectrum disorders (including schizotypal personality disorder (SPD) and schizoaffective disorder (SD)) have implicated numerous autosomes as having a role in the genetic etiology of SZ and related SZ-spectrum disorders (Badner et al, MoI. Psychiatry 7:405-411 (2002)Bennett et al, MoI. Psychiatry 7:189-200 (2002)Cooper-Casey et al., MoI. Psychiatry 10:651-656 (2005)Devlin et al., MoI. Psychiatry 7:689-694 (2002)Fallin et al., Am. J. Hum. Genet. 73:601-611 (2003)Ginns et al., Proc. Natl. Acad. Sci. U. S. A 95: 15531-15536 (1998)Jablensky, MoI. Psychiatry (2006)Kirov et al., J. Clin. Invest 115:1440-1448 (2005)Norton et al., Curr. Opin. Psychiatry 19:158-164 (2006)Owen et al., MoI. Psychiatry 9:14-27 (2004)). Generally, these linkage scans have are too low in resolution to identify specific genes, but increasingly, transmission disequilibrium (TDT, family-based association) and Case/Control association studies have evaluated a number of positional candidate genes with a good measure of success (Fallin et al., Am. J. Hum. Genet. 77:918-936 (2005)).
SUMMARY
The invention includes methods for assessing genetic risk, aiding in diagnosis, and/or stratifying patient populations in order to select optimal treatments based on evaluation of single nucleotide polymorphisms (SNPs) for a number of bioinformatically identified genes on chromosomes 1, 3, 6, 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, and 20 relating to SZ (which herein is broadly defined to include SZ-spectrum disorders, e.g., including schizophrenia (SZ), schizotypal personality disorder (SPD) and schizoaffective disorder (SD)). Exemplary SNPs delimiting each gene region (referred to herein as "delimiting SNPs") are given along with exemplary test SNPs that can be used to capture significant haplotype variation in these genes. Important variants can be identified via TDT using families with multiple affected individuals (such as those collected CCGS) and verified by Case/Control comparisons using the SNP markers presented herein. Using SNP markers lying between the delimiting SNPs, inclusive, and identical to or in linkage disequilibrium with the exemplary SNPs, one can determine the haplotypes in these genes relating to genetic risk of developing SZ. These haplotypes can then be used to determine risk of developing SZ by Case/Control studies as shown in Example 1. The allelic and genotypic variants thus identified can be used for assessing genetic risk, to aid in diagnosis, and/or to stratify patient population in order to select optimal treatments (atypical antipsychotic, typical antipsychotic, and/or psychosocial intervention) for patients.
Numerous pathways have been implicated in SZ etiology. As described herein, genes identified as associated with increased risk of SZ are involved in a number of pathways including: glutamate signaling and metabolism, cell adhesion, cytoskeletal architecture, vesicle formation and trafficking, G-protein coupled receptors, carrier proteins and transporters, ion channels (e.g., potassium channels), and potassium current signaling molecules, cell cycle modulators, neuronal development, calcium/calmodulin signaling, neuropeptide signaling, inositol signaling (e.g., phosphatidylinositol kinases), insulin signaling, diacylglycerol signaling, and several additional genes identified by virtue of their interaction with genes in high impact pathways and their expression in the central nervous system.
Table A lists gene names and delimiting SNPs for bioinformatically identified genes relating to SZ-spectrum disorders. All of the genes are human.
Table A: Delimiting SNPs for Novel SZ Genes (NCBI Genome Build 36.2) Delimiting SNPs for Potassium Channel and Related Genes
Gene Chrom. SNP 1 Location (bp) SNP 2 Location (bp)
KCNC4 1 rsl359149 110,553,057 rsl 1578913 110,578,628
KCNAlO 1 rsl281177 110,859,992 rs 17025957 110,863,572
KCND3 1 rs 197422 112,119,035 rsl 0745323 112,345,127
KCNHl 1 rs 12126648 208,922,743 rsl538287 209,377,867
ANK3 10 rs 1050745 61,457,255 rsl 551684 61,820,209
KCNQl 11 rs 11022827 2,414,908 rs2239897 2,848,541
KCNCl 11 rs7949069 17,711,203 rsl236205 17,760,287
Delimiting SNPs for Cell Adhesion and Related Genes
Gene Chrom. SNP 1 Location (bp) SNP 2 Location (bp)
RP1-21O18.1 1 rs9663010 15,143,609 rs2235789 15,314,645
CTNNDl 11 rs558653 57,285,706 rs652908 57,360,585
DACTl 14 rs464582 58,171,201 rsl 60472 58,185,201
CDHIl 16 rs35148 63,536,690 rs7204464 63,731,895
Delimiting SNPs for Vesicle-Related Genes
Gene Chrom. SNP 1 Location (bp) SNP 2 Location (bp)
VAMP4 1 rsl0913508 169,935,102 rs7556644 169,979,491
SYT14 1 rs9429830 208,177,160 rsl 1119426 208,407,592
BRSK2 11 rs7395835 1,365,307 rsl554857 1,441,643
SYT13 11 rs2863172 45,217,918 rsl 1038382 45,269,392
STX2 12 rs2632601 129,834,650 rs7962097 129,890,817
RTNl 14 rsl 7255975 59,131,314 rs7144589 59,407,620
UNC13C 15 rsl l071015 52,092,152 rs9920150 52,708,142
SV2B 15 rsl l630131 89,569,404 rs7169918 89,640,060
Delimiting SNPs for Genes Related to Glutamate Pathways
Gene Chrom. SNP 1 Location (bp) SNP 2 Location (bp)
Gcoml 15 rsl908202 55,669,589 rsl 808478 55,797,051
GRINLlA 15 rsl908202 55,669,589 rsl 808478 55,797,051
GOT2 16 rs2042445 57,296,647 rs4238801 57,329,680 Delimiting SNPs for G-Protein Coupled Receptor Related Genes
Gene Chrom. SNP 1 Location (bp) SNP 2 Location (bp)
RHOG 11 rs 1055640 3,803,869 rs4406820 3,819,109
GPR135 14 rs 17255731 58,964,865 rs4898989 59,005,097
AKAP13 15 rsl533124 83,674,688 rsl 1637212 84,094,101
Delimiting SNPs for Hormone, Inositol, and Diacylglyceride Related Genes
Gene Chrom. SNP 1 Location (bp) SNP 2 Location (bp)
HSDl 7Bl 2 11 rsl2364003 43,657,684 rsl 1037691 43,848,213 IGFlR 15 rs35554027 97,008,574 rs702497 97,319,104
Delimiting SNPs for Cytoskeletal, Myosin, Actin and Microtubule Relatet 1 Genes
Gene Chrom. SNP 1 Location (bp) SNP 2 Location (bp)
EVL 14 rsl 190954 99,601,206 rs35257667 99,689,766 KATNAL2 18 rs9304340 42,780,580 rsl434528 42,886,321
Delimiting SNPs for Genes for Carrier Proteins and Transporters
Gene Chrom. SNP 1 Location (bp) SNP 2 Location (bp)
SLC6A17 1 rs924181 110,481,637 rs545849 110,546,538
SLC16A4 1 rsl0857820 110,706,448 rsl2127781 110,738,080
SLC6A5 11 rs894747 20,575,165 rsl401793 20,632,993
SLC17A6 11 rsl 155821 22,315,296 rs2593644 22,357,697
SLCO3A1 15 rsl l858120 90,196,267 rsl 060206 90,509,554
Delimiting SNPs for Cell Cycle and Tumor Suppressor/Promoter Related Genes
Gene Chrom. SNP 1 Location (bp) SNP 2 Location (bp)
RERE 1 rslO55236 8,326,680 rs914994 8,839,799
FASLG 1 rs763110 170,894,121 rsl2135884 170,905,123
DEAFl 11 rs936465 633,568 rs6597990 687,761
HCCA2 11 rsl2786504 1,446,780 rs2334652 1,462,030
PTPN5 11 rs873670 18,705,395 rs7932938 18,771,871
CHFR 12 rsl 531822 131,925,194 rs3741494 131,974,573
TTC5 14 rsl0130942 19,826,245 rsl0873395 19,845,685
FUSSEL18 18 rs2137289 43,006,123 rs892583 43,170,372
SMAD2 18 rsl 792666 43,617,212 rs2000709 43,713,512
SMAD7 18 rs9944944 44,699,493 rs736839 44,782,063
SMAD4 18 rs620898 46,763,146 rsl2456284 46,863,966
Delimiting SNPs for Genes Involved in Neuronal Development and Plasticity
Gene Chrom. SNP 1 Location (bp) SNP 2 Location (bp)
DNM3 1 rs6701033 170,076,599 rsl 3932 170,678,391
TOLLIP 11 rs5744038 1,252,012 rs5743854 1,287,830
DUSP8 11 rs6578504 1,532,811 rsl 0734456 1,563,922
NA V2 11 rs890136 19,687,211 rs2246192 20,098,415
LRRC4C 11 rsl 1035693 40,091,818 rslO128639 40,275,738
RTN4RL2 11 rs2729363 56,983,430 rs2955849 57,005,697
DTX4 11 rsl0896947 58,694,659 rs544864 58,735,516
ULKl 12 rsl 1246867 130,943,970 rs7978708 130,977,857 NDRG2 14 rsl263871 20,553,926 rsl 243451 20,564,197
JPH4 14 rsl2897422 23,102,867 rs222732 23,129,120
DAAMl 14 rsl7095965 58,718,491 rs4127823 58,926,458
NEDD4 15 rs4424863 53,905,753 rsl 509408 54,073,605
RGMA 15 rsl2438714 91,386,979 rs4114 91,443,429
N4BP1 16 rs9937623 47,129,091 rs9936446 47,203,308
NDRG4 16 rs7202037 57,054,471 rs2280397 57,109,729
CDH8 16 rs4131634 60,243,900 rs9302540 60,629,024
BEAN 16 rs6499082 64,992,072 rsl2445633 65,114,761
KIAA0513 16 rsl 875246 83,617,069 rsl466864 83,691,111
DYM 18 rsl288812 44,821,479 rsl 7725481 45,241,155
DCC 18 rsl7753970 48,119,269 rs2270954 49,311,296
BMP7 20 rs6014947 55,177,906 rs2208404 55,277,143
TMEPAI 20 rs6025689 55,656,857 rs6015068 55,734,303
Delimiting SNPs for Calcium / Calmodulin Related Genes
Gene Chrom. SNP 1 Location (bp) SNP 2 Location (bp)
CAMTAl 1 rs449250 6,720,271 rs228651 7,833,686
CACNAlE 1 rs541886 179,718,012 rs635118 180,037,358
CAMKlG 1 rsl7014820 207,823,042 rs926387 207,854,836
RIMBP2 12 rsl496858 129,444,850 rs7963990 129,571,289
Delimiting SNPs for Genes Involved in Hereditary Hearing Loss
Gene Chrom. SNP 1 Location (bp) SNP 2 Location (bp)
DPH3 3 rs2292614 16,276,795 rs2245708 16,281,022
EXOC2 6 rsl0900954 428,817 rsl3205146 638,473
USHlC 11 rs4756895 17,470,828 rs2073582 17,523,687
OTOG 11 rs2073582 17,523,687 rsl 1024358 17,624,137
SERGEF 11 rsl236205 17,760,287 rsl 133758 17,998,369
EMLl 14 rsl0140193 99,328,197 rs7149272 99,487,743
PMP22 17 rs230938 15,071,845 rsl 79521 15,113,946
Delimiting SNPs for Genes Encoding Zn-Finger Proteins
Gene Chrom. SNP 1 Location (bp) SNP 2 Location (bp)
PRDM2 1 rs2487657 13,894,681 rs979932 13,987,558
ZFP91-CNTF 11 rsl 944055 58,099,205 rs4319530 58,156,405
ZNF423 16 rsl93907 48,080,956 rsl2443775 48,418,620
Delimiting SNPs for Brain-expressed Genes (not otherwise specified)
Gene Chrom. SNP 1 Location (bp) SNP 2 Location (bp)
PER3 1 rsl72933 7,767,267 rs707472 7,828,595
RABGAPlL 1 rs6681627 172,393,365 rsl2126129 173,194,998
PHACS 11 rsl78512 44,043,887 rs2285029 44,062,444
YPEL4 11 rsl798177 57,168,726 rsl 647394 57,175,164
KIAA1853 12 rs7979864 117,902,236 rs722307 118,094,760
KIAA1545 12 rsl0870551 131,567,365 rs7294615 131,678,218
TEPl 14 rsl713418 19,904,649 rsl 760890 19,951,629
WDR25 14 rs2273802 99,912,652 rsl0151709 100,067,090 BEGAIN 14 rsl 1628965 100,071,902 rs7140556 100,106,211
HERC2 15 rs7495174 26,017,833 rsl 614575 26,236,593
ADAMlO 15 rs3764196 56,674,302 rs514049 56,829,655
KLHL25 15 rsl 1637212 84,094,101 rs7181017 84,145,916
NETO2 16 rsl551188 45,616,796 rs7184206 45,736,527
CBLNl 16 rs3743777 47,869,517 rs9935379 47,884,582
KIAAOl 82 16 rs4240810 84,182,628 rs3815795 84,269,606
C16orf74 16 rsl 1644122 84,298,251 rs301143 84,342,400
COXlO 17 rs4792434 13,912,946 rs7218697 14,074,153
KIAA 0427 18 rslO39989 44,318,592 rs752151 44,697,296
In one aspect, the invention includes methods for obtaining information regarding a subject's risk for developing SZ, i.e., determining the subject's risk of developing SZ. The methods include obtaining a test haplotype associated with schizophrenia as described herein. The methods can also include obtaining a sample comprising genomic DNA (gDNA) from the subject, and determining the identity, absence or presence of a test haplotype associated with SZ as described herein. In some embodiments, the methods include obtaining a test haplotype for the subject comprising at least one test SNP marker that is found within the region delimited by SNPl and SNP2, inclusive, for a given gene as specified in Table A, or comprising one or more of the exemplary SNP markers for each gene, as specified in the Examples and/or SNP markers in linkage disequilibrium with these markers, wherein the haplotype provides information regarding the subject's risk of developing SZ, SD, or SPD. In some embodiments, the test marker is a marker listed in one or more genes of Table A that is in linkage disequilibrium (defined by correlation, [r2] > 0.5) with a marker listed in Table A in Table B as shown in the Examples, wherein the haplotype provides information regarding the subject's risk of developing SZ, e.g., markers lying between the exemplary SNPs for a gene listed in Table A, but not explicitly listed in the Examples.
In some embodiments, the test haplotype includes at least one marker lying between delimiting SNPs (SNPl and SNP2), inclusive, for a given gene as specified in Table A, e.g., the exemplary delimiting SNPs listed in Table A; other delimiting SNPs can be chosen from other SNPs known in the art, e.g., the exemplary test SNPs described herein. In some embodiments, the test haplotype includes two or more markers from one gene. In some embodiments, the test genotype includes at least two markers, each from a different gene listed in Table A.
In some embodiments, the test haplotype includes at least one marker lying between the SNPl and SNP2, inclusive, for a given gene as specified in Table A and provides information regarding a subject's risk of developing SZ under a narrower (DSM III/DSM IV) disease definition.
In some embodiments, the methods include obtaining a test haplotype for the subject by determining the genotype of at least one test marker listed in Table B, or a test marker that lies between the delimiting markers listed in Table A and that is in linkage disequilibrium (LD, defined by correlation, [r2] > 0.5) with markers listed in Table B, wherein the test haplotype indicates the subject's risk of developing SZ. In some embodiments, the at least one test marker is in the KIAAO 182 gene or the KIAA0427 gene. In some embodiments, the test marker is selected from the group consisting rs736845; rs994060; rs381579; rs217556; rs8095199; or is a test marker in LD with these markers.
In some embodiments, the methods described herein can be used for predicting a human subject's likely response to an antipsychotic medication. The methods include obtaining a test haplotype for the subject by determining the genotype for at least one test marker listed in Table B, or at least one test marker that lies between the delimiting markers in Table A and that is in linkage disequilibrium (LD) (defined by correlation, [r2] > 0.5) with a marker listed in Table B, wherein the test haplotype indicates the subject's likely response, e.g., likelihood of responding positively (i.e., an improvement in one or more symptoms of the disease) or negatively (i.e., with no improvement, or even a worsening, of one or more symptoms of the disease, or with excessive side effects) to an antipsychotic medication. A number of antipsychotic medications are known in the art and can include, for example, olanzapine, risperidone, quetiapine, perphenazine, and ziprasidone.
In some embodiments, the treatment is administration of olanzapine, and the at least one test marker is in a gene selected from the group consisting of C16orf74, synaptic vesicle glycoprotein 2B (SV2B), calmodulin binding transcription activator 1 (CAMTAl), otogelin (OTOG), ras homolog gene family, member G (RHOG). In some embodiments, the test marker is selected from the group consisting of rs230535; rs373835; rs386061; rs449250; rs657739; rs657740; rs755475; rs755475; rsl41798; rsl 10300; rsl45172; rsl00349; rslO8328; rs202348; rsl 10243; rsl 1024358; or is a test markers in LD with one of these markers, and the test haplotype indicates the subject's likely response to administration of olanzapine.
In some embodiments, the treatment is administration of risperidone, and the at least one test marker is in a gene selected from the group consisting of neural precursor cell expressed, developmentally down-regulated 4 (NEDD4), cadherin 8, type 2 (CDH8), deformed epidermal autoregulatory factor 1 (DEAFl), hect domain and RLD 2 (HERC2). In some embodiments, the test marker is selected from the group consisting of rs230357; rs230358; rsl39713; rs805733; rs930254; rsllO754; rsl36991; rsl97879; rs649880; rs993999; rs496314; rs659799; rs936465; rs659799; rsl 10743; rsl63516; rs223828; rs7495174; or is a test marker that is in linkage disequilibrium with one of these markers. The test haplotype indicates the subject's likely response to administration of risperidone.
In some embodiments, the treatment is administration of quetiapine, and the at least one test marker is in a gene selected from the group consisting of catenin (cadherin- associated protein), delta 1 (CTNNDl), reticulon 1 (RTNl), A kinase (PRKA) anchor protein 13 (AKAP 13), potassium voltage-gated channel, shaker-related subfamily, member 10 (KCNAlO), solute carrier family 17 (sodium-dependent inorganic phosphate cotransporter), member 6 (SLC 17 A6). In some embodiments, the test marker further is selected from the group consisting of: rs207835; rsllO265; rsll5582; rs207835; rs224671; rs376845; rs708228; rslO8966; rsll5701; rs215663; rs652908; rslO5399; rs206182; rs206182; rs206182; rs338523; rs407525; rs407525; rs484289; rs484307; rs484307; rs716216; rsl 10735; rsl01450; rsl27174; rsl7310036; or is a test marker that is in linkage disequilibrium with one of these markers. The test haplotype indicates the subject's likely response to administration of quetiapine.
In some embodiments, the treatment is administration of perphenazine, and the at least one test marker is in a gene selected from the group consisting of secretion regulating guanine nucleotide exchange factor (SERGEF) potassium voltage-gated channel, subfamily H (eag-related), member 1 (KCNHl), functional smad suppressing element 18 (FUSSELl 8). In some embodiments, the test marker is selected from the group consisting of: rsl 77022; rsl39302; rsl528; rsl72424; rs211130; rs211137; rs211146; rs228323; rsl05028; rsl77854; rs266877; rs723610; rs892583; or is a test marker that is in linkage disequilibrium with one of these markers. The test haplotype indicates the subject's likely response to perphenazine.
In some embodiments, the treatment is administration of ziprasidone, and the at least one test marker is in a gene selected from the group consisting of unc-13 homo log C (C. elegans) (UNC13C), cerebellin 1 precurso (CBLNl), checkpoint with forkhead and ring finger domains (CHFR). In some embodiments, the test marker is selected from the group consisting of: rsl29109; rsllO764; rs993537; rsl25945; rsll6390; rs802519; rs930218; rs230653; rs4758954; or is a test marker that is in linkage disequilibrium with one of these markers. The test haplotype indicates the subject's likely response to administration of ziprasidone. In some embodiments, the treatment is administration of an antipsychotic drug, and the at least one test marker is in a gene selected from the group consisting of cadherin 11 , type 2, OB-cadherin (osteoblast) (CDHIl), deleted in colorectal carcinoma (DCC), Usher syndrome 1C (autosomal recessive, severe) (USHlC). In some embodiments, the test marker is selected from the group consisting of: rs35144 ; rs35148 ; rs35186 ; rs35195 ; rs35144 ; rs222908; rs950278; rsl43174; rsl24574; rs494025; rs750690; rs650823; rsl39333; rsl52023; rslO5557; rslO5557; rs207222; rs475689; rsl6770, or is a test marker that is in linkage disequilibrium with one of these markers. The test haplotype indicates the subject's likely response to administration of an antipsychotic.
In some embodiments, the test haplotype provides information regarding a subject's risk (or likelihood) of having a particular endophenotype, and/or a higher or lower level (e.g., severity) of the endophenotype, e.g., of one or more specific parameters of the PANSS scale, e.g., one or more symptoms, e.g., hallucinations, paranoia, anxiety, depression, or grandiosity, as well as response or lack of response to drugs and comorbidity for substance and alcohol abuse.
In another aspect, the invention provides methods for predicting the degree of severity of a psychiatric endophenotype in a human subject. The methods include obtaining a test haplotype for the subject by determining the genotype for at least one test marker listed in Table B, or at least one test markers that lies between the delimiting markers listed in Table A and that is in linkage disequilibrium (LD) defined by correlation, [r2] > 0.5) with a marker in Table B, wherein the test haplotype indicates the likely degree of severity of a psychiatric endophenotype in the subject. In some embodiments, the psychiatric endophenotype is a quantitative trait that can be measured using one or more of PANSS Total composite score, PANSS Positive composite score, PANSS Negative composite score, and PANSS General Psychopathology composite score.
In some embodiments, the one or more test markers are from calcium channel, voltage-dependent, R type, alpha IE subunit (CACNAlE), echinoderm microtubule associated protein like 1 (EMLl), katanin p60 subunit A- like 2 (KATNAL2) genes. In some embodiments, the test marker is selected from the group consisting of rs 174946; rs 199960; rs385609; rs465267; rs704326; rs218709; rs224722; rs257103; rs257604; rs723351; rs930434; rs996138; rs225071; rslll605; rsll l605; rsl24336; rs657575; rs746698; rs227370; rs2273704; or is a test marker in linkage disequilibrium with one of these markers. The test haplotype indicates the likely degree of severity of a psychiatric endophenotype in the subject. In some embodiments, the psychiatric endophenotype comprises one or more of: a Positive Symptom selected from the group consisting of Pl -delusions, P2-conceptual disorganization, P3 -hallucinatory behavior, P4-exitement, P5 -grandiosity, P6-suspiciousness, P7-hostility; a Negative Symptom selected from the group consisting of Nl -blunted affect, N2-emotional withdrawal, N3-poor rapport, N4-passive/appathetic social withdrawal, N5- difficultiy in abstract thinking, N60 lack of spontaneity and flow of conversation, N7- steryotyped thinking; or a general psychopathology symptom selected from the group consisting of Gl-somatic concern, G2-anxiety, G3-guilt feelings, G4-tension, G5-mannerisms and posturing, Gβ-depression, G7-motor retardation, G8-uncooperativeness, G9-unusual thought content, GlO-disorentation, GI l -poor attention, G12-lack of judgment and insight, Gl 3 disturbance of volition, G14-poor impulse control, G15-preoccupation, and G16-active social avoidance.
In some embodiments, the at least one test marker is from a gene selected from the group consisting of DPH3, KTIIl homo log (DPH3), insulin- like growth factor I receptor (IGFlR), calcium/calmodulin-dependent protein kinase IG (CAMKlG), neuron navigator 2 (NAV2), bone morphogenetic protein 7 (BMP7). In some embodiments, the test marker is selected from the group consisting of rs224572; rs842257; rs859703; rs224570; rs496543; rsll2473; rsl 87961; rs268479; rslO8332; rs712564; rslO375 ; rs601494; rs230198; or is a test marker that is in linkage disequilibrium with one of these markers. The test haplotype indicates the likely severity of a psychiatric endophenotype in the subject.
The methods described herein can include obtaining a haplotype that includes two or more, e.g., two, three, four, five, or six markers.
Additionally, the methods can include determining the presence or absence of other markers known to be associated with SZ, SD, or SPD, e.g., outside of a region identified herein. A number of other such markers are known in the art, e.g., as described herein.
The subject can be a human (e.g., a patient having, or at risk of, SZ). In one embodiment, the subject is a patient having previously diagnosed SZ, SD, or SPD (e.g., a patient suffering from early, intermediate or aggressive SZ, SD, or SPD). In some embodiments, the methods described herein are used to obtain information regarding a subject's risk of developing SZ wherein the disorder is other than catatonic schizophrenia. In some embodiments, the subject is of Caucasian (CA) descent, i.e., has one or more ancestors who are CA.
In one embodiment, a subject to be evaluated by a method described herein is a subject having one or more risk factors associated with SZ, SD, or SPD. For example, the subject may have a relative afflicted with SZ, e.g., one or more of a grandparent, parent, uncle or aunt, sibling, or child who has or had SZ, SD, or SPD; the subject may have a genetically based phenotypic trait associated with risk for SZ, SD, or SPD (e.g., eye tracking dysfunction); deficits in working (short-term) memory; and/or mixed-handedness (the use of different hands for different tasks), particularly in females.
In some embodiments, the subject is a child, fetus, or embryo, and one of the subject's relatives, e.g., a parent or sibling, of the child, fetus, or embryo has SZ, SD, or SPD. In this case, the presence in the child, fetus, or embryo of a haplotype described herein that is shared with the affected parent, but not with the non-affected parent, indicates that the child, fetus, or embryo has an increased risk of developing SZ. In some embodiments, the subject has no overt or clinical signs of SZ, SD, or SPD.
In some embodiments, obtaining a test haplotype includes obtaining a sample comprising DNA from the subject; and determining the identity, presence or absence of at least one test marker that is SNP marker that is found within the region delimited by SNPl and SNP2, inclusive, for a given as specified in Table A, or comprising one or more of the exemplary SNP markers for each gene, as specified in the Table B and/or SNP markers in linkage disequilibrium with these markers (in the particular population) in the DNA . The sample can be obtained, e.g., from the subject by a health care provider, or provided by the subject without the assistance of a health care provider.
In some embodiments, obtaining a test haplotype includes reviewing a subject's medical history, wherein the medical history includes information regarding the presence or absence of at least one test SNP marker that is found within the region delimited by SNPl and SNP2, inclusive, for a given gene as specified in Table A, or comprising one or more of the exemplary SNP markers for each gene, as specified in Table B, and/or SNP markers in linkage disequilibrium with these markers, in the subject.
In some embodiments, the methods described herein include obtaining a reference haplotype including a reference marker that corresponds to a test marker, and comparing the test haplotype to the reference haplotype. A reference marker that "corresponds to" a test marker is the same marker. For example, if the test haplotype includes rs 10766410 in the OTOG gene, then the reference haplotype should also include rs 10766410 for comparison purposes; or if the test haplotype includes rs553042 in the CACNAlE gene, then the reference haplotype should also include rs553042 for comparison purposes. In methods where the haplotype analysis is performed to determine risk of developing SZ, the sharing of a haplotype (e.g., of some or all of the marker alleles) between the test haplotype and a reference haplotype is indicative of whether there is an increased likelihood that the subject will develop SZ. The reference haplotype can be from a relative, e.g., a first or second degree relative, or from an unrelated individual (or population), that has been identified as either having or not having SZ, SD, or SPD. Optionally, a reference haplotype is also obtained from an unaffected person, e.g., an unaffected relative, and lack of sharing of a haplotype of a haplotype between the test haplotype and the reference haplotype indicates that the subject has an increased risk of developing SZ.
In methods where the haplotype analysis is performed to determine risk of having a particular endophenotype or endophenotype severity (e.g., on the PANSS scale), the sharing of a haplotype (e.g., of some or all of the marker alleles) between the test haplotype and a reference haplotype is indicative of whether there is an increased likelihood that the subject will have an elevated (high) or low value for that specific endophenotype. For example, the reference haplotype can be from a relative, e.g., a first or second degree relative, or from an unrelated individual (or population), e.g., a person that has been diagnosed with SZ, and further identified as either having or not having an elevated value for the specific endophenotype. In some embodiments, the presence of the haplotype does not indicate the presence or absence of a specific phenotype, but rather the degree to which the phenotype occurs, e.g., on the PANSS scale; as one example, alleles of the marker rsl 1030008 can impact the severity of delusions and suspiciousness/persecution not necessarily its presence or absence of these symptoms.
In methods where the haplotype analysis is performed to predict response to a particular treatment, the sharing of a haplotype (e.g., of some or all of the marker alleles) between the test haplotype and a reference haplotype is indicative of how the subject is likely to respond to the treatment. For example, the reference haplotype can be from a relative, e.g., a first or second degree relative, or from an unrelated individual (or population), that has been diagnosed with SZ and further identified as responding positively (i.e., with an improvement in one or more symptoms of the disease) or negatively (i.e., with no improvement, or even a worsening, of one or more symptoms of the disease, or with excessive side effects).
In some embodiments, the methods include administering a treatment to a subject identified as being at increased risk for developing SZ, e.g., a pharmacological treatment as described herein. In some embodiments, the subject has no overt or clinical signs of SZ, SD, or SPD, and the treatment is administrated before any such signs appear.
Information obtained using a method described herein can be used, e.g., to select a subject population for a clinical trial, to stratify a subject population in a clinical trial, and/or to stratify subjects that respond to a treatment from those who do not respond to a treatment, or subjects that have negative side effects from those who do not.
In another aspect, the invention provides methods for selecting a subject for inclusion in a clinical trial, e.g., a trial of a treatment for SZ, SD, or SPD. The methods include obtaining a haplotype for the subject including at least one marker that is found within the region delimited by SNPl and SNP2, inclusive, for a given gene as specified in Table A, or comprising one or more of the exemplary SNP markers for each gene, as specified in the Table B and/or SNP markers in linkage disequilibrium with these markers e.g. as shown in the Examples; determining whether the haplotype is associated with an increased risk of developing SZ; and including the subject in the trial or excluding the subject from the trial if the haplotype indicates that the subject has altered drug response for patients with SZ, SD, or SPD.
In another aspect, the invention provides methods for selecting a subject for administration of a treatment for schizophrenia (SZ). The methods include obtaining a haplotype for the subject, wherein the haplotype comprises at least one marker that is listed in Table B, or is in linkage disequilibrium with a marker listed in Table B, as exemplified by the Markers listed in Table C; determining whether the haplotype is associated with altered (e.g., positive or negative) treatment response for patients with SZ; and administering the treatment to the subject if the haplotype indicates that the subject has an improved response to the treatment. In another aspect, the invention provides methods for selecting a treatment for administration to a subject. The methods include obtaining a haplotype for the subject, wherein the haplotype comprises at least one marker that is listed in Table B, or is in linkage disequilibrium unit with a marker listed in Table B; determining whether the haplotype is associated with altered (e.g., positive or negative) treatment response for patients with schizophrenia (SZ); and administering the treatment for SZ to the subject if the haplotype indicates that the subject has an improved response to the treatment.
In another aspect, the invention provides methods for evaluating the effect of a haplotype on the outcome of a treatment for schizophrenia (SZ). The methods include obtaining information regarding outcome of the treatment, wherein the information comprises a parameter relating to the treatment of each subject in a population of subjects; obtaining haplotypes for each subject in the population, wherein the haplotype comprises at least one marker that is listed in Table B, or is in linkage disequilibrium with a marker listed in Table B; and correlating the information regarding outcome with the haplotypes; thereby evaluating the effect of the haplotype on the outcome of the treatment. In some embodiments, the method includes selecting a treatment for administration to a subject who has a selected haplotype, based on the effect of the haplotype on the outcome of the treatment.
In some embodiments, the information regarding outcome of the treatment is from a completed clinical trial, and the analysis is retrospective.
In a further aspect, the invention features methods for detecting the presence of a haplotype associated with susceptibility to SZ (broadly defined as including, in addition to narrowly defined SZ, SD or SPD) in a subject, by analyzing a sample of DNA from the subject.
Additionally, the invention features methods of predicting a test subject's risk of developing SZ. The methods include obtaining a reference haplotype of a reference subject, wherein the reference subject has SZ, SD, or SPD; determining a test haplotype of the test subject in the same region; and comparing the test haplotype to the reference haplotype, wherein the sharing of a haplotype in this region between the test subject and the reference subject is an indication of an increased likelihood that the test subject will develop SZ. In some embodiments, the method further includes comparing the subject's haplotype to a reference subject who does not have SZ, SD, or SPD.
Further, the invention features methods for predicting a test subject's risk of developing SZ. The methods include obtaining a reference haplotype of a reference subject in a region described herein, wherein the reference subject has SZ; obtaining a test haplotype of the test subject in the same region; and comparing the test haplotype to the reference haplotype. The sharing of a haplotype in this region between the test subject and the reference subject is an indication of an increased likelihood that the test subject will develop SZ. In some embodiments, the method also includes comparing the test subject's haplotype to a reference subject who does not have SZ.
Also provided herein are kits for use in detection of haplotypes associated with SZ, including at least one nucleic acid probe that hybridizes to a sequence that includes a polymorphism described herein, or can be used to amplify a sequence that includes a polymorphism described herein.
Also provided are arrays that include a substrate having a plurality of addressable areas, wherein one or more of the addressable areas includes one or more probes that can be used to detect a polymorphism described herein.
In another aspect, the invention provides methods for providing information regarding a subject's risk of developing schizophrenia (SZ). The methods include obtaining a sample from the subject at a first site; transferring the sample to a second site for analysis, wherein the analysis provides data regarding the identity, presence or absence of at least one test marker that is that is found within the region delimited by SNPl and SNP2, inclusive, for a given gene as specified in Table A, or comprising one or more of the exemplary SNP markers for each gene, as specified in the Examples and/or SNP markers in linkage disequilibrium with these markers; and transferring the data to one or more of a health care provider, the subject, or a healthcare payer. In some embodiments, the first site is a health care provider's place of business, or is not a health care provider's place of business, e.g., the subject's home. In some embodiments, the data is transferred to a healthcare payer and used to decide whether to reimburse a health care provider.
Definitions
As defined herein, "Schizophrenia" or "SZ" includes the SZ-spectrum disorders, Schizotypal Personality Disorder (SPD) and Schizoaffective Disorder (SD), as well as Schizophrenia under the narrower, DSM-IV definition (see below).
As used herein, a "haplotype" is one or a set of signature genetic changes (polymorphisms) that are normally grouped closely together on the DNA strand, and are usually inherited as a group; the polymorphisms are also referred to herein as "markers." A "haplotype" as used herein is information regarding the presence or absence of one or more contiguous genetic markers on a given chromosome in a subject. A haplotype can consist of a variety of genetic markers, including indels (insertions or deletions of the DNA at particular locations on the chromosome); single nucleotide polymorphisms (SNPs) in which a particular nucleotide is changed; microsatellites; and minisatellites.
Microsatellites (sometimes referred to as a variable number of tandem repeats or VNTRs) are short segments of DNA that have a repeated sequence, usually about 2 to 5 nucleotides long (e.g., CACACA), that tend to occur in non-coding DNA. Changes in the microsatellites sometimes occur during the genetic recombination of sexual reproduction, increasing or decreasing the number of repeats found at an allele, changing the length of the allele. Microsatellite markers are stable, polymorphic, easily analyzed and occur regularly throughout the genome, making them especially suitable for genetic analysis.
"Linkage disequilibrium" occurs when the observed frequencies of associations of alleles for different polymorphisms in a population do not agree with frequencies predicted by multiplying together the allele frequencies for the individual genetic markers, thus resulting in a specific haplotype in the population. The term "chromosome" as used herein refers to a gene carrier of a cell that is derived from chromatin and comprises DNA and protein components (e.g., histones). The conventional internationally recognized individual human genome chromosome numbering identification system is employed herein. The size of an individual chromosome can vary from one type to another with a given multi-chromosomal genome and from one genome to another. In the case of the human genome, the entire DNA mass of a given chromosome is usually greater than about 100,000,000 base pairs. For example, the size of the entire human genome is about 3 X 109 base pairs.
The term "gene" refers to a DNA sequence in a chromosome that codes for a product (either RNA or its translation product, a polypeptide). A gene contains a coding region and includes regions preceding and following the coding region (termed respectively "leader" and "trailer"). The coding region is comprised of a plurality of coding segments ("exons") and intervening sequences ("introns") between individual coding segments.
The term "probe" refers to an oligonucleotide. A probe can be single stranded at the time of hybridization to a target. As used herein, probes include primers, i.e., oligonucleotides that can be used to prime a reaction, e.g., a PCR reaction.
The term "label" or "label containing moiety" refers in a moiety capable of detection, such as a radioactive isotope or group containing same, and nonisotopic labels, such as enzymes, biotin, avidin, streptavidin, digoxygenin, luminescent agents, dyes, haptens, and the like. Luminescent agents, depending upon the source of exciting energy, can be classified as radioluminescent, chemiluminescent, bioluminescent, and photoluminescent (including fluorescent and phosphorescent). A probe described herein can be bound, e.g., chemically bound to label-containing moieties or can be suitable to be so bound. The probe can be directly or indirectly labeled.
The term "direct label probe" (or "directly labeled probe") refers to a nucleic acid probe whose label after hybrid formation with a target is detectable without further reactive processing of hybrid. The term "indirect label probe" (or "indirectly labeled probe") refers to a nucleic acid probe whose label after hybrid formation with a target is further reacted in subsequent processing with one or more reagents to associate therewith one or more moieties that finally result in a detectable entity.
The terms "target," "DNA target," or "DNA target region" refers to a nucleotide sequence that occurs at a specific chromosomal location. Each such sequence or portion is preferably at least partially, single stranded (e.g., denatured) at the time of hybridization. When the target nucleotide sequences are located only in a single region or fraction of a given chromosome, the term "target region" is sometimes used. Targets for hybridization can be derived from specimens which include, but are not limited to, chromosomes or regions of chromosomes in normal, diseased or malignant human cells, either interphase or at any state of meiosis or mitosis, and either extracted or derived from living or postmortem tissues, organs or fluids; germinal cells including sperm and egg cells, or cells from zygotes, fetuses, or embryos, or chorionic or amniotic cells, or cells from any other germinating body; cells grown in vitro, from either long-term or short-term culture, and either normal, immortalized or transformed; inter- or intraspecific hybrids of different types of cells or differentiation states of these cells; individual chromosomes or portions of chromosomes, or translocated, deleted or other damaged chromosomes, isolated by any of a number of means known to those with skill in the art, including libraries of such chromosomes cloned and propagated in prokaryotic or other cloning vectors, or amplified in vitro by means well known to those with skill; or any forensic material, including but not limited to blood, or other samples.
The term "hybrid" refers to the product of a hybridization procedure between a probe and a target.
The term "hybridizing conditions" has general reference to the combinations of conditions that are employable in a given hybridization procedure to produce hybrids, such conditions typically involving controlled temperature, liquid phase, and contact between a probe (or probe composition) and a target. Conveniently and preferably, at least one denaturation step precedes a step wherein a probe or probe composition is contacted with a target. Guidance for performing hybridization reactions can be found in Ausubel et al., Current Protocols in Molecular Biology. John Wiley & Sons, N. Y. (2003), 6.3.1-6.3.6. Aqueous and nonaqueous methods are described in that reference and either can be used. Hybridization conditions referred to herein are a 50% formamide, 2X SSC wash for 10 minutes at 45°C followed by a 2X SSC wash for 10 minutes at 37°C.
Calculations of "identity" between two sequences can be performed as follows. The sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second nucleic acid sequence for optimal alignment and non-identical sequences can be disregarded for comparison purposes). The length of a sequence aligned for comparison purposes is at least 30%, e.g., at least 40%, 50%, 60%, 70%, 80%, 90% or 100%, of the length of the reference sequence. The nucleotides at corresponding nucleotide positions are then compared. When a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.
The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In some embodiments, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package, using a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.
As used herein, the term "substantially identical" is used to refer to a first nucleotide sequence that contains a sufficient number of identical nucleotides to a second nucleotide sequence such that the first and second nucleotide sequences have similar activities. Nucleotide sequences that are substantially identical are at least 80%, e.g., 85%, 90%, 95%, 97% or more, identical.
The term "nonspecific binding DNA" refers to DNA which is complementary to DNA segments of a probe, which DNA occurs in at least one other position in a genome, outside of a selected chromosomal target region within that genome. An example of nonspecific binding DNA comprises a class of DNA repeated segments whose members commonly occur in more than one chromosome or chromosome region. Such common repetitive segments tend to hybridize to a greater extent than other DNA segments that are present in probe composition.
As used herein, the term "stratification" refers to the creation of a distinction between subjects on the basis of a characteristic or characteristics of the subjects. Generally, in the context of clinical trials, the distinction is used to distinguish responses or effects in different sets of patients distinguished according to the stratification parameters. In some embodiments, stratification includes distinction of subject groups based on the presence or absence of particular markers or haplotypes described herein. The stratification can be performed, e.g., in the course of analysis, or can be used in creation of distinct groups or in other ways.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.
Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a list of exemplary genes useful in the methods described herein, with the sequence identifiers from the GenBank database for their genomic sequences.
DETAILED DESCRIPTION
The present inventors have used bioinformatics and genetic linkages for related neuropsychiatric endophenotypes and DSM disease definitions to define genes in common cellular pathways across various chromosomes as high priority targets for TDT and Case/Control analysis. Resources of the International HapMap project (hapmap.org) were used to define SNPs in these loci, whose pattern of transmission in families and disease association in the population captures extant genetic variation (including important coding variation if present) contributing to genetic susceptibility to SZ-spectrum disorders.
The invention includes methods for assessing genetic risk, aiding in diagnosis, and/or stratifying patient populations in order to select optimal treatments based on evaluation of single nucleotide polymorphisms (SNPs) for a number of bioinformatically identified genes on chromosomes 1, 3, 6, 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, and/or 20 relating to SZ- spectrum disorders including narrowly defined schizophrenia, schizotypal personality disorder (SPD) and schizoaffective disorder (SD) (collectively referred to herein as "SZ"). Specific SNPs delimiting each gene (delimiting SNPs) are given along with exemplary SNPs can be used to capture significant haplotype variation in these genes. Important variants can be verified via TDT using families with multiple affected individuals (such as those collected CCGS) and by Case/Control comparisons using the SNP markers presented herein. Using SNP markers lying between the delimiting SNPs, inclusive, and identical to or in linkage disequilibrium with the exemplary SNPs, one can determine the haplotypes in these genes relating to genetic risk of developing SZ-spectrum disorders via family-based association analyses. These haplotypes can then be used to determine risk of developing these disorders by Case/Control studies. The allelic and genotypic variants thus identified can be used for assessing genetic risk, to aid in diagnosis, and/or to stratify patient population in order to select optimal treatments (atypical antipsychotic, typical antipsychotic, and/or psychosocial intervention) for patients. Methods of Evaluating Susceptibility to SZ, Pharmacological Response, and Psychiatric Endophenotvpes
Described herein are a variety of methods for the determination of a subject's risk of developing SZ (which can also be considered susceptibility to SZ) and related clinical phenotypes, likelihood or risk of having an specific endophenotype or severity of an endophenotype, and for predicting a subject's response to a treatment for SZ.
"Susceptibility" to SZ does not necessarily mean that the subject will develop SZ, but rather that the subject is, in a statistical sense, more likely to develop SZ than an average member of the population, i.e., has an increased risk of developing SZ. As used herein, susceptibility to SZ exists if the subject has a haplotype associated with an increased risk of SZ as described herein. Ascertaining whether the subject has such a haplotype is included in the concept of diagnosing susceptibility to SZ as used herein. Similarly, susceptibility to displaying a particular clinical phenotype does not mean that the subject will have the phenotype, but rather that the subject is, in a statistical sense, more likely to display the phenotype. Thus, the methods described herein can include obtaining a haplotype associated with an increased risk of having a specific clinical phenotype as described herein for the subject. Furthermore, a prediction of response may not provide 100% certainty, but simply a statistical likelihood that the subject will respond in a particular way to a particular treatment. Such determinations are useful, for example, for purposes of diagnosis, treatment selection, and genetic counseling.
As used herein, "obtaining a haplotype" includes obtaining information regarding the identity, presence or absence of one or more genetic markers in a subject. Obtaining a haplotype can, but need not, include obtaining a sample comprising DNA from a subject, and/or assessing the identity, presence or absence of one or more genetic markers in the sample. The individual or organization who obtains the haplotype need not actually carry out the physical analysis of a sample from a subject; the haplotype can include information obtained by analysis of the sample by a third party. Thus the methods can include steps that occur at more than one site. For example, a sample can be obtained from a subject at a first site, such as at a health care provider, or at the subject's home in the case of a self-testing kit. The sample can be analyzed at the same or a second site, e.g., at a laboratory or other testing facility. Obtaining a haplotype can also include or consist of reviewing a subject's medical history, where the medical history includes information regarding the identity, presence or absence of one or more genetic markers in the subject, e.g., results of a genetic test. As described herein, haplotypes associated with SZ include specific alleles for markers in Tables B and C, and makers in linkage disequilibrium with these, as exemplified by the Case/Control results in Table 1.
As one example, haplotypes associated with pharmacological response include one or more markers in Tables B and C and/or markers in linkage disequilibrium with these markers as exemplified by the Examples in Tables 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13. Haplotypes associated with response to olanzapine can include one or more markers listed in Tables 2 and 3 and/or markers in linkage disequilibrium with these markers. Haplotypes associated with response to risperidone can include one or more markers listed in Tables 4 and 5 and/or markers linkage disequilibrium with these markers. Haplotypes associated with response to quetiapine can include one or more markers listed in Tables 6 and 7 and/or markers linkage disequilibrium with these markers. Haplotypes associated with response to perphenazine can include one or more markers listed in Tables 8 and 9 and/or markers linkage disequilibrium with these markers. Haplotypes associated with response to ziprasidone can include one or more markers listed in Tables 10 and 11 and/or markers linkage disequilibrium with these markers. Haplotypes associated with response to antipsychotic medications, as a group, can include one or more markers listed in Tables 12 and 13 and/or markers linkage disequilibrium with these markers. In some embodiments, the haplotype includes one or more of the markers listed in Tables 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13.
As another example, haplotypes associated with specific psychiatric endophenotypes include one or more markers in Tables B and C and/or markers in linkage disequilibrium with these markers as exemplified by the Examples in Tables 14 and 15 and/or markers linkage disequilibrium with these markers. Haplotypes associated with altered scores for the main subscales of the Positive and Negative Syndrome Scale (PANSS) can include one or more markers listed in Table 14. Haplotypes associated with altered scores for specific subscales of the PANSS can include one or more markers listed in Table 15 and/or markers in linkage disequilibrium with these markers. In some embodiments, the haplotype includes one or more of the markers listed in Tables 14 and 15.
In some embodiments, to detect the presence of a haplotype described herein, a biological sample that includes nucleated cells (such as blood, a cheek swab or mouthwash) is prepared and analyzed for the presence or absence of preselected markers. Such diagnoses may be performed by diagnostic laboratories, or, alternatively, diagnostic kits can be manufactured and sold to health care providers or to private individuals for self-diagnosis. Diagnostic or prognostic tests can be performed as described herein or using well known techniques, such as described in U.S. Pat. No. 5,800,998.
Results of these tests, and optionally interpretive information, can be returned to the subject, the health care provider or to a third party payor. The results can be used in a number of ways. The information can be, e.g., communicated to the tested subject, e.g., with a prognosis and optionally interpretive materials that help the subject understand the test results and prognosis. The information can be used, e.g., by a health care provider, to determine whether to administer a specific drug, or whether a subject should be assigned to a specific category, e.g., a category associated with a specific disease endophenotype, or with drug response or non-response. The information can be used, e.g., by a third party payor such as a healthcare payer (e.g., insurance company or HMO) or other agency, to determine whether or not to reimburse a health care provider for services to the subject, or whether to approve the provision of services to the subject. For example, the healthcare payer may decide to reimburse a health care provider for treatments for SZ, SPD, or SD if the subject has an increased risk of developing SZ. As another example, a drug or treatment may be indicated for individuals with a certain haplotype, and the insurance company would only reimburse the health care provider (or the insured individual) for prescription or purchase of the drug if the insured individual has that haplotype. The presence or absence of the haplotype in a patient may be ascertained by using any of the methods described herein.
Information obtained from the methods described herein can also be used to select or stratify subjects for a clinical trial. For example, the presence of a selected haplotype described herein can be used to select a subject for a trial. The information can optionally be correlated with clinical information about the subject, e.g., diagnostic, therapeutic, or endophenotypic information.
Haplotvpes Associated with SZ, Pharmacological Response, and Psychiatric Endophenotvpes
The methods described herein include the analysis of genotypic information for exemplary SNPs described herein as being associated with increased risk of developing SZ, pharmacological response, and having specific psychiatric endophenotypes. The methods can also (or alternatively) include the evaluation of SNPs that are in linkage disequilibrium with the exemplary SNPs (as one of skill in the art will appreciate, those SNPs that are in linkage disequilibrium will provide essentially the same information as the exemplary SNPs). In some embodiments, the methods include the use of SNPs that are in linkage disequilibrium and are within a specified region of the gene. Table B includes exemplary delimiting SNPs and exemplary test SNPs that can be used in capturing significant haplotype variation in these genes. Although exemplary delimiting SNPs are provided, in some embodiments the region can be delimited by one of the other SNPs listed herein, e.g., an exemplary test SNP that is in LD with the primary SNP. In some embodiments, the specific region of the gene is between and excluding the delimiting SNPs; in some embodiments, the specific region is between and including the delimiting SNPs. TABLE B: Delimiting and Exemplary SNPs for Novel SZ Genes
Potassium Channel and Related Genes
Gene CHR Delimiting SNPs Exemplary SNPS
KCNC4 1 rsl359149 to rsl 1578913 rs615204, rs34171476, rs35167146 KCNAlO rsl281177 to rsl7025957 rsl281175, rs34970857, rsl281174, rs3768456
KCND3 rs197422 to rsl0745323 rsl2033257, rs35027371, rs3738298, rsl 1102342, rs4838924, rs4839183, rsl7215423, rs2289723, rs3820673, rsl936061
KCNHl 1 rs12126648 to rsl538287 rs3135473, rsl 135317, rsl770213, rsl770220, rsl 1119627, rsl501569, rsl393026, rsl 1119658, rs4620600, rs4578265, rs867848,
ANK3 10 rsl050745 to rsl551684 rsl049862, rs7911953, rs2393607, rsl2261793, rsl0733757, rs7907721, rs4568956, rs2241540, rs2393596, rsl 1596260, rs3750800, rsl0218875, rs4948254, rs6479694
KCNQl 11 rsl 1022827 to rs2239897 rs2283155, rs6578273, rs34320941, rs4930127, rs2283174, rs45478697, rs45606931, rs45497392, rs231348, rsl7215465, rs760419, rs231899, rs63934, rs45603932, rslO57128, rs81205, rs45594640, rs34516117, rs1800172, rs34150427, rsl 1601907, rs8234
KCNCl 11 rs7949069 to rsl236205 rs2299637, rs4757587, rs757514, rs10766434, rs7942518
Cell Adhesion and Related Genes
Gene CHR Delimiting SNPs Exemplary SNPS
RP1-21O18.1 1 rs9663010 to rs2235789 rs7546786, rs6663699, rsl316257, rs938249, rs6674129, rs2073091, rs2076563, rsl2057431, rs4661572 CTNNDl 11 rs558653 to rs652908 rs2156638, rsl 1570176, rsl0896644, rsl 1570194, rs483030, rsl 1570199, rs612688, rsl 1570222, rs708228
DACTl 14 rs464582 to rs 160472 rsl 67481, rsl 50722, rsl 67481, rs863091, , rs34015825, rsl 7832998, rsl 7094821, rs698025, rsl 1541
CDHIl 16 rs35148 to rs7204464 rs35147, rs35145978, rs35144, rs35229, rs35213, rs4424934, rs35195, rs35186, rsl 520233, rs7188625
Vesicle Related Genes
Gene CHR Delimiting SNPs Exemplary SNPS
VAMP4 rsl0913508 to rs7556644 rsl5655, rsl5655, rsl0913530, rs2073484, rs6672082, rs12096984
SYTU 1 rs9429830 to rsl 1119426 rs227221, rs4844923, rs2205989, rsl 1119392, rs227227, rs2307890, rsl 1119415, rsl7188183, rs4609425
BRSK2 11 rs7395835 to rsl554857 rsl0833086, rs7932863, rs9651643, rs34893167,rsl881504, rsl 1029039, rs3829225, rsl574122
SYT13 11 rs2863172 to rsl 1038382 rs4992029, rs8929, rs2863174, rs4755941, rs7103871, rsl2362429, rs2863182
STX2 12 rs2632601 to rs7962097 rs6486602, rsl236, rs4759517, rs2277336, rs6486600, rs4759794, rs7301926, rs6486602, rsl0848210, rsl0848210
RTNl 14 rsl7255975 to rs7144589 rs7161094, rsl950785, rs4898998, rsl2717467,rs34431036, rs35707243, rs35645652, rs35645652, rs35864480, rsl0145080,rsl7310036
UNC13C 15 rsl 1071015 to rs9920150 rsl7731958, rs2115827, rs2163195, rsl2594549, rsl897069, rsl2910912, rsl2910912,rsll856476,rs4776216, rs7183952, rsl2917364, rsl2914912, rs8035356, rsl 158075, rsl849210, rsl2913366, rs489526, rs8025195, rsl6974691,rs9302181, rsl 1639005, rsl520411, rs9920139
SV2B 15 rsl l630131 to rs7169918 rs2073967, rs35575298, rs8027498, rsl075840, rsl6945475, rs2301665, rs3743444, rsi 117388, rsl 117388, rs 16945529
Genes Related to Glutamate Pathways Gene CHR Delimiting SNPs Exemplary SNPS
Gcoml 15 rsl908202 to rsl808478 rs4774275, rsl908206, rs2470357, rs2069133, ,rsl6977629, rsl6977631, rs986868, rs2733617, rsl6977644, rs2733619, rs2470361, rsl 1854917
GRINLlA 15 rsl908202 to rsl808478 rs4774275, rsl908206, rs2470357, rs2069133, ,rsl6977629, rsl6977631, rs986868, rs2733617, rsl6977644, rs2733619, rs2470361, rsl 1854917
GOT2 16 rs2042445 to rs4238801 rs30839, rs6993, rs30842, rsl 1076256, rs257636, rs257620
G-Protein-Coupled Receptor Genes
Gene CHR Delimiting SNPs Exemplary SNPS
RHOG 11 rsl 055640 to rs4406820 rsl451722, rsl7173879, rslO49388, rsl451719, rsl 1030008
GPR135 14 rsl7255731 to rs4898989 rsl612112, rsl253181, rsl0138199, rs9323348, rsl752427, rsl752428, rsl0136708
AKAP13 15 rsl533124 to rsl 1637212 rsl6977252, rs8024200, rs7180213, rs6497206, rs2291049, rs2061821, U171, rs2061822, rs34434221, rs2061824, rs745191 , rs7177107, rs7177107, rs4075256, rs4075254, rs4843074, rs4843075, rs7162168, rs4842895, rs35079107, rs338523, rs338556, rsl 1073502, rsl 1073502, rs2241268, rs2241268, rslO53992
Delimiting SNPs for Hormone, Inositol, and Diacylglyceride Related Genes Gene CHR Delimiting SNPs Exemplary SNPS
HSDl7Bl2 11 rsl2364003 to rsl 1037691 rs4573669, rsl0838160, rs4755744, rs7129046, rs3802891, rsl 1555762, rsl061810
TMEM55B 14 rsl 130409 to rsl760941 rsl7112002, rsl760943, rs35567022 IGFlR 15 rs35554027 to rs702497 rs8028620, rs7170035, rs7174918, rs8038015, rs4966020, rs4965436, rs8030950, rsl879613, rsl 1247380, rs45445894, rs34516635, rs33958176, , rs33958176, rs45553041, rs2684808, rs3743262, rsl546713, rs2229765, rs2684792, rsl7847203, rs3833015
Cytoskeletal, Myosin, Actin and Microtubulal Related Genes Gene CHR Delimiting SNPs Exemplary SNPS
EVL 14 rsl 190954 to rs35257667 rs748354, rsl 190956, rsl 190974, rs3206354, rs726514, rs941897, rs34073270, rs4905933
KATNAL2 18 rs9304340 to rsl434528 rs2576042, rs2187092, rs2571030, rs2247221, rs7233515, rs9961383, rs2289130
Genes for Carrier Proteins and Transporters Gene CHR Delimiting SNPs Exemplary SNPS
SLC6A17 rs924181 to rs545849 rs877068, rsl010892, rs6689641, rs534276, rs534276, rs6685009, rsl2133992
SLC16Λ4 1 rsl0857820 to rsl2127781 rs2946571, rsl 1120, rs6673423, rs2271885, rs35157487, rs3738750, rsl334882,rs884684
SLC6A5 11 rs894747 to rsl401793 rs2001982, rs2241940, rsl443547, rs7109418, rsl443548, rs34243519, rs894750, rs4923386, rsl6906566, rsl 1827415, rs3740870, rsl805091, rs7944684, rs2298826, rs2276433, rsl6906628, rsl401793
SLC17A6 11 rsl 155821 to rs2593644 rs2246710, rsl 1026523, rs2078352, rsl 1026532, rsl900586, rs764021, rs7117340, rsl979072, rsl979073
SLCO3A1 15 rsl 1858120 to rsl060206 rsl2907294, rs4294800, rs2176452, rsl2912997, rsl878556, rs2286355, rsl517618, rs6496893, rs2074887, rs2302085, rs8174 Cell Cycle and Tumor Suppressor/Promoter Related Genes Gene CHR Delimiting SNPs Exemplary SNPS
RERE 1 rslO55236 to rs914994 rs8627,rsl058766,rsl3596, rs3753275, rs7530745, rsl2136689, rs7532459, rs7554486, rs6698830
FASLG 1 rs763110 to rsl2135884 rs929087, rs6700734, rsl0458360, rs35178418
DEAFl 11 rs936465 to rs6597990 rsl 1822917, rs34114147, rs7109335, rsl0902188, rs6597996, rs34094369, rs7935419, rs7121608, rs4963145
HCCA2 11 rsl2786504 to rs2334652 rs7945160, rs9440, rsl0219175, rs7396514, rs7945160, rslO742185
PTPN5 11 rs873670 to rs7932938 rs7946105, rsl550871, rsl550870, rs6483524, rs4757707, rsl0766500, rs4272766, rs4274187, rs4345940
CHFR 12 rsl531822 to rs3741494 rs3741489, rs3741492, rs2306536, rs2306537, rs9634239, rs2306541, rs4758954, rs35206714, rs34220055, rs2291253, rsl 1147144
TTC5 14 rsl0130942 to rsl0873395 rslO147548, rs3737220, rsl953552, rs3742945, rs34675160, rs2318864
FUSSEL18 18 rs2137289 to rs892583 rs7236105, rsl7785419, rsl0502880, rs2668771
SMAD2 18 rs1792666 to rs2000709 rs7228393, rsl792682, rsl7340985, rsl787176, rsl942158, rsl2457664
SMAD7 18 rs9944944 to rs736839 rsl 1874392, rs8088297,rs34151545, rsl 1874392, rsl873190, rs3736242
SMAD4 18 rs620898 to rsl2456284 rs3764465, rsl2958604, rs2276163, rsl2458752,rs2298617
Genes Involved in Neuronal Development and Plasticity Gene CHR Delimiting SNPs Exemplary SNPS
DNM3 1 rs6701033 to rsl3932 rs965051, rs2206543, rs7554526, rs2093184, rs3736790, rsl0489730, rs3736791, rs3736791, rs4576686, rs4075021, rs4382763, rs34870740, rs9425287, rs2301454, rsl0752946, rs7528296 TOLLIP 11 rs5744038 to rs5743854 rs3750920, rs3168046, rs35365323, rs5744015,rs5743899
DUSP8 11 rs6578504 to rs10734456 rs3740620, rs2008493, rs7934037, rs3740620, rs3740620, rs902224, rs902225
NΛV2 11 rs890136 to rs2246192 rs2278132, rs2042600, rsl0766590, rs7119267, rs6483617, rsl6937196, rs2585788, rsl 1025310, rs7935182, rsl6937251, rsl372989, rsl0833202, rsl 1025335, rsl2284679, rs2707084, rs6483629, rs3802799, rs3802800, rs7125647, rsl442710, rsl867114, rs2028570, rs2289566, rs35891966, rs3802803
LRRC4C 11 rsl 1035693 to rslO128639 rs998447, rs2953310, rsl551833, rs6485187, rsl0837367, rs998447, rs3802787
RTN4RL2 11 rs2729363 to rs2955849 rs2511986, rs3851117 DTX4 11 rsl0896947 to rs544864 rs6591507, rs6591507, rs656163, rs2211912, rs621162, rsl048444, rs3847,rs5029315
ULKl 12 rsl 1246867 to rs7978708 rs3088051, rs9652059, rsl 1616018, rsl2303764, rsl 1609348, rs3088051, rs3088051
NDRG2 14 rsl263871 to rsl243451 rsl0196, rsl243444, rsl243446, rsl243446, rsl243450, rsl0138807
JPH4 14 rsl2897422 to rs222732 rsl 1844366, rsl0149510, rsl0149510,rsl0150089
DAAMl 14 rsl7095965 to rs4127823 rsl7095965, rsl7833769, rsl252989, rsl268579, rs4901909, rsl253005, rs4898983, rslO143918, rsl2147707, rs8022614, rs941884, rsl958180, rs941886, rsl 1626926, rsl0083442
NEDD4 15 rs4424863 to rsl509408 rs3088077, rsl7238461, rs8028559, rs34478706, rsl2232351, rs2303579, rs2303580, rsl912402, rsl6976618, rs2271289, rsl553739, rsl1632974
RGMA 15 rsl2438714 to rs4114 rs2272453, rsl3167, rsl997382, rs2091635,rs6497019 N4BP1 16 rs9937623 to rs9936446 rs3826176, rs 1224, rs 1039342, rs3826176, rsl 120276, rs2354580
NDRG4 16 rs7202037 to rs2280397 rs 13333449, rs2042405, rs2271948, rs2271948, rs42945, rsl 058132
CDH8 16 rs4131634 to rs9302540 rsl 6963768, rsl 6963771, rs4636897, rs9922048, rsl 1862141, rs6498807, rs9939991, rsl369918, rsl978796, rsl 1075445, rsl397131, rs8057338
BEAN 16 rs6499082 to rsl2445633 rsl 1644279, rs34695237, rs4247350 KIAA0513 16 rs 1875246 to rs 1466864 rs7499978, rs3803637, rs4783121, rsl2597135, rsl2446708, rs3794684, rs3751756
DYM 18 rsl288812 to rsl7725481 rs833503, rs357894, rs8096141, rs8092003, rs2276200, rs523373, rs498929, rs35435872, rsl0775493, rsl 943675
DCC 18 rs 17753970 to rs2270954 49311296, rsl 1875475, rsl 145245, rsl465943, rs6508145, rs8089980, rsl3381333, rsl893572, rsl431748, rs2229080, rs950278, rs8096519, rs7506904, rsl 2457407, rs4940251, rs8097413, rs2278339, rsl393331, rs984274, rs984274, rs6508235
BMP7 20 rs6014947 to rs2208404 rsl62316, rslO375, rs3787381, rs230198, rsl93044, rs6025469
TMEPAI 20 rs6025689 to rs6015068 rs6025698, rs427278, rsl3043471, rs4811905
Calcium / Calmodulin Related Genes Gene CHR Delimiting SNPs Exemplary SNPS
CAMTAl rs449250 to rs228651 rsl0864639, rsl2044121, rs6688732, rs6577393, rs7554752, rs6577401, rsl2070592, rs2067995, rs845197, rsl 193219, rsl011124, rs6696544, rsl2751990, rs3737907, rs3737906, rs4908473, rsl417986, rs2071986, rs707455
CACNAlE rs541886 to rs635118 rs553042, rsl7494681, rs506947, rs3856090, rsl99960, rs3766980, rs35606457, rs35737760, rs34488539, rs4652678, rsl99930, rs704326, rs638132
CAMKlG 1 rs 17014820 to rs926387 rs2356933, rs6690557, rs9430004, rs35618105, rsl 1119314, rs 11119315, rs2272879, rs2206107, rs4140599, rs2076230
RIMBP2 12 rsl496858 to rs7963990 rsl 0848094, rs756186, rs749093, rsl 1060869, rs7303240, rs2277356, rs2292663, rs2292664, rs7952756, rs2277361, rs871568, rs4237817, rs4759708
Genes Involved in Hereditary Hearing Loss Gene CHR Delimiting SNPs Exemplary SNPS
DPH3 rs2292614 to rs2245708 rs859703, rs842257, rs2245721, rs2245708
EXOC2 rsl 0900954 to rsl 3205146 rsl 1242914, rsl 2952, rs4072107, rsl473909, rs2493037, rs2064302, rs2277095, rs2493049, rs2294660, rs2294664, rs998777, rs35600069, rsl 7756886, rsl 747599, rs2039713
USHlC 11 rs4756895 to rs2073582 rs2237965, rsl 055577, rsl 055574, rs2072225, rsl 064074, rs34077456, rsl 0832796, rsl 6770, rsl 0766408, rs2240487, rs35336155, rs2041027, rs2237957
OTOG 11 rs2073582 to rsl 1024358 rsl 0766410, rsl 1823045, rs7130190, rsl 1024323, rs7112749, rs7106548, rs4757548, rs2355466, rsl 1024333, rs7936324, rs7936354, rsl 1024335, rs2041028, rsl003490, rs7111528, rsl 1024350, rsl2422210, rsl0832824, rs2023483, rsl 1024357
SERGEF 11 rsl236205 to rsl 133758 rsl0788, rsl528, rs4757589, rs2237930, rs211146, rs2283233, rs211130, rsl72424, rs211137, rs34960078, rs2237908
EMLl 14 rsl0140193 to rs7149272 rslO144785, rs7143905, rsl2433613, rsl 1160553, rs6575751, rs746698, rs7144394, rs2273707, rs34198557, rs2250718, rs2273704, rsl 1160563
PMP22 17 rs230938 to rsl79521 rs231018, rsl3422, rs7215851, rs231021
Genes Encoding Zinc-Finger Proteins
Gene CHR Delimiting SNPs Exemplary SNPS
PRDM2 rs2487657 to rs979932 rsl203682, rsl203677, rs2076324, rsl7350795, rsl203648
ZFP91-CNTF 11 rs 1944055 to rs4319530 rsl938596, rs948562, rs7945889, rs8373, rsl938596, rsl 1229545
ZNF423 16 rsl93907 to rsl2443775 rs729805, rsl344529, rs2287314, rsl 2597210, rsl 6947716, rs34611339, rs34214571, rs34214571, rsl 2924119, rs2292155, rsl0852603, rs8060387
Brain-Expressed Genes Not Otherwise Specified Gene CHR Delimiting SNPs Exemplary SNPS
PER3 rsl72933 to rs707472 rs2797685, rs707463, rs707465, rs35426314, rs228669, rsl7031601, rs10462020, rs35604043, rs35687686, rs35899625, rs228697, rs2640909, rsl0462021
RABGAPlL 1 rs6681627 to rsl2126129 rs6425302, rs6425305, rsl6847624 PHACS 11 rsl78512 to rs2285029 rsl6937817, rs2074038, rs33952257, rs2018795, rsl78521, rs35514614, rs2074043, rs7950395, rsl78529, rs3107275
YPEL4 11 rsl798177 to rsl647394 rs7947357, rs890036, rsl2793139, rs7947357, rsl2294735
KIAA1853 12 rs7979864 to rs722307 rsl568923, rs6490226, rsl405049, rs4766926, rs7134748, rs7969288, rsl0849629, rsl2422371, rs7297606, rs7136574, rs2723880, rs2723882, rs2555269,rsl541764
KIAA1545 12 rsl0870551 to rs7294615 rs36098511, rs7137911, rs2323991, rs4883568, rs4883556, rs3751315, rsl0870472, rs4883513, rsl 1208
TEPl 14 rsl713418 to rsl760890 rs2104978, rs938886, rsl713449, rs34811735,rs35929175, rs35165628, rs7150689, rs34895824, rs2297615, rs35517499, rs938887, rs34401320, rsl713456, rsl713457, rs2229100, rsl 760904, rs2228041, rsl713458, rsl760903, rs34179031, rsl7111188, rs2228035, rs34770935, rsl760898, rsl760897
WDR25 14 rs2273802 to rsl0151709 , rs2273801, , , rs34007610, rs34331240, rs2273800, rs3742387, rs941924, rs4905966, rsl 0873518, rs4905969, rs4905969
BEGAIN 14 rsl 1628965 to rs7140556 rsl 1845025, rsl2893951, rs35286207, rs4073549, rs4074037, rs6575793
HERC2 15 rs7495174 to rsl 614575 rsl 129038, rsl 1074322, rsl 1636232, rsl 133496, rsl 133496, rs4073541, rs2238289, rs3940272, rsl 1631797, rs916977, rsl635168, rsl635163
ADAMlO 15 rs3764196 to rs514049 rs6494032, rsl2592750, rs7166076, rs8039791, rsl2899638, rs7165402, rsl2912286, rs4775086, rs2054096, rs653765
KLHL25 15 rsll637212 to rs7181017 rs2614676, rs2554, rs3743335, rs2430838, rs36031133, rs35582838, rsl 1073537, rs2002909, rs2946365
NETO2 16 rsl551188 to rs7184206 rsl6952126, rsl6952126, rs9923731, rsl 1859615, rs3095622
CBLNl 16 rs3743777 to rs9935379 rsl 1076478, rsl510977, rsl437105 KIAA0182 16 rs4240810 to rs3815795 rs35869664, rs3815794, rs736845, rs2303203, rs9940601, rslO49868
C16orf74 16 rsl 1644122 to rs301143 rs373835, rs2305357, rs386061, rs408988 COXlO 17 rs4792434 to rs7218697 rs2302107, rsl 6948978, rs34342426, rsl 6948986, rs8077302, rs2159132, rs8070339, rs2230354, rsl 1078233
KIAA0427 18 rsl 039989 to rs752151 rs2175565, rs7229395, rs2306514, rs2277712, rs8094634, rsl0853569, rs8095199, rsl038308, rs4939813, rs3764481, rs937021 Additionally, a number of exemplary SNPs in linkage disequilibrium with the SNPs in Table B were evaluated for impact on SZ risk, pharmacological response, and specific psychiatric phenotypes (endophenotypes). These exemplary SNPs in linkage disequilibrium with those in Table B are listed in Table C.
Table C: Exemplary SNPs in Linkage Disequilibrium with Table B SNPs
Gene SNPs in linkage disequilibrium with those in Table B
ADAMlO rs7164844, rs7161889, rs605928 AKAPU rsl2440599, rs2291048, rs2241268, rsl6949988, rs2430838, rs870689, rs2241269, rs2241266, rs8025135, rsl0520596, rsl6941653, rsl7623915, rs745191
ANK3 rsl 1596260, rslO761451, rslO761446, rsl551683, rs2393602, rslO78534, rs1050745
BEAN rsl 1075635, rslO63438
BMP7 rs6123669, rs6127980, rsl62313, rs230191, rs230198
BRSK2 rsl 108991, rsl554857, rs7396009
C16orf74 rs442069, rs394623, rs386061, rsl 1644122
CACNAlE rsl7494681, rsl6857457, rs678643, rs553042, rs7513540, rs3856093, rsl0797729, rs7554158, rsl953690, rs7534913, rs704331, rsl7693196, rs546191
CAMKlG rsl0489339, rs7516885, rs9429821, rs713075, rs7512091, rs6683256 CAMTAl rsl616122, rs277675, rsl7030082, rs845265, rs2097518, rs9919223, rs707463, rs697686, rs2301488, rsl0864255, rs2071918, rs9434833, rs6698901, rs4908575, rs6657847, rsl 1121029, rs4243823
CBLNl rs9935379, rsl2598711, rsl469906, rs893175 CDHIl rs35216, rs35195, rs35186, rs35144, rs40115, rs35140, rs4625747, rs35164, rs35162, rs35165, rs4967886
CDH8 rsl 1075445, rsl397126, rsl3336134, rs9302540, rs9925201, rs7189354, rs4784163, rs6498806, rs4416006, rsl6964164, rsl 1641508, rsl1862752
CHFR rs4758911, rsl 1147101, rs7297261 COXlO rs8077302,rsl003060 CTNNDl rsl786438 DAAMl rs7143953, rslO873113, rs8004164, rsl0483710, rsl271513, rs941886, rs4901909, rsl2590850, rsl958180, rsl547199, rsl2589351, rs4901921, rs2053298, rsl957409, rs6573250, rs2099636, rsl7096088
DACTl rs863091 DCC rsl031062, rs882333, rs4998815, rsl2967277, rs7228674, rs9954344, rs7506909, rs2270954, rs9949949, rsl 1082964, rs2036415, rs8089980, rs9966074, rslO515959, rsl7504520, rsl 1876282, rsl502229, rs4940259, rsl2605899, rsl7506154, rs8088048, rsl6954731, rs7504750, rs9953016, rs9807201, rsl0853622, rslO853621, rsl2455180, rsl0502969
DEAFl rsl0902190, rs936465, rs7123677 DNM3 rs6690848, rs9425606, rs9425598, rs4072117, rsl2410416, rsl2075807, rsl0910966, rs7540873, rslO63412, rs6701929, rs7550558, rs2586389, rs2586392,rsl0158839
DPH3 rs842252, rs842264, rs842261, rs2470508, rs842251, rs842259, rs842254 DTX4 rs2211912, rs3847, rs544864 DUSP8 rsl554857, rs7396009, rsl108991, rsl0734456 DYM rs577979, rs7239949, rs357894, rsl6950298 Table C: Exemplary SNPs in Linkage Disequilibrium with Table B SNPs
Gene SNPs in linkage disequilibrium with those in Table B
EMLl rs8013843, rsl2435250, rs3818279, rs4900447, rsl 1160554, rsl957509, rsl 191109, rsl 1623084, rsl7099031, rsl0150225, rslO131519, rsl005766, rs8020741, rs2250718, rsl2590861, rs975252, rsl 1850280, rs3783322
EVL rsl 190967, rsl0148930, rs2400848, rslO136836, rsl2431406 EXOC2 rsl2154040, rs2073008, rsl 150856, rs9405242, rs2473484, rsl7135931 FASLG rsl0458360 FUSSEL18 rs2164098, rsl 1877471, rs8086549, rs9304344, rs9965170, rsl 1082575, rsl 1663646, rsl7785419, rs7244178
GCOMl rs2470360, rsl873993, rs9302201, rsl425948, rs9806498, rsl6977629, rs7176042, rsl 1638184, rsl 1071337
GPR135 rsl253103, rs2774052, rs4898989, rsl273156, rsl253170 GRINLlA rs2470360, rs9302201, rsl1071337, rs9806498, rs7176042, rsl 1638184, rsl873995, rsl6977629, rsl873993
HCCA2 rs7396009, rsl554857, rsl108991, rsl0734456 HERC2 rs8041209, rs2346050, rs6497292, rs916977, rs6497272 HSDl 7Bl 2 rs7482725, rslO838166, rsl0768983, rsl 1037691, rslO838186, rsl7596617,rsl0838184,rs938942,rs7116641
IGFlR rsl879613, rs4966012, rsll633717, rsl879612, rsl521481, rs7165181, rsl 1634874, rs4966036, rs951715, rs7173377, rs3743258
KATNAL2 rs2010834, rs4986203, rs2571034, rs2576040
KCNAlO rsl281177
KCNCl rs10766426, rs2299637
KCND3 rs584096, rsl373291, rs544941, rsl97412
KCNHl rsl0863854, rsl777264, rsl340127, rsl777256, rsl875438, rs7529770, rs4951495, rsl 1119679, rsl501555, rs7546472
KCNQl rs2283179 KIAAOl 82 rslO53328, rs9940601, rs732460, rs736845 KIAA 0427 rs2337099, rsl2458062, rsl384227, rslO23943, rsl2456253, rs9952398, rs8083702, rsl994559, rs937021
KIAA0513 rs3794682, rs8063083, rs715707 KIAA1545 rs4242909 KIAA1853 rs4298970, rs4767783, rsl541764, rs4075945, rs7966721, rsl568922, rs10851061,rs7298478
KLHL25 rs870689, rsl7623915, rsl0520595, rsl 1637212, rs8025135, rs2241266, rs2430838
LRRC4C rs2953310, rsl0501227, rsl0501225, rsl377106 N4BP1 rs8046716, rs2129243
NA V2 rslO732471, rs2255677, rs2119981, rsl2099330, rs2625312, rsl867116, rsl 1025328, rsl982265, rsl559665, rsl0500860, rs7119267
NDRG2 rsl243446 NDRG4 rslO58132, rsl6960170, rs40359 NEDD4 rsl 1630780, rs4520787, rs9972348, rsl2916104, rsl0518831, rsl509408, rs2175104
NETO2 rs9928466 OTOG rs734640, rs869108, rsl 1024348, rs2237959, rs972676, rsl0766410, rs4757560, rs757982, rs7111528, rsl 1024357
PER3 rs697686, rs707463, rs228688, rs228652
PHACS rs7950395,rs3134907
PMP22 rs231020, rs230915, rsl92046, rs2323653, rsl0852830, rs230911, rsl 1656487 Table C: Exemplary SNPs in Linkage Disequilibrium with Table B SNPs
Gene SNPs in linkage disequilibrium with those in Table B
PTPN5 rs7117716, rs4757718, rs4075664, rs755796, rsl 1024782, rs7950091, rs11024786
RABGAPlL rsl793319,rsl0912854
RERE rs4581300, rs6577499, rsl2024032, rsl0779702
RHOG rs11030008, rs1869002, rs1055640
RIMBP2 rs4759462, rsl877978
RP1-21O18.1 rs761288, rs4501834, rsl000313, rs4661563, rs6665012, rsl0803343
RTNl rsl957311, rsl7731838, rsl884737, rsl2878097, rsl7256003, rsl951366
SERGEF rs4141243, rsl 1024415, rs2299628, rs2283233, rs4757589
SLC16A4 rs3768458
SLC17A6 rsl 562445, rs2078352, rsl 1026546, rs721840
SLC6A17 rsl7671169, rs6689641, rs2784140, rsl571346
SLC6A5 rsl 6906507
SLCOMl rs8027160, rs975721, rsl2905912, rsl 1630872, rs207954, rs8032981
SMAD2 rsl0502890, rsl792670
SMAD4 rs7243135,rsl789223
SMAD7 rs2337153, rsl2953717
STX2 rs10848205, rs7956851
SV2B rsl 117387, rsl002556, rsl1631712, rs6496778, rsl7516708, rs2269799, rslO79535, rs6496780, rs2106692, rsl 1630131, rs2239994
SYT13 rs7943596, rslO75778, rslO77491, rs6485608, rs7118408, rs7124508, rsl2362444, rs4755941, rs7117240
SYTU rs6701631, rs7543650, rsl2029138
TEPl rsl760909, rsl713448, rsl713449, rsl713419
TOLLIP rs2672812,rs2014486
TTC5 rs2318864, rsl 1623837, rs4981148, rs4981951, rs8022565, rs4981948
ULKl rsl0794440
UNC13C rs8023723, rs500853, rs8025195, rs573320, rsl2912762, rs934192, rs7163424, rs8024165, rsl2917023, rsl6974712, rsl2900128, rsl961635, rsl864416, rs2115820, rs8024845, rs2115825, rsl2148800, rsl897069, rs9920150,rsl7731958
USHlC rs4756895, rslO76311, rs2237961, rs2041032, rs972676, rsl064074, rs10766410,rs2237959
VAMP4 rs9943293,rsl0913529 WDR25 rsl 1160589, rs7492607 YPEL4 rsl798173 ZFP91-CNTF rs2509920, rs948562
ZNF423 rs4785185
Identification of Additional Markers by Linkage Disequilibrium Analysis Linkage disequilibrium (LD) is a measure of the degree of association between alleles in a population. One of skill in the art will appreciate that haplotypes involving markers in LD with the polymorphisms described herein can also be used in a similar manner to those described herein. Methods of calculating LD are known in the art (see, e.g., Morton et al., Proc Natl Acad Sci USA 98(9):5217-21 (2001); Tapper et al., Proc Natl Acad Sci USA 102(33):l 1835-11839 (2005); Maniatis et al, Proc Natl Acad Sci USA 99:2228-2233 (2002)).
Thus, in some embodiments, the methods include analysis of polymorphisms that are in LD with a polymorphism described herein. Methods are known in the art for identifying such polymorphisms; for example, the International HapMap Project provides a public database that can be used, see hapmap.org, as well as The International HapMap Consortium, Nature 426:789-796 (2003), and The International HapMap Consortium, Nature 437:1299- 1320 (2005). Generally, it will be desirable to use a HapMap constructed using data from individuals who share ethnicity with the subject, e.g., a HapMap for African Americans would ideally be used to identify markers in LD with an exemplary marker described herein for use in genotyping a subject of African American descent.
Alternatively, methods described herein can include analysis of polymorphisms that show a correlation coefficient (r2) of value > 0.5 with the markers described herein. Results can be obtained, e.g., from on line public resources such as HapMap.org. The correlation coefficient is a measure of LD, and reflects the degree to which alleles at two loci (for example two SNPs) occur together, such that an allele at one SNP position can predict the correlated allele at a second SNP position, in the case where r2 is > 0.
Incorporation of Additional Haplotvpes Associated with SZ, Pharmacological Response, and Psychiatric Endophenotvpes
In some embodiments, the methods described herein can include determining the presence of a haplotype that includes one or more additional polymorphisms associated with SZ, pharmacological response, and psychiatric endophenotypes.
By way of example, numerous studies have implicated various phosphatidylinositol kinases in SZ, including PIP5K2A (Bakker et al., Genes Brain Behav. 6:113-119 (2007)) and PBK via interaction with AKT (Kalkman, Pharmacol. Ther. 110:117- 134 (2006)). The use of variants in the PI4K2B gene in SZ diagnosis and pharmacogenomics has been described, see, e.g., International Patent Application No. PCT/US2007/078399. Additionally, insulin and diacylglycerol interact with the inositol pathways. As described herein, combining such findings with protein-protein interaction data, pathway analyses, and the large literature on genetic linkage studies for neuropsychiatric illnesses, has allowed the present inventors to identify a number of inositol, insulin and diacylglycerol genes that can be used for SZ risk assessment, diagnosis and pharmacogenomics. As a second example, potassium channels and potassium current signaling molecules interact with many pathways including dopamine signaling pathways (Canavier et al., J. Neurophysiol. 98:3006-3022 (2007)). The potassium channel gene KCNIP4 has been implicated in schizophrenia risk, see, e.g., International Patent Application No. PCT/US2007/078399. Other groups have reported the possible involvement ofKCNN3 polymorphisms in SZ (Ivkovic et al., Int. J. Neurosci. 116: 157-164 (2006). As described herein, several additional potassium channel genes, as well as genes that produce proteins that interact with potassium pathways, have been identified that are predicted to play a role in SZ risk and/or drug response.
In some embodiments, the methods described herein can include determining the presence of a haplotype that includes one or more polymorphisms near D22S526 and/or the polymorphisms in the Sult4al gene and/or polymorphisms within 1 LDU of these markers, e.g., as described in U.S. Pat. Pub. No. 2006-0177851, incorporated herein in its entirety.
In some embodiments, the methods described herein can include determining the presence of a haplotype that includes one or more polymorphisms in the PI4K2B gene and/or polymorphisms in the KCNIP4 gene and/or polymorphisms in the CERK gene and/or polymorphisms in the SHANK3 gene and/or polymorphisms within 1 LDU of these markers, e.g., as described in International Pat. Application No. PCT/US2007/078399 and US Pat. Pub. No. 2009-0012371, incorporated herein in its entirety.
In some embodiments, the methods described herein can include determining the presence of a haplotype that includes one or more polymorphisms in the HPCALl gene and/or the polymorphisms in the SV2C gene and/or polymorphisms in linkage disequilibrium with these markers, e.g., as described in International Pat. Application No. PCT/US2008/088061, incorporated herein in its entirety.
In some embodiments, the methods include determining the presence of a haplotype that includes one or more polymorphisms in the novel SZ-spectrum genes and/or the polymorphisms in linkage disequilibrium with specific markers in these genes, e.g., as described in PCT/US2009/030057, incorporated herein in its entirety.
Identification of Additional Markers for Use in the Methods Described Herein
In general, genetic markers can be identified using any of a number of methods well known in the art. For example, numerous polymorphisms in the regions described herein are known to exist and are available in public databases, which can be searched using methods and algorithms known in the art. Alternately, polymorphisms can be identified by sequencing either genomic DNA or cDNA in the region in which it is desired to find a polymorphism. According to one approach, primers are designed to amplify such a region, and DNA from a subject is obtained and amplified. The DNA is sequenced, and the sequence (referred to as a "subject sequence" or "test sequence") is compared with a reference sequence, which can represent the "normal" or "wild type" sequence, or the "affected" sequence. In some embodiments, a reference sequence can be from, for example, the human draft genome sequence, publicly available in various databases, or a sequence deposited in a database such as GenBank. In some embodiments, the reference sequence is a composite of ethnically diverse individuals.
In general, if sequencing reveals a difference between the sequenced region and the reference sequence, a polymorphism has been identified. The fact that a difference in nucleotide sequence is identified at a particular site that determines that a polymorphism exists at that site. In most instances, particularly in the case of SNPs, only two polymorphic variants will exist at any location. However, in the case of SNPs, up to four variants may exist since there are four naturally occurring nucleotides in DNA. Other polymorphisms, such as insertions and deletions, may have more than four alleles.
Other Genetic Markers of Schizophrenia
The methods described herein can also include determining the presence or absence of other markers known or suspected to be associated with SZ, or with SD, or SPD, e.g., markers outside of a region identified herein, see, e.g., Harrison and Owen, Lancet, 361(9355):417-419 (2003), including, for example, markers on chromosome 22 and other chromosomes, e.g., in the region of 22ql2.3 (e.g., near D22S283), 22qll.2, 22qll.2, 22ql l- ql3, Iq42.1, Iq42.1, Iq21-q22, 2p, 2q, 3p25, 4p, 4q, 5qll.2-ql3.3, 6p22.3, 6p23, 6ql3-q26, 7q, 8pl2-21, 8q, 9p, 10pl5-pl3 (e.g., near D10S189), 10q22.3, Ilql4-q21, 12q24, 13q34, 13q32, 14q32.3, 15ql5, 16p, 17q , 18p, 18q, 19p. 2Op, 2 Iq, Xq, and/or the X/Y pseudoautosomal region. In some embodiments, the methods include determining the presence or absence of one or more other markers that are or may be associated with SZ, or with SZ, SD or SPD, e.g., in one or more genes, e.g., ACE (IHi et al, Eur Neuropsychopharmacol 13:147-151 (2003));ADRAl A (Clark et al., Biol Psychiatry. 58(6):435-9 (2005)); ADHlB (Xu et al., MoI Psychiatry. 9(5):510-21 (2004); Vawter et al., Hum Genet. 119(5):558-70 (2006)); AHIl (Eur J Hum Genet. 14(10): 1111-9 (2006)); AKTl (Emamian et al., Nature Genet. 36:131-137 (2004)); ALDH3B1 (Sun et al. Sci. China C. Life. Sci. 48(3):263-9 (2005)); ALK (Kunagi et al., J Neural Transm. 113(10): 1569-73 (2006)); APC (Cui et al, MoI Psychiatry (7):669-77 (2005)); APOE (Liu et al, Schizophr Res 62: 225-230 (2003)); ARSA (Marcao et al., MoI Genet Metab. 79(4):305-7 (2003); ARVCF (Chen et al., Schizophr Res. 72(2-3):275-7 (2005)); ATXNl (Pujana et al Hum Genet 99:772- 775 (1997); Joo et al., Psychiatr Genet 9:7-11 (1999); Fallin et al., Am J Hum Genet 77:918- 936 (2005)); BDNF (Neves-Pereira et al., Molec. Psychiat. 10:208-212 (2005)); BRDl (Severinsen et al., MoI Psychiatry. 11(12): 1126-38 (2006)); BZRP (Kurumaji et al., J Neural Transm. 107(4):491-500 (2000)); DAO (Owen et al., Trends Genet. 21(9):518-25 (2005)); DAOA (Owen et al., 2005, supra); CAPON (Brzustowicz et al., Am J Hum Genet. 74(5): 1057-63 (2004)); CCKAR (Zhang et al., MoI Psychiatry 5:239-240 (2000); Sanjuan et al., Eur Psychiatry 19:349-353 (2004)); CHGB (Kitao et al., Psychiatr Genet 10:139-143 (2000); Zhang et al., Neurosci Lett 323:229-233 (2002)); CHI3L1 (Zhao et al., Am J Hum Genet. 80(1): 12-8 (2007)); CHRNA2 (Blaveri et al., Europ. J. Hum. Genet. 9: 469-472 (2001)); CHRNA7 (Leonard et al. Arch Gen Psychiatry. 2002 59:1085-1096 (2002); De Luca et al. Neuropsychobiology. 50:124-127 (2004)); CLDN5 (Sun et al., Eur Psychiatry 19:354- 357 (2004); Wei and Hemmings, Prostaglandins Leukot Essent Fatty Acids 73(6)4:41-445 (2005)); COMT (Shifman et al., Am. J. Hum. Genet. 71 :1296-1302 (2002)); CNRl (Ujike et al., MoI Psychiatry 7:515-518 (2002)); CPLX2 (Lee et al., Behav Brain Funct. 1 :15 (2005)); DGCR8 (Jacquet et al., Hum MoI Genet. ll(19):2243-9 (2002)); DISCI (Owen et al., 2005, supra; see, e.g., the D1S2709 marker (Ekelend et al., Hum. Molec. Genet. 10:1611-1617 (2001), DDRl (Roig et al., MoI Psychiatry. 12(9); 833-41 (2007); DRD4 (Lung et al., Schizophr Res 57:239-245 (2002)); DDR3 (Williams et al., MoI Psychiatry 3:141-149 (1998)); DRD5 (Williams et al., Psychiatr Genet 7:83-85 (1997); Muir et al., Am J Med Genet 105:152-158 (2001)); HEP3 haplotype, Hennah et al., Hum. Molec. Genet. 12: 3151- 3159 (2003), and Leu607Pro, Hodgkinson et al., Am. J. Hum. Genet. 75:862-872 (2004), Erratum: Am. J. Hum. Genet. 76:196 (2005)); DISC2 (Millar et al., Ann Med. 36(5):367-78 (2004)); DPYSL2 (Hong et al., Am J Med Genet B Neuropsychiatr Genet. 136(1):8-11 (2005)); DRDl (Coon et al., Am. J. Hum. Genet. 52: 327-334 (1993)); DRD2 (Glatt et al., Am. J. Psychiat. 160:469-476 (2003)); DRD3 (Rybakowski et al., Molec. Psychiat. 6:718-724 (2001)); DTNBPl (Owen et al., 2005, supra); EGR3 (Yamada et al., Proc Natl Acad Sci 104(8):2815-20 (2007)); EPSIN4 (Am J Hum Genet. 76(5):902-7 (2005)); ErbB; EGF (Futamura et al., Am. J. Hum. Genet. 52: 327-334 (2002)); ENTH (Pimm et al., Am J Hum Genet 76:902-907 (2005); Tang et al., MoI Psychiatry 11 :395-399 (2006)); ERBB4 (Norton et al., Am J Med Genet B Neuropsychiatr Genet 14;ll;96-101 (2005); Silberberg et al., Am J Med Genet B Neuropsychiatr Genet 141B;2;142-148 (2006)); FEZl (Yamada et al., Biol Psychiatry 56:683-690(2004)); FOXP2 (Sanjuan et al, Psychiatr Genet. 16(2):67-72 (2006)); FXYD6 (Choudhury et al., Am J Hum Genet. 80(4):664-72 (2007)); FZD3 (Katsu et al., Neurosci Lett 353:53-56 (2003); Yang et al., Biol Psychiatry 54:1298-1301 (2003); Zhang et al., Am J Med Genet 129B:16-19 (2004)); GABRAl, GABRA2, GABRA6, GABRP (Petryshen et al., MoI Psychiatry. 10(12): 1057 (2005)); GABBRl (Zai et al. Eur Neuropsychopharmacol. 15:347-52 (2005); Le-Niculescu et al. Am J Med Genet B Neuropsychiatr Genet. 144:129-58 (2007)); GADl (Addington et al., MoI Psychiatry 10:581- 588(2005)); GFRAl (Semba et al., Brain Res MoI Brain Res. 124(l):88-95 (2004)); GCLM (Tosic et al., Am J Hum Genet. 79(3):586-92 (2006)); GNB3 (Kunugi et al., J. Neural Transm. 109(2):213-8 (2002)); GPR78 (Underwood et al., MoI Psychiatry. l l(4):384-94 (2006)); GRIAl (Magri et al., Am J Med Genet B Neuropsychiatr Genet 141(3):287-93 (2006)); GNPAT ( Lin et al., Biol Psychiatry. 60(6):554-62 (2006)); GRIDl (Fallin et al., Am J Hum Genet 77:918-936(2005)); GRIKl (Shibata et al., Psychiatr Genet. l l(3):139-44 (2001)); GRIK2 (Shibata et al., Psychiatry Res. 113(l-2):59-67 (2002)); GRIK3 (Shibata et al., Psychiatry Res. 30: 141(1): 39-51 (2006)); GRIK4 (Pikard et al., MoI Psychiatry ll(9):847-57(2006)); GRINl (Qin et al., Eur J Hum Genet. 13(7):807-14 (2005)); GRIN2A, GRIN2B (Abdolmaleky et al., Am J Pharmacogenomics. 5(3): 149-60 (2005)); GRIN2D (Makino et al., Psychiatr Genet. 15(3):215-21 (2005)); GRM3 (Egan et al., Proc Natl Acad Sci U S A. 101(34): 12604-9 (2004)); GRM4 (Ohtsuki et al., Psychiatr Genet. ll(2):79-83 (2001)); GRM5 (Devon et al., MoI Psychiatry. 6(3):311-4 (2001)); GSTMl (Harada et al., Biochem Biophys Res Commun 281 :267-271 (2001); Pae et al., Psychiatr Genet 14:147-150 (2004)); G30/G72 (Schulze et al., Am J Psychiatry. 162(11):2101-8 (2005)); HTR2A (Baritaki et al., Eur J Hum Genet. 12(7):535-41 (2004)); HLA-DRBl (Schwab et al., Am J Med Genet. 114(3):315-20 (2002)); HLA-BRB3 (Yu et al., Zhonghua Liu Xing Bing Xue Za Zhi. 24(9):815-8 (2003)); HTR5 A (Abdolmaleky et al., Schizophr Res 67:53-62 (2004)); HTR6 (Tsai et al., Neurosci Lett. 271(2): 135-7 (1999)); ILlB (Katila et al., MoI Psychiatry 4:179-181(1999); Meisenzahal et al., Am J Psychiatry 158:1316-1319 (2001); Zanardini et al., J Psychiatr Res 37:457-462 (2003)); ILlRN (Zanardini et al., J Psychiatr Res 37:457-462 (2003); Kim et al., Psychiatr Genet 14:165-167 (2004); Papiol et al., Neuroimage 27:1002- 1006 (2005)); ILlO (Chiavetto et al., Biol Psychiatry 51 :480-484 (2002); Jun et al., Psychiatry Clin Neurosci 56:177-180 (2002)); IL2RB (Schwab et al., Am J Med Genet. 60(5):436-43 (1995)); KCNN3 (Ujike et al., Psychiatry Res. 101(3):203-7 (2001)); KIF13A (Jamain et al., Genomics. 74(l):36-44 (2001)); KIF2A (Li et al., Neurosci Letters 407(2) 151- 5 (2006)); KPNA3 (Wei and Hemmings, Neurosci Res. 52(4):342-6 (2005)); LGIl (Fallin et al. A J Hum Genet. 77:918-36 (2005)); MAG (Wan et al, Neurosci Lett. 388(3): 126-31 (2005)); MAOA (Jonsson et al., Schizophr Res 61 :31-37 (2003); Wei and Hemmings. Psychiatr Genet 9, 177-181 (1999)); MED12 (Sandhu et al., Am J Med Genet B Neuropsychiatr Genet. 123B: 33-38 (2003); Spinks et al., Am J Med Genet B Neuropsychiatr Genet. 127B:20-27 (2004)); MLCl (Verma et al., Biol Psychiatry. 58(1): 16-22 (2005)); MTHFR (Lewis et al., Am. J. Med. Genet. (Neuropsychiat. Genet.) 135B:2-4 (2005)); MTR (Kempisty et al., Psychiatr Genet. 17(3):177-81 (2007)); MTHFDl (Kempisty et al., Psychiatr Genet. 17(3):177-81 (2007)); NCAMl (Sullivan et al., Biol Psychiatry. 61(7):902- 10 (2007)); NDEl (Hennah et al., Hum MoI Genet. 16(5):453-62 (2006)); NDUFV2 (Waskizuka et al., Am J Med Genet B Neuropsychiatr Genet. 141(3):301-4 (2006)); NOSl (Liou et al., Schizophr Res. 65(l):57-9 (2003)); NOTCH4 (Wei and Hemmings, (Letter) Nature Genet. 25:376-377 (2000)); NPAS3 (Kamnasaran et al., J Med Genet 40:325-332 (2003)); NRGl (Owen et al., 2005, supra); NRG3 (Fallin et al. A J Hum Genet. 77:918-36 (2005)); NTNGl (Fukawasa et al., J Med Dent Sci 51 :121-128 (2004); Aoki-Suzuki et al., Biol Psychiatry 57:382-393 (2005)); NTNG2 (Aoki-Suzuki et al., Biol Psychiatry 57:382-393 (2005)); NTF3 (Jonsson et al., Acta Psychiatr Scand 95:414-419 (1997)); OLIG2 (Georgieva et al., Proc Natl Acad Sci 103(33): 12469-74 (2006)); PCQAP (Sandhu et al., Psychiatr Genet. 14(3):169-72 (2004)); PDE4B (Millar et al., Science 310:1187-1191 (2005)); PDLIM5 (Horiuchi et al., Biol Psychiatry 59(5):434-9 (2005)); PICKl (Hong et al., Neuroreport 15:1965-1967 (2004); Fujii et al., Molecular Psychiatry 11 :150-157 (2005)); PIK3C3 ( Stopkova et al., Biol Psychiatry 55:981-988 (2004); Duan et al., Neurosci Lett.,379:32-36 (2005)); PIK4CA (Saito et al., Am J Med Genet B Neuropsychiatr Genet. 116(l):77-83 (2003)); PIP5K2A (Stopkova et al., Psychiatr Genet.l5(3): 223-7 (2005)); PLA2G4A, PLA2G4C (Yu et al., Prostaglandins Leukot Essent Fatty Acids. 73(5):351-4 (2005)); PLA2G4B (Tao et al., Am J Med Genet B Neuropsychiatr Genet 137:56-58 (2005)); PLXNA2 (Mah et al., Molecular Psychiatry 11 :471-478 (2006)); PTGS2 ( Wei and Hemmings. Prostaglandins Leukot Essent Fatty Acids 70:413-415 (2004)); PPP3CC (Gerber et al., Proc Natl Acad Sci U S A. 100(15):8993-8 (2003)); PNOC (Blaveri et al., 2001); PRODH (Chakravarti, Proc. Nat. Acad. Sci. 99:4755-4756 (2002)); QKI (Aberg et al., Am J Med Genet B Neuropsychiatr Genet. 2005 Dec 9; [Epub ahead of print]); RGS4 (Chowdari et al., Hum. Molec. Genet. 11 :1373-1380 (2002), Erratum: Hum. Molec. Genet. 12:1781 (2003)); RELN (Costa et al., MoI Interv. 2(l):47-57 (2002)); RTN4 (Novak et al., Brain Res MoI Brain Res 107:183-189 (2002); Tan et al., Brain Res MoI Brain Res 139:212-216 (2005)); SCAl (Culkjovic et al., Am J Med Genet. 96(6):884-7 (2000)); SLC15A1 (Maheshwari et al, BMC Genomics. 3(l):30 (2002)); SLC18A1 (BIy, Schizophr Res. 78(2- 3):337-8 (2005)); SLC18A2 (Gutierrez et al. Am J Med Genet B Neuropsychiatr Genet. 144(4):502-7 (2007)); SLC6A4 (Fan and Sklar, MoI Psychiatry. 10(10):928-38, 891 (2005)); SNAP29 (Saito et al., MoI Psychiatry 6(2): 193-201 (2001); Erratum in: MoI Psychiatry 6(5):605 (2001); SULT4A1 (Brennan and Chondra. Am J Med Genet B Neuropsychiatr Genet. 139(l):69-72 (2005)); SYNGRl (Verma et al., Biol Psychiatry. 55(2): 196-9 (2004)); SYN2 (Chen et al., Bio. Psychiat. 56:177-181 (2004)); SYN3 (Porton et al. Biol Psychiatry. 55(2): 118-25 (2004)); TAAR4 (Duan et al., Am J Hum Genet 75:624-638 (2004));TBP/SCA17 (Chen et al., Schizophr Res. 78(2-3): 131-6 (2005)); TH (Kurumaji et al., J Neural Transm 108:489-495 (2001); Meloni et al., C R Acad Sci III 318:803-809 (1995)); TNFA (Morar et al, Am J Med Genet B Neuropsychiatr Genet. 144(3):318-24 (2007)); TPHl ( Nolan et al., Psychiatr Genet 10:109-115 (2000); Hong et al., Schizophr Res 49:59-63 (2001); Sekizawa et al., Am J Med Genet B Neuropsychiatr Genet 128:24-26 (2004)); TPP2 (Fallin et al. A J Hum Genet. 77:918-36 (2005)); TPS3 (Park et al., Schizophr Res 67:71-74 (2004); Ni et al., Neurosci Lett 388:173-178 (2005)); TRAR4 (Am J Hum Genet. 75(4):624- 38 (2004)); TRAX (Thomson et al., MoI Psychiatry. 10(7):657-68, 616 (2005)); UFDlL (De Luca et al., Am J Med Genet. 105(6):529-33 (2001)); UCP2 (Yasuno et al., Am J Med Genet B Neuropsychiatr Genet. 144(2):250-3 (2007)); UCP4 (Yasuno et al., : Am J Med Genet B Neuropsychiatr Genet. 144(2):250-3 (2007)); UHMKl (Puri et al., Biol Psychiatry 61(7):873- 9 (2007)); XBPl (Chen et al., Biochem Biophys Res Commun 319:866-870 (2004); Kakiuchi et al., Psychiatry Clin Neurosci 58:438-440 (2004)); YWHAH (Toyooka et al., Am J Med Genet. 88(2): 164-7 (1999)); ZDHHC8 (Mukai et al., Nature Genet. 36:725-731 (2004)); or ZNF74 (Takase et al., Schizophr Res. 52(3): 161-5 (2001)). See also, e.g., OMIM entry no. 181500 (SCZD).
Methods of Determining the Presence or Absence of a Haplotype Associated with SZ, Pharmacological Response, and Psychiatric Endophenotypes
The methods described herein include determining the presence or absence of haplotypes associated with SZ, pharmacological response, and psychiatric endophenotypes. In some embodiments, an association with SZ is determined by the presence of a shared haplotype between the subject and an affected reference individual, e.g., a first or second- degree relation of the subject, or population of affected individuals, and the absence of the haplotype in an unaffected reference individual. In some embodiments, an association with a pharmacological response is determined by the presence of a shared haplotype between the subject and a reference individual (or population) who had an identified response to a pharmacological treatment. In some embodiments, an association with a specific psychiatric endophenotype is determined by the presence of a shared haplotype between the subject and a reference subject or population with (or without) the specific endophenotype. Thus the methods can also include obtaining and analyzing a sample from a suitable reference individual.
Samples that are suitable for use in the methods described herein contain genetic material, e.g., genomic DNA (gDNA). Non-limiting examples of sources of samples include urine, blood, and tissue. The sample itself will typically consist of nucleated cells (e.g., blood or buccal cells), tissue, etc., removed from the subject. The subject can be an adult, child, fetus, or embryo. In some embodiments, the sample is obtained prenatally, either from a fetus or embryo or from the mother (e.g., from fetal or embryonic cells in the maternal circulation). Methods and reagents are known in the art for obtaining, processing, and analyzing samples. In some embodiments, the sample is obtained with the assistance of a health care provider, e.g., to draw blood. In some embodiments, the sample is obtained without the assistance of a health care provider, e.g., where the sample is obtained non- invasively, such as a sample comprising buccal cells that is obtained using a buccal swab or brush, or a mouthwash sample.
The sample may be further processed before the detecting step. For example, DNA in a cell or tissue sample can be separated from other components of the sample. The sample can be concentrated and/or purified to isolate DNA. Cells can be harvested from a biological sample using standard techniques known in the art. For example, cells can be harvested by centrifuging a cell sample and resuspending the pelleted cells. The cells can be resuspended in a buffered solution such as phosphate -buffered saline (PBS). After centrifuging the cell suspension to obtain a cell pellet, the cells can be lysed to extract DNA, e.g., gDNA. See, e.g., Ausubel et al, 2003, supra. All samples obtained from a subject, including those subjected to any sort of further processing, are considered to be obtained from the subject.
The absence or presence of a haplotype associated with SZ, pharmacological response, and/or psychiatric endophenotypes, as described herein can be determined using methods known in the art, e.g., gel electrophoresis, capillary electrophoresis, size exclusion chromatography, sequencing, and/or arrays to detect the presence or absence of the marker(s) of the haplotype. Amplification of nucleic acids, where desirable, can be accomplished using methods known in the art, e.g., PCR. Methods of nucleic acid analysis to detect polymorphisms and/or polymorphic variants include, e.g., microarray analysis. Hybridization methods, such as Southern analysis, Northern analysis, or in situ hybridizations, can also be used (see Current Protocols in Molecular Biology, Ausubel, F. et al, eds., John Wiley & Sons 2003). To detect microdeletions, fluorescence in situ hybridization (FISH) using DNA probes that are directed to a putatively deleted region in a chromosome can be used. For example, probes that detect all or a part of a microsatellite marker can be used to detect microdeletions in the region that contains that marker.
Other methods include direct manual sequencing (Church and Gilbert, Proc. Natl. Acad. Sci. USA 81 :1991-1995 (1988); Sanger et al., Proc. Natl. Acad. Sci. 74:5463-5467 (1977); Beavis et al. U.S. Pat. No. 5,288,644); automated fluorescent sequencing; single- stranded conformation polymorphism assays (SSCP); clamped denaturing gel electrophoresis (CDGE); two-dimensional gel electrophoresis (2DGE or TDGE); conformational sensitive gel electrophoresis (CSGE); denaturing gradient gel electrophoresis (DGGE) (Sheffield et al., Proc. Natl. Acad. Sci. USA 86:232-236 (1989)), mobility shift analysis (Orita et al., Proc. Natl. Acad. Sci. USA 86:2766-2770 (1989)), restriction enzyme analysis (Flavell et al., Cell 15:25 (1978); Geever et al., Proc. Natl. Acad. Sci. USA 78:5081 (1981)); quantitative realtime PCR (Raca et al., Genet Test 8(4):387-94 (2004)); heteroduplex analysis; chemical mismatch cleavage (CMC) (Cotton et al., Proc. Natl. Acad. Sci. USA 85:4397-4401 (1985)); RNase protection assays (Myers et al., Science 230:1242 (1985)); use of polypeptides that recognize nucleotide mismatches, e.g., E. coli mutS protein; allele-specifϊc PCR, for example. See, e.g., U.S. Patent Publication No. 2004/0014095, to Gerber et al., which is incorporated herein by reference in its entirety. In some embodiments, the methods described herein include determining the sequence of the entire region of the genes listed in Tables A and B e.g. between and including the delimiting SNPs for the particular gene. In some embodiments, the sequence is determined on both strands of DNA.
In order to detect polymorphisms and/or polymorphic variants, it will frequently be desirable to amplify a portion of genomic DNA (gDNA) encompassing the polymorphic site. Such regions can be amplified and isolated by PCR using oligonucleotide primers designed based on genomic and/or cDNA sequences that flank the site. See e.g., PCR Primer: A Laboratory Manual, Dieffenbach and Dveksler, (Eds.); McPherson et al., PCR Basics: From Background to Bench (Springer Verlag, 2000); Mattila et al., Nucleic Acids Res., 19:4967 (1991); Eckert et al., PCR Methods and Applications, 1 :17 (1991); PCR (eds. McPherson et al., IRL Press, Oxford); and U.S. Pat. No. 4,683,202. Other amplification methods that may be employed include the ligase chain reaction (LCR) (Wu and Wallace, Genomics, 4:560 (1989), Landegren et al, Science, 241 :1077 (1988), transcription amplification (Kwoh et al, Proc. Natl. Acad. Sci. USA, 86:1173 (1989)), self-sustained sequence replication (Guatelli et al., Proc. Nat. Acad. Sci. USA, 87:1874 (1990)), and nucleic acid based sequence amplification (NASBA). Guidelines for selecting primers for PCR amplification are well known in the art. See, e.g., McPherson et al., PCR Basics: From Background to Bench, Springer- Verlag, 2000. A variety of computer programs for designing primers are available, e.g., 'Oligo' (National Biosciences, Inc, Plymouth Minn.), MacVector (Kodak/IBI), and the GCG suite of sequence analysis programs (Genetics Computer Group, Madison, Wis. 53711).
In one example, a sample (e.g., a sample comprising genomic DNA), is obtained from a subject. The DNA in the sample is then examined to determine a haplotype as described herein. The haplotype can be determined by any method described herein, e.g., by sequencing or by hybridization of the gene in the genomic DNA, RNA, or cDNA to a nucleic acid probe, e.g., a DNA probe (which includes cDNA and oligonucleotide probes) or an RNA probe. The nucleic acid probe can be designed to specifically or preferentially hybridize with a particular polymorphic variant.
In some embodiments, a peptide nucleic acid (PNA) probe can be used instead of a nucleic acid probe in the hybridization methods described above. PNA is a DNA mimetic with a peptide-like, inorganic backbone, e.g., N-(2-aminoethyl)glycine units, with an organic base (A, G, C, T or U) attached to the glycine nitrogen via a methylene carbonyl linker (see, e.g., Nielsen et al., Bioconjugate Chemistry, The American Chemical Society, 5:1 (1994)). The PNA probe can be designed to specifically hybridize to a nucleic acid comprising a polymorphic variant conferring susceptibility to or indicative of the presence of SZ.
In some embodiments, restriction digest analysis can be used to detect the existence of a polymorphic variant of a polymorphism, if alternate polymorphic variants of the polymorphism result in the creation or elimination of a restriction site. A sample containing genomic DNA is obtained from the individual. Polymerase chain reaction (PCR) can be used to amplify a region comprising the polymorphic site, and restriction fragment length polymorphism analysis is conducted (see Ausubel et al., Current Protocols in Molecular Biology, supra). The digestion pattern of the relevant DNA fragment indicates the presence or absence of a particular polymorphic variant of the polymorphism and is therefore indicative of the presence or absence of susceptibility to SZ.
Sequence analysis can also be used to detect specific polymorphic variants. A sample comprising DNA or RNA is obtained from the subject. PCR or other appropriate methods can be used to amplify a portion encompassing the polymorphic site, if desired. The sequence is then ascertained, using any standard method, and the presence of a polymorphic variant is determined.
Allele-specifϊc oligonucleotides can also be used to detect the presence of a polymorphic variant, e.g., through the use of dot-blot hybridization of amplified oligonucleotides with allele-specific oligonucleotide (ASO) probes (see, for example, Saiki et al, Nature (London) 324:163-166 (1986)). An "allele-specifϊc oligonucleotide" (also referred to herein as an "allele-specifϊc oligonucleotide probe") is typically an oligonucleotide of approximately 10-50 base pairs, preferably approximately 15-30 base pairs, that specifically hybridizes to a nucleic acid region that contains a polymorphism. An allele-specifϊc oligonucleotide probe that is specific for particular a polymorphism can be prepared using standard methods (see Ausubel et al., Current Protocols in Molecular Biology, supra).
Generally, to determine which of multiple polymorphic variants is present in a subject, a sample comprising DNA is obtained from the individual. PCR can be used to amplify a portion encompassing the polymorphic site. DNA containing the amplified portion may be dot-blotted, using standard methods (see Ausubel et al., Current Protocols in Molecular Biology, supra), and the blot contacted with the oligonucleotide probe. The presence of specific hybridization of the probe to the DNA is then detected. Specific hybridization of an allele-specifϊc oligonucleotide probe (specific for a polymorphic variant indicative of susceptibility to SZ) to DNA from the subject is indicative of susceptibility to SZ.
In some embodiments, fluorescence polarization template-directed dye-terminator incorporation (FP-TDI) is used to determine which of multiple polymorphic variants of a polymorphism is present in a subject (Chen et al., (1999) Genome Research, 9(5):492-498). Rather than involving use of allele-specifϊc probes or primers, this method employs primers that terminate adjacent to a polymorphic site, so that extension of the primer by a single nucleotide results in incorporation of a nucleotide complementary to the polymorphic variant at the polymorphic site.
Real-time pyrophosphate DNA sequencing is yet another approach to detection of polymorphisms and polymorphic variants (Alderborn et al., (2000) Genome Research, 10(8): 1249-1258). Additional methods include, for example, PCR amplification in combination with denaturing high performance liquid chromatography (dHPLC) (Underhill, P. A., et al., Genome Research, Vol. 7, No. 10, pp. 996-1005, 1997). The methods can include determining the genotype of a subject with respect to both copies of the polymorphic site present in the genome. For example, the complete genotype may be characterized as -/-, as -/+, or as +/+, where a minus sign indicates the presence of the reference or wild type sequence at the polymorphic site, and the plus sign indicates the presence of a polymorphic variant other than the reference sequence. If multiple polymorphic variants exist at a site, this can be appropriately indicated by specifying which ones are present in the subject. Any of the detection means described herein can be used to determine the genotype of a subject with respect to one or both copies of the polymorphism present in the subject's genome.
In some embodiments, it is desirable to employ methods that can detect the presence of multiple polymorphisms (e.g., polymorphic variants at a plurality of polymorphic sites) in parallel or substantially simultaneously. Oligonucleotide arrays represent one suitable means for doing so. Other methods, including methods in which reactions (e.g., amplification, hybridization) are performed in individual vessels, e.g., within individual wells of a multi- well plate or other vessel may also be performed so as to detect the presence of multiple polymorphic variants (e.g., polymorphic variants at a plurality of polymorphic sites) in parallel or substantially simultaneously according to certain embodiments of the invention.
Probes
Nucleic acid probes can be used to detect and/or quantify the presence of a particular target nucleic acid sequence within a sample of nucleic acid sequences, e.g., as hybridization probes, or to amplify a particular target sequence within a sample, e.g., as a primer. Probes have a complimentary nucleic acid sequence that selectively hybridizes to the target nucleic acid sequence. In order for a probe to hybridize to a target sequence, the hybridization probe must have sufficient identity with the target sequence, i.e., at least 70%, e.g., 80%, 90%, 95%, 98% or more identity to the target sequence. The probe sequence must also be sufficiently long so that the probe exhibits selectivity for the target sequence over non-target sequences. For example, the probe will be at least 20, e.g., 25, 30, 35, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900 or more, nucleotides in length. In some embodiments, the probes are not more than 30, 50, 100, 200, 300, 500, 750, or 1000 nucleotides in length. Probes are typically about 20 to about I X lO6 nucleotides in length. Probes include primers, which generally refers to a single-stranded oligonucleotide probe that can act as a point of initiation of template-directed DNA synthesis using methods such as PCR (polymerase chain reaction), LCR (ligase chain reaction), etc., for amplification of a target sequence. In some embodiments, the probe is a test probe, e.g., a probe that can be used to detect polymorphisms in a region described herein, e.g., polymorphisms as described herein. In some embodiments, the probe can hybridize to a target sequence within a region delimited by delimiting SNPs, SNPl and SNP2, inclusive as specified for the particular genes in Tables A and B.
In some embodiments, the probe can bind to another marker sequence associated with SZ as described herein.
Control probes can also be used. For example, a probe that binds a less variable sequence, e.g., repetitive DNA associated with a centromere of a chromosome, can be used as a control. Probes that hybridize with various centromeric DNA and locus-specific DNA are available commercially, for example, from Vysis, Inc. (Downers Grove, 111.), Molecular Probes, Inc. (Eugene, Oreg.), or from Cytocell (Oxfordshire, UK). Probe sets are available commercially, e.g., from Applied Biosystems, e.g., the Assays-on-Demand SNP kits Alternatively, probes can be synthesized, e.g., chemically or in vitro, or made from chromosomal or genomic DNA through standard techniques. For example, sources of DNA that can be used include genomic DNA, cloned DNA sequences, somatic cell hybrids that contain one, or a part of one, human chromosome along with the normal chromosome complement of the host, and chromosomes purified by flow cytometry or microdissection. The region of interest can be isolated through cloning, or by site-specific amplification via the polymerase chain reaction (PCR). See, for example, Nath and Johnson, Biotechnic. Histochem., 1998, 73(l):6-22, Wheeless et al., Cytometry 1994, 17:319-326, and U.S. Pat. No. 5,491,224.
In some embodiments, the probes are labeled, e.g., by direct labeling, with a fluorophore, an organic molecule that fluoresces after absorbing light of lower wavelength/higher energy. A directly labeled fluorophore allows the probe to be visualized without a secondary detection molecule. After covalently attaching a fluorophore to a nucleotide, the nucleotide can be directly incorporated into the probe with standard techniques such as nick translation, random priming, and PCR labeling. Alternatively, deoxycytidine nucleotides within the probe can be transaminated with a linker. The fluorophore then is covalently attached to the transaminated deoxycytidine nucleotides. See, e.g., U.S. Pat. No. 5,491,224.
Fluorophores of different colors can be chosen such that each probe in a set can be distinctly visualized. For example, a combination of the following fluorophores can be used: 7-amino-4-methylcoumarin-3-acetic acid (AMCA), Texas Red™ (Molecular Probes, Inc., Eugene, Oreg.), 5-(and-6)-carboxy-X-rhodamine, lissamine rhodamine B, 5-(and-6)- carboxyfluorescein, fluorescein-5-isothiocyanate (FITC), 7-diethylaminocoumarin-3- carboxylic acid, tetramethylrhodamine-5-(and-6)-isothiocyanate, 5-(and-6)- carboxytetramethylrhodamine, 7-hydroxycoumarin-3-carboxylic acid, 6-[fluorescein 5-(and- 6)-carboxamido]hexanoic acid, N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a diaza-3- indacenepropionic acid, eosin-5-isothiocyanate, erythrosin-5-isothiocyanate, and Cascade™ blue acetylazide (Molecular Probes, Inc., Eugene, OR). Fluorescently labeled probes can be viewed with a fluorescence microscope and an appropriate filter for each fluorophore, or by using dual or triple band-pass filter sets to observe multiple fluorophores. See, for example, U.S. Pat. No. 5,776,688. Alternatively, techniques such as flow cytometry can be used to examine the hybridization pattern of the probes. Fluorescence-based arrays are also known in the art.
In other embodiments, the probes can be indirectly labeled with, e.g., biotin or digoxygenin, or labeled with radioactive isotopes such as 32P and 3H. For example, a probe indirectly labeled with biotin can be detected by avidin conjugated to a detectable marker. For example, avidin can be conjugated to an enzymatic marker such as alkaline phosphatase or horseradish peroxidase. Enzymatic markers can be detected in standard colorimetric reactions using a substrate and/or a catalyst for the enzyme. Catalysts for alkaline phosphatase include 5-bromo-4-chloro-3-indolylphosphate and nitro blue tetrazolium. Diaminobenzoate can be used as a catalyst for horseradish peroxidase.
Oligonucleotide probes that exhibit differential or selective binding to polymorphic sites may readily be designed by one of ordinary skill in the art. For example, an oligonucleotide that is perfectly complementary to a sequence that encompasses a polymorphic site (i.e., a sequence that includes the polymorphic site, within it or at one end) will generally hybridize preferentially to a nucleic acid comprising that sequence, as opposed to a nucleic acid comprising an alternate polymorphic variant.
Arrays and Uses Thereof
In another aspect, the invention features arrays that include a substrate having a plurality of addressable areas, and methods of using them. At least one area of the plurality includes a nucleic acid probe that binds specifically to a sequence comprising a polymorphism listed in Table B, and can be used to detect the absence or presence of said polymorphism, e.g., one or more SNPs, microsatellites, minisatellites, or indels, as described herein, to determine a haplotype. For example, the array can include one or more nucleic acid probes that can be used to detect a polymorphism listed in Table B. In some embodiments, the array further includes at least one area that includes a nucleic acid probe that can be used to specifically detect another marker associated with SZ as described herein. The substrate can be, e.g., a two-dimensional substrate known in the art such as a glass slide, a wafer (e.g., silica or plastic), a mass spectroscopy plate, or a three-dimensional substrate such as a gel pad. In some embodiments, the probes are nucleic acid capture probes.
Methods for generating arrays are known in the art and include, e.g., photolithographic methods (see, e.g., U.S. Patent Nos. 5,143,854; 5,510,270; and 5,527,681), mechanical methods (e.g., directed-flow methods as described in U.S. Patent No. 5,384,261), pin-based methods (e.g., as described in U.S. Pat. No. 5,288,514), and bead-based techniques (e.g., as described in PCT US/93/04145). The array typically includes oligonucleotide probes capable of specifically hybridizing to different polymorphic variants. According to the method, a nucleic acid of interest, e.g., a nucleic acid encompassing a polymorphic site, (which is typically amplified) is hybridized with the array and scanned. Hybridization and scanning are generally carried out according to standard methods. See, e.g., Published PCT Application Nos. WO 92/10092 and WO 95/11995, and U.S. Pat. No. 5,424,186. After hybridization and washing, the array is scanned to determine the position on the array to which the nucleic acid hybridizes. The hybridization data obtained from the scan is typically in the form of fluorescence intensities as a function of location on the array.
Arrays can include multiple detection blocks (i.e., multiple groups of probes designed for detection of particular polymorphisms). Such arrays can be used to analyze multiple different polymorphisms. Detection blocks may be grouped within a single array or in multiple, separate arrays so that varying conditions (e.g., conditions optimized for particular polymorphisms) may be used during the hybridization. For example, it may be desirable to provide for the detection of those polymorphisms that fall within G-C rich stretches of a genomic sequence, separately from those falling in A-T rich segments.
Additional description of use of oligonucleotide arrays for detection of polymorphisms can be found, for example, in U.S. Pat. Nos. 5,858,659 and 5,837,832. In addition to oligonucleotide arrays, cDNA arrays may be used similarly in certain embodiments of the invention.
The methods described herein can include providing an array as described herein; contacting the array with a sample, e.g., a portion of genomic DNA that includes at least a portion of human chromosome 1, 3, 6, 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, and/or 20, e.g., a region between delimiting SNPs, SNPl and SNP2 for each of the genes listed in Tables A and B, and/or optionally, a different portion of genomic DNA, e.g., a portion that includes a different portion of human chromosomes 1, 3, 6, 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, and/or 20, or another chromosome, e.g., including another region associated with SZ, pharmacological response, and/or psychiatric endophenotypes, and detecting binding of a nucleic acid from the sample to the array. Optionally, the method includes amplifying nucleic acid from the sample, e.g., genomic DNA that includes a portion of a human chromosome described herein, and, optionally, a region that includes another region associated with SZ, pharmacological response, and/or psychiatric endophenotypes, prior to or during contact with the array.
In some aspects, the methods described herein can include using an array that can ascertain differential expression patterns or copy numbers of one or more genes in samples from normal and affected individuals (see, e.g., Redon et al., Nature. 444(7118):444-54 (2006)). For example, arrays of probes to a marker described herein can be used to measure polymorphisms between DNA from a subject having SZ and control DNA, e.g., DNA obtained from an individual that does not have SZ and has no familial risk factors for SZ. Since the clones on the array contain sequence tags, their positions on the array are accurately known relative to the genomic sequence. Different hybridization patterns between DNA from an individual afflicted with SZ and DNA from a normal individual at areas in the array corresponding to markers in human chromosome 1, 3, 6, 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, and/or 20 as described herein, and, optionally, one or more other regions associated with SZ, SD, or SPD, are indicative of a risk of SZ-spectrum disorders. Methods for array production, hybridization, and analysis are described, e.g., in Snijders et al., (2001) Nat. Genetics 29:263-264; Klein et al., (1999) Proc. Natl Acad. Sci. U.S.A. 96:4494-4499; Albertson et al., (2003) Breast Cancer Research and Treatment 78:289-298; and Snijders et al. "BAC microarray based comparative genomic hybridization." In: Zhao et al. (eds), Bacterial Artificial Chromosomes: Methods and Protocols, Methods in Molecular Biology, Humana Press, 2002. Real time quantitative PCR can also be used to determine copy number.
In another aspect, the invention features methods of determining the absence or presence of a haplotype associated with SZ, pharmacological response, and/or psychiatric endophenotypes, as described herein, using an array described above. For example, in some embodiments the methods include providing a two dimensional array having a plurality of addresses, each address of the plurality being positionally distinguishable from each other address of the plurality having a unique nucleic acid capture probe, contacting the array with a first sample from a test subject who is suspected of having or being at risk for SZ, and comparing the binding of the first sample with one or more references, e.g., binding of a sample from a subject who is known to have SZ and/or binding of a sample from a subject who is unaffected, e.g., a control sample from a subject that does not have SZ. In some embodiments, the methods include contacting the array with a second sample from a subject who has SZ; and comparing the binding of the first sample with the binding of the second sample. In some embodiments, the methods include contacting the array with a third sample from a subject that does not have SZ; and comparing the binding of the first sample with the binding of the third sample. In some embodiments, the second and third samples are from first or second-degree relatives of the test subject. Binding, e.g., in the case of a nucleic acid hybridization, with a capture probe at an address of the plurality, can be detected by any method known in the art, e.g., by detection of a signal generated from a label attached to the nucleic acid.
Schizophrenia, Schizotypal Personality Disorder, and Schizoaffective Disorder
The methods described herein can be used to determine an individual's risk of developing schizophrenia (SZ), which as defined herein includes narrowly defined SZ as well as schizotypal personality disorder (SPD), and/or schizoaffective disorder (SD).
Schizophrenia (SZ)
SZ is considered a clinical syndrome, and is probably a constellation of several pathologies. Substantial heterogeneity is seen between cases; this is thought to reflect multiple overlapping etiologic factors, including both genetic and environmental contributions. A diagnosis of SZ is typically indicated by chronic psychotic symptoms, e.g., hallucinations and delusions. Disorganization of thought and behavior are common and are considered distinguishing factors in the diagnosis of SZ. Patients typically have some subtle impairments in cognition. Reduced emotional experience and expression, low drive, and impaired speech are observed in a subgroup of patients. Cognitive, emotional and social impairments often appear early in life, while the psychotic symptoms typically manifest in late adolescence or early adulthood in men, a little later in women.
A diagnosis of SZ can be made according to the criteria reported in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, American Psychiatric Association, 2000, (referred to herein as DSM-IV) as follows: Diagnostic Criteria for SZ
All six criteria must be met for a diagnosis of SZ.
A. Characteristic symptoms: Two (or more) of the following, each present for a significant portion of time during a one month period (or less if successfully treated):
(1) delusions
(2) hallucinations
(3) disorganized speech (e.g., frequent derailment or incoherence)
(4) grossly disorganized or catatonic behavior
(5) negative symptoms, e.g., affective flattening, alogia, or avolition
Only one criterion A symptom is required if delusions are bizarre or hallucinations consist of a voice keeping up a running commentary on the person's behavior or thoughts, or two or more voices conversing with each other.
B. Social/occupational dysfunction: For a significant portion of the time since the onset of the disturbance, one or more major areas of functioning such as work, interpersonal relations, or self-care are markedly below the level achieved prior to the onset (or when the onset is in childhood or adolescence, failure to achieve expected level of interpersonal, academic, or occupational achievement).
C. Duration: Continuous signs of the disturbance persist for at least 6 months. This 6-month period must include at least 1 month of symptoms (or less if successfully treated) that meet Criterion A (i.e., active-phase symptoms) and may include periods of prodromal or residual symptoms. During these prodromal or residual periods, the signs of the disturbance may be manifested by only negative symptoms or two or more symptoms listed in Criterion A present in an attenuated form (e.g., odd beliefs, unusual perceptual experiences).
D. Schizoaffective and Mood Disorder Exclusion: Schizoaffective Disorder and Mood Disorder With Psychotic Features have been ruled out because either (1) no major depressive, manic, or mixed episodes have occurred concurrently with the active-phase symptoms; or (2) if mood episodes have occurred during active-phase symptoms, their total duration has been brief relative to the duration of the active and residual periods.
E. Substance/General Medical Condition Exclusion: The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.
F. Relationship to a Pervasive Developmental Disorder: If the patient has a history of Autistic Disorder or another Pervasive Developmental Disorder, the additional diagnosis of SZ is made only if prominent delusions or hallucinations are also present for at least a month (or less if successfully treated).
Schizoaffective Disorder (SD)
SD is characterized by the presence of affective (depressive or manic) symptoms and schizophrenic symptoms within the same, uninterrupted episode of illness.
Diagnostic Criteria for Schizoaffective Disorder
The DSM-IV Criteria for a diagnosis of schizoaffective disorder is as follows:
An uninterrupted period of illness during which, at some time, there is either (1) a Major Depressive Episode (which must include depressed mood), (2) a Manic Episode, or (3) a Mixed Episode, concurrent with symptoms that meet (4) Criterion A for SZ, above.
A. Criteria for Major Depressive Episode
At least five of the following symptoms must be present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.
(1) depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful). In children and adolescents, this can be an irritable mood.
(2) markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others)
(3) significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. (In children, failure to make expected weight gains is considered).
(4) insomnia or hypersomnia nearly every day
(5) psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down)
(6) fatigue or loss of energy nearly every day
(7) feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick)
(8) diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others)
(9) recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide In addition, the symptoms do not meet criteria for a Mixed Episode. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism) .
The symptoms are not better accounted for by Bereavement, i.e., after the loss of a loved one, the symptoms persist for longer than 2 months, or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.
B. Criteria for Manic Episode
A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least one week (or any duration, if hospitalization is necessary).
During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree:
(1) inflated self-esteem or grandiosity
(2) decreased need for sleep (e.g., feels rested after only 3 hours of sleep)
(3) more talkative than usual or pressure to keep talking
(4) flight of ideas or subjective experience that thoughts are racing
(5) distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli)
(6) increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation
(7) excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)
The symptoms do not meet criteria for a Mixed Episode. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism).
C. Criteria for Mixed Episode A mixed episode occurs when the criteria are met both for a Manic Episode and for a Major Depressive Episode (except for duration) nearly every day during at least a 1-week period. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.
The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism) .
D. Criterion A of SZ See above.
E. Types of SD
The type of SD may be may be specifiable, as either Bipolar Type, if the disturbance includes a Manic or a Mixed Episode (or a Manic or a Mixed Episode and Major Depressive Episodes), or Depressive Type, if the disturbance only includes Major Depressive Episodes.
F. Associated Features
Features associated with SD include Learning Problems, Hypoactivity, Psychotic, Euphoric Mood, Depressed Mood, Somatic/Sexual Dysfunction, Hyperactivity, Guilt/Obsession, Odd/Eccentric/Suspicious Personality, Anxious/Fearful/Dependent Personality, and Dramatic/Erratic/ Antisocial Personality.
Schizotypal Personality Disorder (SPD)
Diagnostic Criteria for SPD
A diagnosis of SPD under the criteria of the DSM-IV is generally based on a pervasive pattern of social and interpersonal deficits marked by acute discomfort with, and reduced capacity for, close relationships as well as by cognitive or perceptual distortions and eccentricities of behavior, beginning by early adulthood and present in a variety of contexts, as indicated by five (or more) of the following:
(1) ideas of reference (excluding delusions of reference)
(2) odd beliefs or magical thinking that influences behavior and is
(3) inconsistent with subcultural norms (e.g., superstitiousness, belief in clairvoyance, telepathy, or "sixth sense;" in children and adolescents, bizarre fantasies or preoccupations)
(4) unusual perceptual experiences, including bodily illusions (5) odd thinking and speech (e.g., vague, circumstantial, metaphorical, overelaborate, or stereotyped)
(6) suspiciousness or paranoid ideation
(7) inappropriate or constricted affect
(8) behavior or appearance that is odd, eccentric, or peculiar
(9) lack of close friends or confidants other than first-degree relatives
(10) excessive social anxiety that does not diminish with familiarity and tends to be associated with paranoid fears rather than negative judgments about self
SPD is diagnosed if the symptoms do not occur exclusively during the course of SZ, a Mood Disorder With Psychotic Features, another Psychotic Disorder, or a Pervasive Developmental Disorder, and the disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.
Associated features of SPD include Depressed Mood and Odd/Eccentric/ Suspicious Personality.
Psychiatric Endophenotvpes in SZ
A number of endophenotypes, i.e., intermediate phenotypes, that may more closely reflect biological mechanisms behind SZ, have been suggested, such as prepulse inhibition, structural abnormalities evident in MRI scans, specific domains of cognition (e.g., executive function), fine motor performance, working memory, etc.
Endophenotypes can also include clinical manifestations such as hallucinations, paranoia, mania, depression, obsessive-compulsive symptoms, etc., as well as response or lack of response to drugs and comorbidity for substance and alcohol abuse. See, e.g., Kendler et al, Am J Psychiatry 152(5):749-54 (1995); Gottesman and Gould, Am J Psychiatry 160(4):636-45 (2003); Cadenhead, Psychiatric Clinics of North America. 25(4):837-53 (2002); Gottesman and Gould, American Journal of Psychiatry. 160(4):636-45 (2003); Heinrichs, Neuroscience & Biobehavioral Reviews. 28(4):379-94 (2004); and Zobel and Maier, Nervenarzt. 75(3):205-14 (2004). There is now evidence that some candidate genes that were identified using DSM-IV type categorical definitions for "affected" individuals may influence specific endophenotypes, see, e.g., Baker et al., Biol Psychiatry 58(1):23-31 (2005); Cannon et al., Arch Gen Psychiatry 62(11):1205-13 (2005); Gothelf et al., Nat Neurosci 8(11): 1500-2 (2005); Hallmayer et al., Am J Hum Genet 77(3):468-76 (2005); Callicott et al., Proc Natl Acad Sci U S A 102(24):8627-32 (2005); Gornick et al., J Autism Dev Disord 1-8 (2005). Thus, the methods described herein can be used to associate haplotypes with specific psychiatric endophenotypes.
Positive and Negative Syndrome Scale (PANSS)
The Positive and Negative Syndrome Scale (PANSS) is a comprehensive psychometric scale used to classify psychopathology for severe neuropsychiatric diseases, including SZ. It measures a number of psychiatric endophenotypes or dimensions using quantitative scales based on the scoring of patients by clinicians. It is widely used to classify patients into specific subtypes, and is commonly used for measuring the improvement of symptoms in response to clinical interventions (Kay et al., Schizophr. Bull. 13:261-276 (1987); Kay et al., Br. J. Psychiatry Suppl 59-67 (1989); Leucht et al., Schizophr. Res. 79:231-238 (2005)).
Detailed information on PANSS and Scoring Criteria can be found in the art, e.g., on the world wide web at panss.org, or in the book by Kay, Positive and Negative Syndromes in Schizophrenia, (Routledge, 1991) which is incorporated herein in its entirety by reference. Based on these sources, the methodology is summarized briefly below.
PANSS comprises 30 individual subscales. Seven constitute a Positive Symptom Scale, seven the Negative Symptom Scale, and the remaining 16 items make up a General Psychopathology Scale. The scores for these scales are arrived at by summation of ratings across component items. Therefore, the potential ranges are 7 to 49 for the Positive and Negative Scales, and 16 to 112 for the General Psychopathology Scale (Source: The PANSS Institute).
Each of the 30 items is accompanied by a specific definition as well as detailed anchoring criteria for all seven rating points. These seven points represent increasing levels of psychopathology, as follows:
1- absent
2- minimal
3- mild
4- moderate
5- moderate severe
6- severe
7- extreme
The PANSS Individual subscales are described below.
Pl . DELUSIONS - Beliefs which are unfounded, unrealistic and idiosyncratic. P2. CONCEPTUAL DISORGANISATION - Disorganized process of thinking characterized by disruption of goal-directed sequencing, e.g., circumstantiality, loose associations, tangentiality, gross illogicality or thought block.
P3. HALLUCINATORY BEHAVIOUR - Verbal report or behaviour indicating perceptions which are not generated by external stimuli. These may occur in the auditory, visual, olfactory or somatic realms.
P4. EXCITEMENT - Hyperactivity as reflected in accelerated motor behaviour, heightened responsivity to stimuli, hypervigilance or excessive mood lability.
P5. GRANDIOSITY - Exaggerated self-opinion and unrealistic convictions of superiority, including delusions of extraordinary abilities, wealth, knowledge, fame, power and moral righteousness.
P6. SUSPICIOUSNESS/PERSECUTION - Unrealistic or exaggerated ideas of persecution, as reflected in guardedness, ad distrustful attitude, suspicious hypervigilance or frank delusions that others mean harm.
P7. HOSTILITY - Verbal and nonverbal expressions of anger and resentment, including sarcasm, passive-aggressive behavior, verbal abuse and assualtiveness.
Nl. BLUNTED AFFECT - Diminished emotional responsiveness as characterized by a reduction in facial expression, modulation of feelings and communicative gestures.
N2. EMOTIONAL WITHDRAWAL - Lack of interest in, involvement with, and affective commitment to life's events.
N3. POOR RAPPORT - Lack of interpersonal empathy, openness in conversation and sense of closeness, interest or involvement with the interviewer. This is evidenced by interpersonal distancing and reduced verbal and nonverbal communication.
N4. PASSIVE/APATHETIC SOCIAL WITHDRAWAL - Diminished interest and initiative in social interactions due to passivity, apathy, anergy or avolition. This leads to reduced interpersonal involvements and neglect of activities of daily living.
N5. DIFFICULTY IN ABSTRACT THINKING - Impairment in the use of the abstract-symbolic mode of thinking, as evidenced by difficulty in classification, forming generalizations and proceeding beyond concrete or egocentric thinking in problem-solving tasks.
N6. LACK OF SPONTANEITY AND FLOW OF CONVERSATION - Reduction in the normal flow of communication associated with apathy, avolition, defensiveness or cognitive deficit. This is manifested by diminished fluidity and productivity of the verbal interactional process. N7. STEREOTYPED THINKING - Decreased fluidity, spontaneity and flexibility of thinking, as evidenced in rigid, repetitious or barren thought content.
Gl . SOMATIC CONCERN - Physical complaints or beliefs about bodily illness or malfunctions. This may range from a vague sense of ill being to clear-cut delusions of catastrophic physical disease.
G2. ANXIETY - Subjective experience of nervousness, worry, apprehension or restlessness, ranging from excessive concern about the present or future to feelings of panic.
G3. GUILT FEELINGS - Sense of remorse or self-blame for real or imagined misdeeds in the past.
G4. TENSION -Overt physical manifestations of fear, anxiety, and agitation, such as stiffness, tremor, profuse sweating and restlessness.
G5. MANNERISMS AND POSTURING - Unnatural movements or posture as characterized be an awkward, stilted, disorganized, or bizarre appearance.
G6. DEPRESSION - Feelings of sadness, discouragement, helplessness and pessimism.
G7. MOTOR RETARDATION - Reduction in motor activity as reflected in slowing or lessening or movements and speech, diminished responsiveness of stimuli, and reduced body tone.
G8. UNCOOPERATIVENESS - Active refusal to comply with the will of significant others, including the interviewer, hospital staff or family, which may be associated with distrust, defensiveness, stubbornness, negativism, rejection of authority, hostility or belligerence.
G9. UNUSUAL THOUGHT CONTENT - Thinking characterized by strange, fantastic or bizarre ideas, ranging from those which are remote or atypical to those which are distorted, illogical and patently absurd.
GlO. DISORIENTATION - Lack of awareness of one's relationship to the milieu, including persons, place and time, which may be due to confusion or withdrawal.
GI l. POOR ATTENTION - Failure in focused alertness manifested by poor concentration, distractibility from internal and external stimuli, and difficulty in harnessing, sustaining or shifting focus to new stimuli.
G12. LACK OF JUDGEMENT AND INSIGHT - Impaired awareness or understanding of one's own psychiatric condition and life situation. This is evidenced by failure to recognize past or present psychiatric illness or symptoms, denial of need for psychiatric hospitalization or treatment, decisions characterized by poor anticipation or consequences, and unrealistic short-term and long-range planning.
G 13. DISTURBANCE OF VOLITION - Disturbance in the willful initiation, sustenance and control of one's thoughts, behavior, movements and speech.
G14. POOR IMPULSE CONTROL - Disordered regulation and control of action on inner urges, resulting in sudden, unmodulated, arbitrary or misdirected discharge of tension and emotions without concern about consequences.
G 15. PREOCCUPATION - Absorption with internally generated thoughts and feelings and with autistic experiences to the detriment of reality orientation and adaptive behavior.
G16. ACTIVE SOCIAL AVOIDANCE - Diminished social involvement associated with unwarranted fear, hostility, or distrust.
Use of PANSS score for differential diagnosis
Each patient's disease manifestation and process is unique. PANSS provides a structured, objective way of describing the various aspects of psychopathology of a given patient. However, proper implementation of the PANSS requires highly trained personnel to conduct the assessment and to interpret the results, and there is potential for site to site variability, especially outside the research setting.
Each of the PANSS composite scales and subscales can be considered a clinical endophenotype. The ability to link genetic profiles to these clinical endophenotypes, as described in the examples, will enable clinicians to refine a patient's diagnosis and develop a personalized therapeutic strategy for each patient. For example, the "A" allele of rs4832524, located in the KCNS3 gene, is associated with lower Negative Symptom burden as shown in the regression analysis in Table 14. Another example is the "A" allele of rs9823803, located in the GADLl gene, which is significantly associated with lower scores on the Grandiosity Subscale as shown in the regression analysis in Table 15. By identifying these genetic contributions to specific endophenotypes, the physician can create a personalized diagnosis and treatment regime for the patient.
Current Treatment of SZ
Subjects with SZ typically require acute treatment for psychotic exacerbations, and long-term treatment including maintenance and prophylactic strategies to sustain symptom improvement and prevent recurrence of psychosis. Subjects with schizoaffective disorder experience the symptoms of both SZ and affective disorder (manic and/or depressive), thus require the specific treatments for each disorder. Subjects with SPD sometimes require medication for acute psychotic episodes but are often treated using psychosocial methods. The methods described herein can include the administration of one or more accepted or experimental treatment modalities to a person identified as at risk of developing SZ, SPD, or a SD, based on the presence of a haplotype associated with SZ, SPD, or SD. Currently accepted treatments presently include both pharmacologic and psychosocial management, and occasionally electroconvulsive therapy (ECT).
Standard pharmacologic therapies for SZ and SD include the administration of one or more antipsychotic medications, which are typically antagonists acting at postsynaptic D2 dopamine receptors in the brain. Antipsychotic medications include conventional, or first generation, antipsychotic agents, which are sometimes referred to as neuroleptics because of their neurologic side effects, and second generation antipsychotic agents, which are less likely to exhibit neuroleptic effects and have been termed atypical antipsychotics.
In some embodiments, the methods described herein include the administration of one or more antipsychotic medications to a person identified by a method described herein as being at risk of developing SZ. Antipsychotic medications substantially reduce the risk of relapse in the stable phase of illness. In some embodiments, the methods include the administration of a first generation antipsychotic medication at a dose that is around the "extrapyramidal symptom (EPS) threshold" (i.e., the dose that will induce extrapyramidal side effects, e.g., bradykinesia, rigidity, or dyskinesia, with minimal rigidity detectable on physical examination, and/or a second-generation antipsychotics at a dose that is therapeutic, yet below the EPS threshold.
Standard pharmacologic therapies for SD also include the administration of a combination of antidepressant, and anti-anxiety medication. Suitable antidepressants include serotonergic antidepressants, e.g., fluoxetine or trazodone. Suitable anxiolytics include benzodiazepines, e.g., lorazepam, clonazepam. Lithium can also be administered. Thus, in some embodiments, the methods can include the administration of one or more antidepressant and/or anti-anxiety medications to a person identified as at risk of developing SZ.
The methods can also include psychosocial and rehabilitation interventions, e.g., interventions that are generally accepted as therapeutically beneficial, e.g., cognitive- behavioral therapy for treatment-resistant positive psychotic symptoms; supportive, problem- solving, educationally oriented psychotherapy; family therapy and education programs aimed at helping patients and their families understand the patient's illness, reduce stress, and enhance coping capabilities; social and living skills training; supported employment programs; and/or the provision of supervised residential living arrangements.
Currently accepted treatments for SZ are described in greater detail in the Practice Guideline for the Treatment of Patients With Schizophrenia, American Psychiatric Association, Second Edition, American Psychiatric Association, 2004, which is incorporated herein by reference in its entirety.
Methods of Determining Treatment Regimens and Methods of Treating SZ
As described herein, the presence of certain haplotypes described herein has been correlated with an increased risk of developing or having SZ; in addition, haplotypes are described herein that are correlated with altered response to a treatment, e.g., a pharmacological treatment. An altered response can be, for example, a positive response (i.e., an improvement in one or more symptoms of the disease), negative response (worsening of one or more symptoms of the disease), no response, or the presence or absence of side effects. Thus, the new methods can also include selecting a treatment regimen for a subject determined to have SZ or to be at risk for developing SZ, based upon the absence or presence of a haplotype described herein. The determination of a treatment regimen can also be based upon the absence or presence of other risk factors associated with SZ, e.g., as described herein. Therefore, the methods of the invention can include selecting a treatment regimen for a subject having one or more risk factors for SZ, and having a haplotype described herein. The methods can also include administering a selected treatment regimen to a subject having, or at risk for developing, SZ, to thereby treat, prevent or delay further progression of the disease. A treatment regimen can include the administration of a selected antipsychotic medications to a subject identified as at risk of developing SZ, before the onset of any psychotic episodes. The medications can be selected based on the presence of a haplotype that is associated with, for example, positive response, or the absence of significant side effects.
As used herein, the term "treat" or "treatment" is defined as the application or administration of a treatment regimen, e.g., a therapeutic agent or modality, to a subject, e.g., a patient. The subject can be a patient having SZ a symptom of SZ or at risk of developing (i.e., a predisposition toward) SZ. The treatment can be to cure, heal, alleviate, relieve, alter, remedy, ameliorate, palliate, improve or affect SZ, the symptoms of SZ or the predisposition toward SZ. The methods described herein, e.g., methods of determining a treatment regimen and methods of treatment or prevention of SZ can further include the step of monitoring the subject, e.g., for a change (e.g., an increase or decrease) in one or more of the diagnostic criteria for SZ listed herein, or any other parameter related to clinical outcome. The subject can be monitored in one or more of the following periods: prior to beginning of treatment; during the treatment; or after one or more elements of the treatment have been administered. Monitoring can be used to evaluate the need for further treatment with the same or a different therapeutic agent or modality. Generally, a decrease in one or more of the parameters described above is indicative of the improved condition of the subject, although with red blood cell and platelet levels, an increase can be associated with the improved condition of the subject.
The methods can be used, e.g., to evaluate the suitability of, or to choose between alternative treatments, e.g., a particular dosage, mode of delivery, time of delivery, inclusion of adjunctive therapy, e.g., administration in combination with a second agent, or generally to determine the subject's probable drug response genotype. In a preferred embodiment, a treatment for SZ can be evaluated by administering the same treatment or combinations or treatments to a subject having SZ and a haplotype as described herein and to a subject that has SZ but does not have a haplotype as described herein. The effects of the treatment or combination of treatments on each of these subjects can be used to determine if a treatment or combination of treatments is particularly effective on a sub-group of subjects having SZ. In other embodiments, various treatments or combinations of treatments can be evaluated by administering two different treatments or combinations of treatments to at least two different subjects having SZ, and a haplotype as described herein. Such methods can be used to determine if a particular treatment or combination of treatments is more effective than others in treating this subset of SZ patients.
Various treatment regimens are known for treating SZ, e.g., as described herein.
Pharmacogenomics
With regards to both prophylactic and therapeutic methods of treatment of SZ, such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics. "Pharmacogenomics," as used herein, refers to the application of genomics technologies such as structural chromosomal analysis, to drugs in clinical development and on the market. See, for example, Eichelbaum et al., Clin. Exp. Pharmacol. Physiol. 23:983-985 (1996) and Linder et al., Clin. Chem. 43:254-266 (1997). Specifically, as used herein, the term refers the study of how a patient's genes determine his or her response to a drug (e.g., a patient's "drug response phenotype," or "drug response genotype"). Thus, another aspect of the invention provides methods for tailoring an individual's prophylactic or therapeutic treatment according to that individual's drug response genotype.
Information generated from pharmacogenomic research using a method described herein can be used to determine appropriate dosage and treatment regimens for prophylactic or therapeutic treatment of an individual. This knowledge, when applied to dosing or drug selection, can avoid adverse reactions or therapeutic failure and thus enhance therapeutic or prophylactic efficiency when administering a therapeutic composition, e.g., a cytotoxic agent or combination of cytotoxic agents, to a patient, as a means of treating or preventing SZ.
In one embodiment, a physician or clinician may consider applying knowledge obtained in relevant pharmacogenomics studies, e.g., using a method described herein, when determining whether to administer a pharmaceutical composition, e.g., an antipsychotic agent or a combination of antipsychotic agents, to a subject. In another embodiment, a physician or clinician may consider applying such knowledge when determining the dosage, e.g., amount per treatment or frequency of treatments, of a treatment, e.g., a antipsychotic agent or combination of antipsychotic agents, administered to a patient.
As one example, a physician or clinician may determine (or have determined, e.g., by a laboratory) the haplotype of a subject as described herein, and optionally one or more other markers associated with SZ of one or a group of subjects who may be participating in a clinical trial, wherein the subjects have SZ, and the clinical trial is designed to test the efficacy of a pharmaceutical composition, e.g., an antipsychotic or combination of antipsychotic agents, and wherein the physician or clinician attempts to correlate the genotypes of the subjects with their response to the pharmaceutical composition.
As another example, information regarding a haplotype associated with an altered pharmacogenomic response for SZ as described herein, can be used to stratify or select a subject population for a clinical trial. The information can, in some embodiments, be used to stratify individuals that may exhibit a toxic response to a treatment from those that will not. In other cases, the information can be used to separate those that are more likely to be non- responders from those who will be responders. The haplotypes described herein can be used in pharmacogenomics-based design and to manage the conduct of a clinical trial, e.g., as described in U.S. Pat. Pub. No. 2003/0108938.
As another example, information regarding a haplotype associated with an increased risk of SZ, or with altered pharmacogenomic response for SZ, as described herein, can be used to stratify or select human cells or cell lines for drug testing purposes. Human cells are useful for studying the effect of a polymorphism on physiological function, and for identifying and/or evaluating potential therapeutic agents for the treatment of SZ e.g., antipsychotics. Thus the methods can include performing the present methods on genetic material from a cell line. The information can, in some embodiments, be used to separate cells that respond particular drugs from those that do not respond, e.g. which cells show altered second messenger signaling.
Theranostics
Also included herein are compositions and methods for the identification and treatment of subjects who have an increased risk of SZ, or altered clinical presentation of SZ, such that a theranostic approach can be taken to test such individuals to determine the effectiveness of a particular therapeutic intervention (e.g., a pharmaceutical or non- pharmaceutical intervention as described herein) and to alter the intervention to 1) reduce the risk of developing adverse outcomes and 2) enhance the effectiveness of the intervention. Thus, in addition to diagnosing or confirming the predisposition to SZ, the methods and compositions described herein also provide a means of optimizing the treatment of a subject having SZ. Provided herein is a theranostic approach to treating and preventing SZ, by integrating diagnostics and therapeutics to improve the real-time treatment of a subject. Practically, this means creating tests that can identify which patients are most suited to a particular therapy, and providing feedback on how well a drug is working to optimize treatment regimens.
Within the clinical trial setting, a theranostic method or composition of the invention can provide key information to optimize trial design, monitor efficacy, and enhance drug safety. For instance, "trial design" theranostics can be used for patient stratification, determination of patient eligibility (inclusion/exclusion), creation of homogeneous treatment groups, and selection of patient samples that are representative of the general population. Such theranostic tests can therefore provide the means for patient efficacy enrichment, thereby minimizing the number of individuals needed for trial recruitment. "Efficacy" theranostics are useful for monitoring therapy and assessing efficacy criteria. Finally, "safety" theranostics can be used to prevent adverse drug reactions or avoid medication error.
The methods described herein can include retrospective analysis of clinical trial data as well, both at the subject level and for the entire trial, to detect correlations between a haplotype as described herein and any measurable or quantifiable parameter relating to the outcome of the treatment, e.g., efficacy (the results of which may be binary (i.e., yes and no) as well as along a continuum), side-effect profile (e.g., weight gain, metabolic dysfunction, lipid dysfunction, movement disorders, or extrapyramidal symptoms), treatment maintenance and discontinuation rates, return to work status, hospitalizations, suicidality, total healthcare cost, social functioning scales, response to non-pharmacological treatments, and/or dose response curves. The results of these correlations can then be used to influence decision- making, e.g., regarding treatment or therapeutic strategies, provision of services, and/or payment. For example, a correlation between a positive outcome parameter (e.g., high efficacy, low side effect profile, high treatment maintenance/low discontinuation rates, good return to work status, low hospitalizations, low suicidality, low total healthcare cost, high social function scale, favorable response to non-pharmacological treatments, and/or acceptable dose response curves) and a selected haplotype can influence treatment such that the treatment is recommended or selected for a subject having the selected haplotype.
Kits
Also within the scope of the invention are kits comprising a probe that hybridizes with a region of human chromosome as described herein and can be used to detect a polymorphism described herein. The kit can include one or more other elements including: instructions for use; and other reagents, e.g., a label, or an agent useful for attaching a label to the probe. Instructions for use can include instructions for diagnostic applications of the probe for assessing risk of SZ in a method described herein. Other instructions can include instructions for attaching a label to the probe, instructions for performing in situ analysis with the probe, and/or instructions for obtaining a sample to be analyzed from a subject. As discussed above, the kit can include a label, e.g., any of the labels described herein. In some embodiments, the kit includes a labeled probe that hybridizes to a region of human chromosome as described herein, e.g., a labeled probe as described herein.
The kit can also include one or more additional probes that hybridize to the same chromosome, e.g., chromosome 1, 3, 6, 10, 11, 12, 13, 14, 15, 15, 17, 18, 19, or 20, or another chromosome or portion thereof that can have an abnormality associated with risk for SZ. For example, the additional probe or probes can be: a probe that hybridizes to human chromosome 22ql 1-12 or a portion thereof, (e.g., a probe that detects a sequence associated with SZ or BD in this region of chromosome 22), or probes that hybridize to all or a portion of 22ql2.3 (e.g., near D22S283), 22qll.2, 22qll.2, 22qll-ql3, Iq42.1, Iq42.1, Iq21-q22, 2p, 2q, 3p25, 4p, 4q, 5qll.2-ql3.3, 6p22.3, 6p23, 6ql3-q26, 7q, 8pl2-21, 8q, 9p, 10pl5-pl3 (e.g., near D10S189), 10q22.3, I lql4-q21, 12q24, 13q34, 13q32, 14q32.3, 15ql5, 16p, 17q , 18p, 18q, 19p. 2Op, 2 Iq, Xq, and/or the X/Y pseudoautosomal region. A kit that includes additional probes can further include labels, e.g., one or more of the same or different labels for the probes. In other embodiments, the additional probe or probes provided with the kit can be a labeled probe or probes. When the kit further includes one or more additional probe or probes, the kit can further provide instructions for the use of the additional probe or probes.
Kits for use in self-testing can also be provided. For example, such test kits can include devices and instructions that a subject can use to obtain a sample, e.g., of buccal cells or blood, without the aid of a health care provider. For example, buccal cells can be obtained using a buccal swab or brush, or using mouthwash.
Kits as provided herein can also include a mailer, e.g., a postage paid envelope or mailing pack, that can be used to return the sample for analysis, e.g., to a laboratory. The kit can include one or more containers for the sample, or the sample can be in a standard blood collection vial. The kit can also include one or more of an informed consent form, a test requisition form, and instructions on how to use the kit in a method described herein. Methods for using such kits are also included herein. One or more of the forms, e.g., the test requisition form, and the container holding the sample, can be coded, e.g., with a bar code, for identifying the subject who provided the sample.
Databases
Also provided herein are databases that include a list of polymorphisms as described herein, and wherein the list is largely or entirely limited to polymorphisms identified as useful in performing genetic diagnosis of or determination of susceptibility to SZ as described herein. The list is stored, e.g., on a flat file or computer-readable medium. The databases can further include information regarding one or more subjects, e.g., whether a subject is affected or unaffected, clinical information such as endophenotype, age of onset of symptoms, any treatments administered and outcomes (e.g., data relevant to pharmacogenomics, diagnostics or theranostics), and other details, e.g., about the disorder in the subject, or environmental or other genetic factors. The databases can be used to detect correlations between a particular haplotype and the information regarding the subject, e.g., to detect correlations between a haplotype and a particular endophenotype, or treatment response. Engineered Cells
Also provided herein are engineered cells that harbor one or more polymorphism described herein, e.g., one or more polymorphisms that constitute a haplotype associated with SZ, altered drug response or a specific endophenotype. Such cells are useful for studying the effect of a polymorphism on physiological function, and for identifying and/or evaluating potential therapeutic agents for the treatment of SZ-spectrum disorders e.g., anti-psychotics.
As one example, included herein are cells in which one of the various alleles of the genes described herein has be re-created that is associated with an increased risk of SZ. Methods are known in the art for generating cells, e.g., by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell, e.g., a cell of an animal. In some embodiments, the cells can be used to generate transgenic animals using methods known in the art.
The cells are preferably mammalian cells, e.g., neuronal type cells, in which an endogenous gene has been altered to include a polymorphism as described herein. Techniques such as targeted homologous recombinations, can be used to insert the heterologous DNA as described in, e.g., Chappel, US 5,272,071; WO 91/06667, published in May 16, 1991.
EXAMPLES
The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.
Example 1: Novel Markers Associated with SZ
The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), a large federally funded clinical trial designed to assess the efficacy of antipsychotics in a real world setting, is a valuable resource for determining the role of genes in drug response (Stroup et al, Schizophr. Bull. 29:15-31 (2003); Lieberman et al, N. Engl. J. Med. 353:1209-1223 (2005)). As part of the CATIE trial, SNP genotyping was performed for roughly half of the trial participants (Sullivan et al., MoI. Psychiatry 13:570-584 (2008)). When combined with disease status, PANSS scores, and clinical drug response data, the genotyping data allows the identification of genetic variants (e.g., SNPs) that are statistically associated with increased risk of developing SZ.
The design of the CATIE study has been described in detail by others (see, e.g., Stroup et al., Schizophr. Bull. 29:15-31 (2003); Lieberman et al., N. Engl. J. Med. 353:1209- 1223 (2005)). Briefly, 1460 subjects were randomly assigned one of several antipsychotics and those who did not respond or chose to quit their current medication were re-randomized to another drug. Details regarding SNP genotyping and quality control have been recently published (Sullivan et al, MoI. Psychiatry 13:570-584 (2008)).
Genotype and phenotype data for the CATIE trial were made available to qualified researchers through the NIMH Center for Collaborative Genetic Studies on Mental Disorders. Data for 417 patients with schizophrenia and 419 unaffected controls self reported as having exclusively European ancestry were evaluated. This same patient population was described in a recent study by Sullivan and co workers, which confirmed that there is no hidden stratification in the sample (Sullivan et al., MoI. Psychiatry 13:570-584 (2008)).
In addition, for this example, genotyping and phenotype data were obtained from the Genetic Analysis Information Network (GAIN)Database found at ncbi.nlm.nih.gov through dbGaP, at accession number PHSOOOO 17.vl .pi . Genotypes and associated phenotype data for the GAIN Genome- Wide Association Study of Schizophrenia were provided by P. Gejman, and genotyping of these samples was provided through the Genetic Association Information Network (GAIN). Data for 1172 cases and 1378 controls with Caucasian ancestry were evaluated for the GAIN sample.
For both the CATIE and GAIN studies, individual cases were diagnosed as having SZ based on DSM-III/IV criteria.
Statistical methods:
Genetic analysis to document the influence of haplotypes on SZ risk was performed using the PLINK 1.03 whole genome analysis toolset developed by Purcell and coworkers (Purcell et al., Am. J. Hum. Genet. 81 :559-575 (2007)). PLINK calculates P values for the allele-specific chi-squared test and the odds ratio (OR; or relative risk) associated with the minor allele.
Confirmation of Novel Markers Associated with SZ risk:
Table 1 provides numerous examples of SNP-based alleles that influence SZ risk. Table 1 reports the minor allele frequencies, P values, and ORs for numerous SNPs, in Tables B and C, that affect SZ risk. ORs of > 1.0 indicate that the minor SNP allele is associated with greater susceptibility, and ORs of < 1.0 indicate that the minor SNP allele is associated with decreased susceptibility to SZ.
Note in Table 1 that haplotype blocks result in the same Test SNP being in linkage disequilibrium with multiple SNPs in Table B. Similarly, haplotype blocks result in multiple Test SNPs that can be used for each SNP listed in Table B, though such redundant examples are not presented in Table 1 , unless the test SNP was evaluated in both the CATIE and GAIN samples.
Table 1 : Confirmation of Novel Markers Associated with SZ risk
Gene Name Table B Test SNP in Allele Frequency P OR Study
SNP linkage in Cases disequilibrium I
CAMTAl rs 10864639 rs 1542899 1.00 C 0.086 0.008304 0.78 GAIN
CAMTAl rs845197 rs2097518 0.71 C 0.249 0.02548 0.87 GAIN
CAMTAl rs2071986 rs9919223 1.00 T 0.267 0.0347 0.88 GAIN
RERE rsl2136689 rs 10779702 0.76 A 0.355 0.006746 1.18 GAIN
RERE rs8627 rs 10779702 0.52 A 0.355 0.006746 1.18 GAIN
RP1-21O18.1 rs7546786 rs7546786 N/A C 0.211 0.0356 0.78 CATIE
RP1-21O18.1 rs2073091 rs761288 0.69 C 0.269 0.04654 1.14 GAIN
RP1-21O18.1 rs4661572 rs761288 0.56 C 0.269 0.04654 1.14 GAIN
RP1-21O18.1 rs 12057431 rsl0803343 1.00 C 0.016 0.03243 3.20 CATIE
KCND3 rs4838924 rs 1373291 0.86 T 0.224 0.04121 1.28 CATIE
VAMP4 rsl0913530 rs9943293 1.00 T 0.311 0.01885 1.29 CATIE
VAMP4 rsl2096984 rs9943293 1.00 T 0.311 0.01885 1.29 CATIE
VAMP4 rs2073484 rs9943293 1.00 T 0.311 0.01885 1.29 CATIE
VAMP4 rs6672082 rs9943293 1.00 T 0.311 0.01885 1.29 CATIE
VAMP4 rs 15655 rs 10913529 1.00 C 0.182 0.00696 0.83 GAIN
DNM3 rs2093184 rs7540873 0.62 T 0.282 0.03038 0.88 GAIN
DNM3 rs7554526 rs7540873 0.61 T 0.282 0.03038 0.88 GAIN
DNM3 rs9425287 rslO158839 1.00 C 0.513 0.04037 1.12 GAIN
FASLG rsl0458360 rsl0458360 N/A G 0.474 0.02088 1.14 GAIN
FASLG rsl2135884 rsl0458360 0.56 G 0.474 0.02088 1.14 GAIN
CACNAlE rs553042 rs553042 N/A G 0.304 0.006968 1.18 GAIN
CACNAlE rs 17494681 rs 17494681 N/A A 0.188 0.01055 1.21 GAIN
CACNAlE rs506947 rs7554158 1.00 A 0.109 0.01115 0.80 GAIN
CACNAlE rs638132 rs546191 0.67 T 0.193 0.01582 0.75 CATIE
CAMKlG rs6690557 rs9429821 0.69 C 0.317 0.04072 0.88 GAIN
SYT14 rs9429830 rs7543650 0.52 T 0.236 0.02059 0.77 CATIE
SYT14 rs9429830 rs227193 0.90 G 0.400 0.0183 0.87 GAIN
KCNHl rs 1770220 rsl340127 0.51 G 0.437 0.01888 0.87 GAIN
ANK3 rs 1050745 rs 1050745 N/A T 0.209 0.02123 0.86 GAIN
ANK3 rs2393607 rslO78534 0.82 C 0.173 0.01647 0.74 CATIE
ANK3 rs 11596260 rs 11596260 N/A T 0.351 0.03773 0.89 GAIN
ANK3 rs2241540 rs 11596260 1.00 T 0.351 0.03773 0.89 GAIN
ANK3 rs 1551684 rs 1551683 1.00 T 0.114 0.0462 0.75 CATIE
KCNQl rs2283174 rs2283179 0.52 C 0.132 0.04204 1.19 GAIN
KCNQl rs231348 rs 10832405 0.80 A 0.126 0.0203 1.45 CATIE
RHOG rs 11030008 rs 1869002 0.67 G 0.312 0.007693 1.34 CATIE
USHlC rs2237965 rs 1076311 0.63 G 0.472 0.03922 1.23 CATIE
USHlC rs 10766408 rs2237959 0.53 G 0.454 0.01149 1.29 CATIE
USHlC rs2041027 rs 10766410 0.54 A 0.461 0.0002016 1.45 CATIE
USHlC rs2237957 rs 10766410 0.62 A 0.461 0.0002016 1.45 CATIE
OTOG rs 10766410 rs 10766410 N/A A 0.461 0.0002016 1.45 CATIE
OTOG rs2073582 rs 10766410 0.55 A 0.461 0.0002016 1.45 CATIE
SERGEF rs4757589 rs4757589 N/A G 0.497 0.001605 1.19 GAIN
NAV2 rs 10766590 rs 10500860 0.59 G 0.308 0.02614 1.15 GAIN
NAV2 rs2042600 rs 1559665 0.93 T 0.480 0.02766 0.88 GAIN
NAV2 rs2278132 rs 1559665 0.87 T 0.480 0.02766 0.88 GAIN
NAV2 rs7119267 rs7119267 N/A C 0.346 0.02078 1.15 GAIN Table 1 : Confirmation of Novel Markers Associated with SZ risk
2
Gene Name Table B Test SNP in r Allele Frequency P OR Study
SNP linkage in Cases disequilibrium I
NAV2 rs2028570 rs2255677 0.58 A 0.441 0.01665 1.15 GAIN
NAV2 rs2289566 rsl 0732471 0.57 A 0.227 0.009299 0.84 GAIN
SLC17A6 rs 11026532 rsl l55331 0.96 T 0.265 0.02007 0.86 GAIN
LRRC4C rsl551833 rs4237678 0.54 C 0.188 0.002021 1.26 GAIN
LRRC4C rsl0837367 rsl377106 1.00 A 0.067 0.00126 0.57 CATIE
HSDl 7Bl 2 rsl061810 rs7116641 0.54 G 0.346 0.02577 1.27 CATIE
HSDl 7Bl 2 rs4755744 rs7116641 0.65 G 0.346 0.02577 1.27 CATIE
HSDl 7Bl 2 rsl0838160 rslO838166 1.00 G 0.383 0.003094 0.75 CATIE
HSDl 7Bl 2 rs3802891 rslO838166 1.00 G 0.383 0.003094 0.75 CATIE
PHACS rs 16937817 rs7950395 0.58 A 0.141 0.00271 1.29 GAIN
PHACS rs7950395 rs7950395 N/A A 0.141 0.00271 1.29 GAIN
SYT13 rs 12362429 rs7124508 0.64 A 0.425 0.02358 0.88 GAIN
SYT13 rsl 1038382 rsl 077491 1.00 T 0.290 0.0195 0.78 CATIE
SYT13 rs2863182 rsl 077491 0.84 T 0.290 0.0195 0.78 CATIE
SYT13 rs4992029 rsl 077491 0.61 T 0.290 0.0195 0.78 CATIE
SYT13 rsl 2362429 rs7118408 0.70 G 0.419 0.01028 0.78 CATIE
ZFP91-CNTF rsl938596 rs2509920 0.97 G 0.404 0.01056 0.86 GAIN
ZFP91-CNTF rs4319530 rs2509920 0.90 G 0.404 0.01056 0.86 GAIN
ZFP91-CNTF rs7945889 rs948562 0.95 G 0.160 0.04957 0.86 GAIN
ZFP91-CNTF rs948562 rs948562 N/A G 0.160 0.04957 0.86 GAIN
DTX4 rsl 048444 rs3847 1.00 A 0.353 0.01537 0.87 GAIN
DTX4 rs2211912 rs3847 0.77 A 0.353 0.01537 0.87 GAIN
DTX4 rs3847 rs3847 N/A A 0.353 0.01537 0.87 GAIN
DTX4 rs5029315 rs3847 0.77 A 0.353 0.01537 0.87 GAIN
DTX4 rs544864 rs3847 0.55 A 0.353 0.01537 0.87 GAIN
DTX4 rs621162 rs3847 0.55 A 0.353 0.01537 0.87 GAIN
DTX4 rs656163 rs3847 0.64 A 0.353 0.01537 0.87 GAIN
KIAA1853 rsl 568923 rs7298478 0.69 G 0.275 0.006263 0.84 GAIN
KIAA1853 rs7134748 rs4767783 0.72 A 0.404 0.03728 1.13 GAIN
KIAA1853 rs7969288 rs4767783 0.57 A 0.404 0.03728 1.13 GAIN
KIAA1853 rs7297606 rs4075945 1.00 T 0.093 0.01915 1.27 GAIN
RIMBP2 rs4237817 rsl 877986 0.62 T 0.415 0.0264 0.80 CATIE
CHFR rs2306541 rs7297261 0.96 A 0.315 0.04659 1.13 GAIN
TTC5 rs3737220 rs4981948 1.00 C 0.175 0.006939 0.82 GAIN
TTC5 rs2318864 rs4981951 0.52 C 0.185 0.01689 0.84 GAIN
TTC5 rs3742945 rs4981951 0.52 C 0.185 0.01689 0.84 GAIN
DACTl rsl 1541 rs863091 1.00 A 0.202 0.04207 1.16 GAIN
DACTl rsl 60472 rs863091 0.54 A 0.202 0.04207 1.16 GAIN
DACTl rs863091 rs863091 N/A A 0.202 0.04207 1.16 GAIN
DAAMl rs4127823 rsl2590850 0.61 A 0.416 0.02325 1.26 CATIE
GPR135 rslO138199 rsl273156 0.81 T 0.459 0.02265 1.25 CATIE
GPR135 rsl253181 rsl273156 1.00 T 0.459 0.02265 1.25 CATIE
GPR135 rsl 7255731 rsl273156 0.62 T 0.459 0.02265 1.25 CATIE
GPR135 rs4898989 rsl273156 0.81 T 0.459 0.02265 1.25 CATIE
GPR135 rs9323348 rsl273156 0.81 T 0.459 0.02265 1.25 CATIE
EMLl rs2273704 rsl2590861 0.61 G 0.311 0.00485 1.19 GAIN
EMLl rs7143905 rsl2590861 0.70 G 0.311 0.00485 1.19 GAIN
EMLl rs746698 rsl 1850280 0.91 G 0.190 0.008545 1.21 GAIN
EMLl rsl 1160553 rsl2435250 0.67 G 0.254 0.02602 0.87 GAIN
EMLl rsl2433613 rsl2435250 0.56 G 0.254 0.02602 0.87 GAIN
EMLl rs6575751 rsl2435250 0.67 G 0.254 0.02602 0.87 GAIN Table 1 : Confirmation of Novel Markers Associated with SZ risk
2
Gene Name Table B Test SNP in r Allele Frequency P OR Study
SNP linkage in Cases disequilibrium
EVL rs3206354 rs3206354 N/A T 0.053 0.03254 1.33 GAIN
HERC2 rs 11074322 rs6497272 1.00 G 0.017 0.03882 2.82 CATIE
HERC2 rs 1635168 rs8041209 0.87 T 0.087 0.0183 1.57 CATIE
HERC2 rs2238289 rs8041209 0.51 T 0.087 0.0183 1.57 CATIE
HERC2 rs7495174 rs8041209 0.58 T 0.087 0.0183 1.57 CATIE
HERC2 rsl 1631797 rs916977 0.86 T 0.195 0.03981 1.30 CATIE
HERC2 rs916977 rs916977 N/A T 0.195 0.03981 1.30 CATIE
UNC13C rs2115827 rsl2148800 0.97 C 0.470 0.02906 0.88 GAIN
UNC13C rs2163195 rs2115825 0.57 A 0.501 0.02333 1.14 GAIN
UNC13C rsl2594549 rs934192 0.85 T 0.175 0.001305 1.28 GAIN
UNC13C rsl 897069 rsl 897069 N/A C 0.449 0.01113 0.87 GAIN
UNC13C rsl2910912 rsl2900128 0.52 G 0.295 0.01764 1.16 GAIN
UNC13C rsl 1856476 rsl 2917023 0.70 G 0.172 0.04217 1.17 GAIN
NEDD4 rs4424863 rs4520787 0.90 A 0.397 0.03785 1.24 CATIE
NEDD4 rs8028559 rsl 1630780 0.69 C 0.396 0.01945 0.79 CATIE
NEDD4 rsl 7238461 rs2175104 0.53 A 0.108 0.03922 1.42 CATIE
NEDD4 rsl 509408 rsl 509408 N/A C 0.225 0.03142 0.78 CATIE
ΛKAP13 rs2291049 rsl6941653 0.59 T 0.070 0.01822 0.66 CATIE
ΛKAP13 rs338556 rs2241266 1.00 T 0.071 0.0406 0.81 GAIN
KLHL25 rs2430838 rs2241266 0.91 T 0.071 0.0406 0.81 GAIN
SV2B rsl 075840 rs2269799 0.72 C 0.325 0.004465 1.36 CATIE
SV2B rsl 117388 rs2269799 0.55 C 0.325 0.004465 1.36 CATIE
SV2B rs2301665 rs2269799 0.59 C 0.325 0.004465 1.36 CATIE
SV2B rs8027498 rs2269799 0.72 C 0.325 0.004465 1.36 CATIE
SV2B rs3743444 rs2239994 0.50 T 0.113 0.01159 1.53 CATIE
SLCO3A1 rsl 2912997 rsl2905912 0.96 A 0.297 0.03912 0.81 CATIE
IGFlR rs4965436 rsl 1634874 0.76 C 0.111 0.02439 1.46 CATIE
IGFlR rsl 1247380 rs7165181 0.55 G 0.194 0.03684 0.78 CATIE
IGFlR rsl 879613 rs7165181 0.96 G 0.194 0.03684 0.78 CATIE
N4BP1 rsl 039342 rs8046716 0.61 T 0.500 0.003166 1.34 CATIE
N4BP1 rsl 120276 rs8046716 0.61 T 0.500 0.003166 1.34 CATIE
N4BP1 rsl 224 rs8046716 0.61 T 0.500 0.003166 1.34 CATIE
N4BP1 rs2354580 rs8046716 1.00 T 0.500 0.003166 1.34 CATIE
N4BP1 rs3826176 rs8046716 1.00 T 0.500 0.003166 1.34 CATIE
N4BP1 rs9937623 rs8046716 0.59 T 0.500 0.003166 1.34 CATIE
NDRG4 rsl3333449 rsl6960170 0.80 G 0.311 0.02137 1.15 GAIN
NDRG4 rs7202037 rsl6960170 0.67 G 0.311 0.02137 1.15 GAIN
KIAAOl 82 rs736845 rs736845 N/A A 0.310 0.0005682 1.24 GAIN
KIAAOl 82 rs9940601 rs9940601 N/A A 0.403 0.01452 1.15 GAIN
KIAAOl 82 rs3815794 rslO53328 0.73 A 0.327 0.00984 0.86 GAIN
KIAAOl 82 rs3815794 rslO53328 0.73 T 0.315 0.002786 0.74 CATIE
C16orf74 rsl 1644122 rsl 1644122 N/A T 0.293 0.03696 0.88 GAIN
C16orf74 rs2305357 rs394623 0.55 G 0.403 0.0003797 1.23 GAIN
C16orf74 rs373835 rs394623 0.68 G 0.403 0.0003797 1.23 GAIN
C16orf74 rs386061 rs394623 0.68 G 0.403 0.0003797 1.23 GAIN
PMP22 rsl 3422 rs230915 0.76 C 0.413 0.03188 1.13 GAIN
PMP22 rs230938 rs230915 0.97 C 0.413 0.03188 1.13 GAIN
PMP22 rs231021 rs230915 0.55 C 0.413 0.03188 1.13 GAIN
FUSSEL18 rsl0502880 rs8086549 0.85 C 0.473 0.04802 1.22 CATIE
FUSSEL18 rsl 7785419 rs8086549 0.85 C 0.473 0.04802 1.22 CATIE
FUSSEL18 rs2668771 rs8086549 0.64 C 0.473 0.04802 1.22 CATIE Table 1 : Confirmation of Novel Markers Associated with SZ risk
2
Gene Name Table B Test SNP in r Allele Frequency P OR Study
SNP linkage in Cases disequilibrium
FUSSEL18 rs7236105 rs8086549 1.00 C 0.473 0.04802 1.22 CATIE
SMAD2 rs 12457664 rs 1792670 0.85 G 0.445 0.039 0.89 GAIN
SMAD2 rs 1787176 rs 1792670 0.97 G 0.445 0.039 0.89 GAIN
SMΛD2 rs 1792666 rs 1792670 0.71 G 0.445 0.039 0.89 GAIN
SMAD2 rs 1792682 rs 1792670 0.94 G 0.445 0.039 0.89 GAIN
SMΛD2 rs2000709 rs 1792670 0.84 G 0.445 0.039 0.89 GAIN
SMAD2 rs7228393 rs 1792670 0.91 G 0.445 0.039 0.89 GAIN
KIAA 0427 rs2175565 rs9952398 1.00 C 0.253 0.003642 1.41 CATIE
KIAAO 427 rs8095199 rs 1384227 0.51 C 0.254 0.004491 0.84 GAIN
KIAA 0427 rs8095199 rs8083702 0.51 C 0.251 0.04846 0.80 CATIE
SMAD4 rsl2458752 rs 1789223 0.53 G 0.365 0.03536 0.89 GAIN
SMAD4 rsl2958604 rs 1789223 0.53 G 0.365 0.03536 0.89 GAIN
SMAD4 rs2276163 rs 1789223 0.53 G 0.365 0.03536 0.89 GAIN
SMAD4 rs2298617 rs 1789223 0.53 G 0.365 0.03536 0.89 GAIN
SMAD4 rs3764465 rs 1789223 0.53 G 0.365 0.03536 0.89 GAIN
DCC rs 1893572 rs882333 0.76 T 0.326 0.03294 1.26 CATIE
BMP7 rsl62316 rsl62313 0.57 T 0.109 0.01705 0.81 GAIN
BMP7 rsl62316 rs6127980 0.57 A 0.152 0.03952 1.35 CATIE
Example 2: Novel Markers Associated with Olanzapine Response
To assess drug response, the last observation for each patient in treatment Phase 1 of the CATIE trial was used as a primary assessment of efficacy. The standard FDA registration trial definition of response of >20% decrease in Positive and Negative Syndrome Scale (PANSS Total Score) was used to assign subjects to a response category. Individuals having composite ordinal effectiveness outcome (COMPEFF) scores of 1 of 2, indicating efficacy, were combined as were those with scores of 3 or 4, indicating lack of efficacy (Davis et al., Schizophr. Bull. 29:73-80 (2003)). The side effects category consisted of individuals discontinued for safety concerns (COMPEFF score 5).
Genetic analysis to document the influence of haplotypes on olanzapine response was performed using as described in Example 1 with the PLINK 1.03 whole genome analysis toolset developed by Purcell and coworkers (Purcell et al., Am. J. Hum. Genet. 81 :559-575 (2007)). PLINK calculates P values for the allele-specific chi-squared test and the odds ratio (OR; or relative risk) associated with the minor allele.
Confirmation of SNP effects on olanzapine response and side effects:
Tables 2 and 3 report the minor allele frequencies, P values, and ORs for SNPs in Tables B and C, that affect olanzapine response and side effect rates, respectively. Note in Tables 2 and 3 that haplotype blocks result in the same Test SNP being in linkage disequilibrium with multiple SNPs in Table B. Similarly, haplotype blocks result in multiple Test SNPs that can be used for each SNP listed in Table B, though such redundant examples are not presented in Tables 2 and 3. Tables 2 and 3, provide numerous examples of SNP-based alleles that predict altered response to olanzapine. For Table 2, ORs of > 1.0 indicate that the minor SNP allele is associated with greater clinical improvement, and ORs of < 1.0 indicate that the minor SNP allele is associated with decreased susceptibility. For Table 3 ORs of > 1.0 indicate that the minor SNP allele is associated with an increase in study ending side effects, and ORs of < 1.0 indicate that the minor SNP allele is associated a decrease in study ending side effects.
Table 2: Alleles Affecting Positive Response to Olanzapine
2
Gene Name Table B Test SNP in r Allele Frequency P OR
SNP linkage in disequilibrium responders
CAMTAl rs449250 rs277675 0.82 C 0.306 0.01603 0.47
CAMTAl rs6577393 rs6657847 0.51 T 0.264 0.01963 0.47
CAMTAl rs6577401 rs4243823 0.53 A 0.361 0.0152 0.48
CAMTAl rs7554752 rsl0864255 0.96 T 0.458 0.0121 2.18
PER3 rs2640909 rs228652 0.70 A 0.361 0.01662 2.21
RP1-21O18.1 rs4661572 rsl 000313 0.63 G 0.250 0.01139 2.69
RP1-21O18.1 rs6674129 rs6665012 0.74 G 0.347 0.0226 0.50
KCND3 rs 197422 rsl97412 0.94 C 0.556 0.02599 1.96
KCND3 rs3738298 rs544941 0.65 T 0.206 0.04845 2.29
DNM3 rs 10489730 rsl0910966 1.00 C 0.444 0.0202 2.06
DNM3 rs 10752946 rslO63412 0.97 G 0.542 0.04115 1.85
DNM3 rs3736791 rsl0910966 0.93 C 0.444 0.0202 2.06
DNM3 rs4576686 rsl0910966 0.79 C 0.444 0.0202 2.06
SYTU rsl 1119426 rs6701631 1.00 T 0.250 0.01892 2.48
DPH3 rs2245708 rs2470508 0.97 T 0.514 0.0172 2.06
DPH3 rs2245721 rs842254 1.00 T 0.343 0.02042 0.49
DPH3 rs842257 rs842254 1.00 T 0.343 0.02042 0.49
DPH3 rs859703 rs842254 1.00 T 0.343 0.02042 0.49
ANK3 rsl0733757 rsl 0761446 0.90 C 0.306 0.01208 2.44
ANK3 rs4568956 rsl 0761446 0.57 C 0.306 0.01208 2.44
ANK3 rs7907721 rsl 0761446 0.50 C 0.306 0.01208 2.44
USHlC rsl 6770 rs2237961 0.92 C 0.042 0.02566 0.26
NAV2 rs2585788 rs2625312 0.84 A 0.292 0.04703 2.02
DAAMl rslO143918 rs6573250 0.69 T 0.542 0.00853 2.22
DAAMl rsl252989 rs7143953 0.67 T 0.286 0.03629 0.51
DAAMl rsl253005 rs7143953 0.66 T 0.286 0.03629 0.51
DAAMl rsl268579 rsl7096088 0.60 G 0.069 0.03473 0.34
DAAMl rs4127823 rsl2589351 0.61 C 0.528 0.03651 1.88
DAAMl rs4901909 rs7143953 0.60 T 0.286 0.03629 0.51
DAAMl rs8022614 rs7143953 0.93 T 0.286 0.03629 0.51
DAAMl rs941884 rs7143953 0.51 T 0.286 0.03629 0.51
GPR135 rsl0136708 rsl253170 0.67 T 0.556 0.01391 2.10
GPR135 rslO138199 rsl253170 0.54 T 0.556 0.01391 2.10
GPR135 rsl253181 rsl253170 0.74 T 0.556 0.01391 2.10
GPR135 rsl 7255731 rsl273156 0.62 T 0.597 0.03629 1.88
GPR135 rs4898989 rsl253170 0.54 T 0.556 0.01391 2.10
GPR135 rs9323348 rsl 253170 0.54 T 0.556 0.01391 2.10
EMLl rsl 1160553 rsl 1623084 0.88 C 0.485 0.0387 1.91
EMLl rsl2433613 rsl 1623084 0.77 C 0.485 0.0387 1.91
EMLl rs2250718 rsl 0150225 0.53 T 0.667 0.01353 2.14
EMLl rs2273707 rsl 0150225 1.00 T 0.667 0.01353 2.14 Table 2: Alleles Affecting Positive Response to Olanzapine
Gene Name Table B Test SNP in r2 Allele Frequency P OR
SNP linkage in disequilibrium I responders
EMLl rs6575751 rsl 1623084 0.88 C 0.485 0.0387 1.91
HERC2 rs 1635168 rs8041209 0.87 T 0.028 0.02867 0.21
HERC2 rs2238289 rs8041209 0.51 T 0.028 0.02867 0.21
HERC2 rs7495174 rs8041209 0.58 T 0.028 0.02867 0.21
UNC13C rsl2910912 rsl2900128 0.52 C 0.361 0.01107 2.34
NEDD4 rs2303579 rslO518831 0.51 G 0.194 0.02723 2.61
NEDD4 rs2303580 rslO518831 0.51 G 0.194 0.02723 2.61
SV2B rsl l630131 rsl002556 0.83 C 0.250 0.01139 2.69
SV2B rs2073967 rsl002556 0.51 C 0.250 0.01139 2.69
SLCO3Λ1 rsl517618 rs207954 0.72 T 0.167 0.00355 0.35
SLCO3A1 rs2176452 rs8027160 0.58 G 0.444 0.02815 1.98
IGFlR rs4966020 rsl l633717 0.88 C 0.236 0.02174 0.47
IGFlR rs7174918 rsl l633717 0.88 C 0.236 0.02174 0.47
IGFlR rs8038015 rsl l633717 0.82 C 0.236 0.02174 0.47
NDRG4 rs 1058132 rsl 058132 N/A T 0.371 0.02093 2.15
NDRG4 rs2271948 rslO58132 0.74 T 0.371 0.02093 2.15
NDRG4 rs2280397 rslO58132 0.92 T 0.371 0.02093 2.15
C16orf74 rs2305357 rs442069 0.77 G 0.250 0.00821 0.42
C16orf74 rs373835 rs442069 0.93 G 0.250 0.00821 0.42
C16orf74 rs386061 rs442069 1.00 G 0.250 0.00821 0.42
C16orf74 rs386061 rs386061 N/A C 0.278 0.01847 0.47
KIAA0427 rs8094634 rslO23943 0.72 T 0.208 0.0413 0.49
SMAD 7 rs 11874392 rsl2953717 0.65 T 0.528 0.02717 1.95
SMAD 7 rs736839 rs2337153 0.73 A 0.486 0.00224 2.59
DYM rs498929 rs577979 0.96 A 0.125 0.01752 0.38
DYM rs833503 rs577979 0.53 A 0.125 0.01752 0.38
NDRG4 rs 1058132 rsl 058132 N/A T 0.371 0.02093 2.15
UNC13C rsl2910912 rsl2910912 N/A G 0.250 0.01139 2.69
SV2B rsl l630131 rsl l630131 N/A A 0.222 0.01349 2.78
Table 3: Alleles Affecting Negative Side Effects for Olanzapine
Gene Table B Test SNP in r2 Allele Frequency in P OR
Name SNP linkage discontinuers disequilibrium
CAMTAl rsl417986 rs2301488 0.54 T 0.630 0.03409 2.08
CAMTAl rs7554752 rsl 7030082 0.63 A 0.239 0.02475 0.43
DNM3 rsl 0752946 rsl 063412 0.97 G 0.283 0.009837 0.39
DNM3 rsl3932 rs9425606 0.75 G 0.130 0.007451 0.30
DNM3 rs2206543 rs6690848 0.52 G 0.500 0.03358 2.06
DNM3 rs4075021 rsl2075807 0.71 G 0.565 0.03158 2.09
DNM3 rs4382763 rs4072117 1.00 C 0.326 0.01406 2.55
DNM3 rs6701033 rs6690848 0.52 G 0.500 0.03358 2.06
DNM3 rs965051 rs6690848 0.52 G 0.500 0.03358 2.06
RHOG rsl 1030008 rsl 1030008 N/A G 0.522 0.01711 2.25 Table 3: Alleles Affecting Negative Side Effects for Olanzapine
Gene Table B Test SNP in r2 Allele Frequency in P OR
Name SNP linkage discontinuers disequilibrium
RHOG rs 1451722 rs 11030008 0.76 G 0.522 0.01711 2.25
RHOG rs 11030008 rs 11030008 N/A G 0.522 0.01711 2.25
OTOG rs 1003490 rs 11024348 0.77 T 0.370 0.003588 2.93
OTOG rs 10832824 rs 11024348 0.52 T 0.370 0.003588 2.93
OTOG rs 11024357 rs869108 0.85 G 0.370 0.0001953 4.10
OTOG rs 11024358 rs869108 0.85 G 0.370 0.0001953 4.10
OTOG rs2023483 rs 11024348 0.50 T 0.370 0.003588 2.93
OTOG rs 11024357 rs 11024357 N/A C 0.370 0.0001953 4.10
NΛV2 rs2585788 rs2625312 0.84 A 0.065 0.00435 0.19
NAV2 rs6483629 rsl2099330 0.59 T 0.261 0.0278 2.47
NΛV2 rs7125647 rs2119981 0.61 A 0.238 0.004283 0.33
ULKl rsl l616018 rs 10794440 0.51 G 0.087 0.02249 0.30
ULKl rs9652059 rs 10794440 0.55 G 0.087 0.02249 0.30
TTC5 rsl953552 rsl 1623837 0.60 G 0.261 0.02693 0.44
TEPl rsl713418 rsl713419 1.00 G 0.283 0.04278 0.48
DAAMl rs4127823 rsl2589351 0.61 C 0.304 0.04536 0.49
GPR135 rsl0136708 rsl 253170 0.67 T 0.304 0.0307 0.46
GPR135 rslO138199 rsl 253170 0.54 T 0.304 0.0307 0.46
GPR135 rsl253181 rsl 253170 0.74 T 0.304 0.0307 0.46
GPR135 rs4898989 rsl 253170 0.54 T 0.304 0.0307 0.46
GPR135 rs9323348 rsl 253170 0.54 T 0.304 0.0307 0.46
RTNl rsl0145080 rsl2878097 0.55 C 0.087 0.01469 0.28
RTNl rs 12717467 rsl7731838 0.52 T 0.087 0.01821 0.29
RTNl rs 17310036 rsl 957311 0.79 A 0.182 0.008994 0.34
EVL rs4905933 rsl0148930 0.85 A 0.283 0.004807 0.36
EVL rs726514 rsl0148930 0.85 A 0.283 0.004807 0.36
HERC2 rsl635168 rs2346050 0.87 C 0.152 0.03438 3.05
HERC2 rs2238289 rs2346050 0.51 C 0.152 0.03438 3.05
HERC2 rs7495174 rs2346050 0.58 C 0.152 0.03438 3.05
UNC13C rs 11856476 rs8024165 0.84 T 0.413 0.01984 2.28
UNC13C rs 12594549 rs2115820 0.90 G 0.068 0.04824 0.30
UNC13C rsl2914912 rs8024165 0.63 T 0.413 0.01984 2.28
UNC13C rs4776216 rs8024165 0.52 T 0.413 0.01984 2.28
NEDD4 rs 17238461 rs9972348 0.57 G 0.326 0.04861 2.10
Gcoml rs 1908202 rs2470360 0.64 T 0.413 0.03002 2.15
GRINLlA rs2069133 rsl 873993 0.84 G 0.522 0.02761 2.12
ADAMlO rs3764196 rs7164844 0.51 C 0.043 0.02586 0.21
N4BP1 rs 1039342 rs8046716 0.61 T 0.348 0.04956 0.50
N4BP1 rs 1120276 rs8046716 0.61 T 0.348 0.04956 0.50
N4BP1 rsl224 rs8046716 0.61 T 0.348 0.04956 0.50
N4BP1 rs2354580 rs8046716 1.00 T 0.348 0.04956 0.50
N4BP1 rs3826176 rs8046716 1.00 T 0.348 0.04956 0.50
N4BP1 rs9937623 rs8046716 0.59 T 0.348 0.04956 0.50
CDH8 rs4636897 rsl 1641508 1.00 A 0.023 0.03974 0.15
BEAN rs4247350 rs4247350 N/A C 0.174 0.02628 0.40
KIAA0513 rs4783121 rs4783121 N/A A 0.087 0.01362 6.76
KIAA0182 rs736845 rs736845 N/A T 0.182 0.04535 0.43
PMP22 rs 13422 rs230911 0.59 A 0.326 0.03223 0.47
PMP22 rs230938 rs230911 0.61 A 0.326 0.03223 0.47
PMP22 rs231018 rs230911 0.75 A 0.326 0.03223 0.47 Table 3: Alleles Affecting Negative Side Effects for Olanzapine
Gene Table B Test SNP in r2 Allele Frequency in P OR
Name SNP linkage discontinuers disequilibrium
PMP22 rs231021 rs230911 0.78 A 0.326 0.03223 0.47
FUSSEL18 rs892583 rs7244178 0.68 T 0.217 0.009474 0.37
FUSSEL18 rs892583 rs892583 N/A G 0.205 0.04865 0.45
DCC rs 12457407 rs 11876282 0.65 G 0.591 0.04231 2.02
DCC rsl393331 rs 17506154 1.00 C 0.587 0.01453 2.30
DCC rs4940251 rs 17506154 0.53 C 0.587 0.01453 2.30
DCC rs6508145 rs 1031062 0.67 G 0.065 0.01905 0.25
DCC rs6508235 rs2036415 0.58 G 0.548 0.03016 2.14
DCC rs7506904 rs 11876282 0.58 G 0.591 0.04231 2.02
DCC rs8097413 rs 10502969 1.00 C 0.196 0.01433 3.21
DCC rs950278 rs 11876282 0.56 G 0.591 0.04231 2.02
TMEPAI rs427278 rs203386 0.51 C 0.591 0.0107 2.43
Example 3: Novel Markers Associated with Risperidone Response
To assess drug response, the last observation for each patient in treatment Phase 1 of the CATIE trial was used as a primary assessment of efficacy. The standard FDA registration trial definition of response of >20% decrease in Positive and Negative Syndrome Scale (PANSS Total Score) was used to assign subjects to a response category. Individuals having composite ordinal effectiveness outcome (COMPEFF) scores of 1 of 2, indicating efficacy, were combined as were those with scores of 3 or 4, indicating lack of efficacy (Davis et al., Schizophr. Bull. 29:73-80 (2003)). The side effects category consisted of individuals discontinued for safety concerns (COMPEFF score 5).
Genetic analysis to document the influence of haplotypes on risperidone response was performed using as described in Example 2 with the PLINK 1.03 whole genome analysis toolset developed by Purcell and coworkers (Purcell et al., Am. J. Hum. Genet. 81 :559-575 (2007)). PLINK calculates P values for the allele-specific chi-squared test and the odds ratio (OR; or relative risk) associated with the minor allele.
Confirmation of SNP effects on risperidone response and side effects:
Tables 4 and 5 report the minor allele frequencies, P values, and ORs for SNPs, in Tables B and C that affect risperidone response and side effect rates, respectively. Note in Tables 4 and 5 that haplotype blocks result in the same Test SNP being in linkage disequilibrium with multiple SNPs in Table B. Similarly, haplotype blocks result in multiple Test SNPs that can be used for each SNP listed in Table B, though such redundant examples are not presented in Tables 4 and 5.
Tables 4 and 5, provide numerous examples of SNP-based alleles that predict altered response to risperidone. For Table 4, ORs of > 1.0 indicate that the minor SNP allele is associated with greater clinical improvement, and ORs of < 1.0 indicate that the minor SNP allele is associated with lesser clinical improvement. For Table 5 ORs of > 1.0 indicate that the minor SNP allele is associated with an increase in study ending side effects, and ORs of < 1.0 indicate that the minor SNP allele is associated a decrease in study ending side effects.
Table 4: Alleles Affecting Positive Response to Risperidone
Gene Name Table B Test SNP in r2 Allele Frequency P OR
SNP linkage in disequilibrium responders
RERE rsl2136689 rsl 0779702 0.76 A 0.266 0.03124 0.49
RERE rs8627 rsl 0779702 0.52 A 0.266 0.03124 0.49
DNM3 rs4382763 rs6701929 0.84 C 0.156 0.04448 0.46
RABGAPlL rs6425302 rsl 793319 0.59 A 0.500 0.02472 2.00
CACNAlE rs 199960 rs3856093 0.51 C 0.281 0.04197 0.51
CACNAlE rs3856090 rs3856093 1.00 C 0.281 0.04197 0.51
ANK3 rs2393607 rs2393602 0.56 C 0.484 0.04133 1.88
PTPN5 rs4345940 rs4757718 0.53 G 0.219 0.04081 0.49
SYT13 rsl 1038382 rs7943596 1.00 C 0.194 0.03562 0.46
SYT13 rs2863182 rs7943596 0.84 C 0.194 0.03562 0.46
SYT13 rs4992029 rs7943596 0.61 C 0.194 0.03562 0.46
CHFR rs3741494 rs3741494 N/A T 0.194 0.0429 2.40
JPH4 rsl 2897422 rsl 2897422 N/A A 0.188 0.00592 3.58
DAAMl rs4898983 rs2099636 0.96 A 0.203 0.03748 0.48
NEDD4 rs2303579 rslO518831 0.51 G 0.266 0.002306 3.31
NEDD4 rs2303580 rslO518831 0.51 G 0.266 0.002306 3.31
GRINLlA rs4774275 rsl 873995 0.51 G 0.359 0.0403 0.53
Gcoml rs986868 rsl lO71337 0.59 C 0.609 0.01971 2.05
SLCO3A1 rs2286355 rsl 1630872 0.85 T 0.469 0.03077 1.96
N4BP1 rsl 039342 rs2129243 1.00 T 0.258 0.03604 0.49
N4BP1 rsl 120276 rs2129243 1.00 T 0.258 0.03604 0.49
N4BP1 rsl 224 rs2129243 1.00 T 0.258 0.03604 0.49
N4BP1 rs2354580 rs2129243 0.61 T 0.258 0.03604 0.49
N4BP1 rs3826176 rs2129243 0.61 T 0.258 0.03604 0.49
N4BP1 rs9937623 rs2129243 0.96 T 0.258 0.03604 0.49
CBLNl rsl 1076478 rsl2598711 0.89 G 0.422 0.01435 2.19
CBLNl rs9935379 rsl2598711 0.72 G 0.422 0.01435 2.19
CDH8 rsl397131 rs9925201 0.76 G 0.594 0.02591 1.98
CDH8 rs8057338 rs9925201 0.79 G 0.594 0.02591 1.98
CDH8 rs9302540 rs9925201 0.79 G 0.594 0.02591 1.98
CDH8 rs9302540 rs9302540 N/A G 0.563 0.04052 1.88
SMAD 7 rs736839 rs2337153 0.73 A 0.563 0.003133 2.49
DYM rs8096141 rs7239949 0.87 G 0.113 0.04631 3.18
TMEPAI rs427278 rs203386 0.51 C 0.258 0.03803 0.50 Table 5: Alleles Affecting I Vegative Side Effects for Risperidone
2
Gene Name Table B Test SNP in r Allele Frequency in P OR
SNP linkage discontinuers disequilibrium
CAMTAl rs228651 rsl 1121029 0.51 A 0.000 0.009148 0.00
PER3 rs2640909 rs228652 0.70 A 0.542 0.01808 2.77
RP1-21O18.1 rs2073091 rs761288 0.69 C 0.542 0.004869 3.34
RP1-21O18.1 rs4661572 rs761288 0.56 C 0.542 0.004869 3.34
SLC6A17 rsl2133992 rs2784140 0.90 G 0.708 0.0434 2.54
SLC6A17 rs534276 rs2784140 0.60 G 0.708 0.0434 2.54
KCND3 rs 197422 rsl 97412 0.94 C 0.167 0.01199 0.26
DNM3 rsl3932 rs9425606 0.75 G 0.500 0.00697 3.21
DNM3 rs4382763 rsl2410416 1.00 C 0.417 0.008488 3.20
DNM3 rs4382763 rs4382763 N/A A 0.375 0.0302 2.68
KCNHl rs 1770213 rsl 777264 0.94 C 0.000 0.01943 0.00
DPH3 rs2245708 rs842252 1.00 A 0.583 0.02254 2.68
EXOC2 rs2493049 rs 12154040 0.54 C 0.667 0.00848 3.21
ANK3 rsl551684 rsl 551683 1.00 T 0.292 0.007594 3.71
ANK3 rsl551684 rsl 551684 N/A A 0.250 0.03112 3.04
DEAFl rs4963145 rs936465 0.53 G 0.182 0.002149 0.20
DEAFl rs6597990 rsl 0902190 0.58 T 0.083 0.01958 0.20
DEAFl rs6597996 rs936465 0.58 G 0.182 0.002149 0.20
DEAFl rs936465 rs936465 N/A G 0.182 0.002149 0.20
PTPN5 rs4345940 rs7117716 0.97 T 0.583 0.004185 3.42
PTPN5 rs7932938 rs7117716 0.54 T 0.583 0.004185 3.42
SLC17A6 rsl 1026532 rsl l55331 0.96 T 0.042 0.01523 0.12
SYT13 rs4992029 rs7117240 0.55 C 0.625 0.0497 2.37
SYT13 rs8929 rs7117240 0.54 C 0.625 0.0497 2.37
RTN4RL2 rs2511986 rs2649667 0.87 T 0.000 0.006313 0.00
KIAA1853 rs7297606 rs4075945 1.00 T 0.333 0.0007673 4.88
RIMBP2 rs2277356 rs4759462 0.76 T 0.292 0.0369 2.77
NDRG2 rsl 243444 rsl 243446 0.58 G 0.167 0.01347 0.26
NDRG2 rsl 243446 rsl 243446 N/A G 0.167 0.01347 0.26
DAAMl rsl7833769 rsl958180 0.95 G 0.083 0.03279 0.22
DAAMl rsl958180 rsl 958180 N/A G 0.083 0.03279 0.22
GPR135 rsl0136708 rsl253103 0.54 C 0.250 0.04172 0.38
GPR135 rslO138199 rsl253103 0.88 C 0.250 0.04172 0.38
GPR135 rsl253181 rsl253103 0.71 C 0.250 0.04172 0.38
GPR135 rsl7255731 rsl253103 0.57 C 0.250 0.04172 0.38
GPR135 rs4898989 rsl253103 0.88 C 0.250 0.04172 0.38
GPR135 rs9323348 rsl253103 0.88 C 0.250 0.04172 0.38
HERC2 rsl 1074322 rs6497272 1.00 G 0.083 0.003758 15.55
HERC2 rsl635168 rs6497292 0.87 G 0.208 0.002843 5.40
HERC2 rs2238289 rs6497292 0.51 G 0.208 0.002843 5.40
HERC2 rs7495174 rs6497292 0.58 G 0.208 0.002843 5.40
UNC13C rsl 6974691 rsl 6974712 0.96 T 0.042 0.04931 0.16
SV2B rsl 117388 rsl 117387 1.00 T 0.042 0.03508 0.15
SV2B rs3743444 rsl 117387 0.57 T 0.042 0.03508 0.15
SLCO3A1 rs2176452 rs8027160 0.58 G 0.500 0.01784 2.78
IGFlR rsl 1247380 rs3743258 0.93 A 0.500 0.02156 2.70 Table 5: Alleles Affecting Negative Side Effects for Risperidone
Gene Name Table B Test SNP in r2 Allele Frequency in P OR
SNP linkage discontinuers disequilibrium
IGFlR rsl879613 rs3743258 0.51 A 0.500 0.02156 2.70
CBLNl rs3743777 rs8052939 0.89 G 0.167 0.03498 3.62
CDH8 rs 11075445 rsl3336134 0.80 C 0.583 0.02155 2.72
CDH8 rsl369918 rsl3336134 0.80 C 0.583 0.02155 2.72
CDH8 rsl978796 rsl3336134 0.80 C 0.583 0.02155 2.72
CDH8 rs6498807 rsl3336134 1.00 C 0.583 0.02155 2.72
CDH8 rs9939991 rsl3336134 0.55 C 0.583 0.02155 2.72
CDHIl rs35144 rs40115 1.00 T 0.500 0.01784 2.78
CDHIl rs35148 rs40115 0.68 T 0.500 0.01784 2.78
CDHIl rs35186 rs40115 0.56 T 0.500 0.01784 2.78
CDHIl rs35195 rs35195 N/A A 0.500 0.01938 2.74
CDHIl rs35144 rs35144 N/A C 0.500 0.02156 2.70
DCC rsl393331 rs 1502229 0.84 G 0.136 0.01594 0.24
DCC rs4940251 rs 1502229 0.59 G 0.136 0.01594 0.24
DCC rs6508235 rs 1502229 0.58 G 0.136 0.01594 0.24
Example 4: Novel Markers Associated with Quetiapine Response
To assess drug response, the last observation for each patient in treatment Phase 1 of the CATIE trial was used as a primary assessment of efficacy. The standard FDA registration trial definition of response of >20% decrease in Positive and Negative Syndrome Scale (PANSS Total Score) was used to assign subjects to a response category. Individuals having composite ordinal effectiveness outcome (COMPEFF) scores of 1 of 2, indicating efficacy, were combined as were those with scores of 3 or 4, indicating lack of efficacy (Davis et al., Schizophr. Bull. 29:73-80 (2003)). The side effects category consisted of individuals discontinued for safety concerns (COMPEFF score 5).
Genetic analysis to document the influence of haplotypes on quetiapine response was performed using as described in Example 2 with the PLINK 1.03 whole genome analysis toolset developed by Purcell and coworkers (Purcell et al., Am. J. Hum. Genet. 81 :559-575 (2007)). PLINK calculates P values for the allele-specific chi-squared test and the odds ratio (OR; or relative risk) associated with the minor allele.
Confirmation of SNP effects on quetiapine response and side effects:
Tables 6 and 7 report the minor allele frequencies, P values, and ORs for SNPs, in Tables B and C that affect quetiapine response and side effect rates, respectively. Note in Tables 6 and 7 that haplotype blocks result in the same Test SNP being in linkage disequilibrium with multiple SNPs in Table B. Similarly, haplotype blocks result in multiple Test SNPs that can be used for each SNP listed in Table B, though such redundant examples are not presented in Tables 6 and 7. Tables 6 and 7, provide numerous examples of SNP-based alleles that predict altered response to quetiapine. For Table 6, ORs of > 1.0 indicate that the minor SNP allele is associated with greater clinical improvement, and ORs of < 1.0 indicate that the minor SNP allele is associated with lesser clinical improvement. For Table 7 ORs of > 1.0 indicate that the minor SNP allele is associated with an increase in study ending side effects, and ORs of < 1.0 indicate that the minor SNP allele is associated a decrease in study ending side effects.
Table 6: Alleles Affecting Positive Response to Quetiapine
2
Gene Name Table B Test SNP in i Allele Frequency P OR
SNP linkage in disequilibrium responders
RP1-21O18.1 rs7546786 rs7546786 N/A C 0.340 0.03888 2.12
CACNAlE rs638132 rs678643 ( ).86 G 0.300 0.04268 2.14
CAMKlG rs2356933 rs6683256 [.00 T 0.208 0.02384 0.42
EXOC2 rs2294660 rsl 150856 ( ).55 C 0.280 0.03354 2.28
EXOC2 rs998777 rsl7135931 ( ).66 A 0.300 0.0313 2.26
YPEL4 rs 1798177 rsl798173 ( ).84 T 0.280 0.01513 0.42
YPEL4 rs7947357 rsl798173 ( ).84 T 0.280 0.01513 0.42
CTNNDl rs 10896644 rsl 786438 ( ).97 T 0.313 0.007608 0.40
CTNNDl rsl 1570176 rsl 786438 ( ).97 T 0.313 0.007608 0.40
CTNNDl rs2156638 rsl 786438 [.00 T 0.313 0.007608 0.40
CTNNDl rs652908 rsl 786438 [.00 T 0.313 0.007608 0.40
CTNNDl rs708228 rs576859 [.00 A 0.458 0.01184 2.36
KIAA1853 rs7297606 rs4075945 [.00 T 0.200 0.009895 3.30
STX2 rsl236 rsl 0848205 [.00 T 0.580 0.02392 2.11
STX2 rs4759517 rsl 0848205 ( ).81 T 0.580 0.02392 2.11
STX2 rs6486600 rsl 0848205 ( ).79 T 0.580 0.02392 2.11
STX2 rs6486602 rsl 0848205 ( ).81 T 0.580 0.02392 2.11
DACTl rs464582 rs464582 N/A C 0.520 0.03106 2.04
DAAMl rslO143918 rslO873113 ( ).58 T 0.280 0.0335 2.29
DAAMl rsl 1626926 rs4901921 ( ).85 T 0.563 0.01108 2.36
DAAMl rs 12147707 rslO873113 ( ).86 T 0.280 0.0335 2.29
DAAMl rsl 7095965 rslO873113 ( ).86 T 0.280 0.0335 2.29
DAAMl rs4127823 rs4901921 ( ).6O T 0.563 0.01108 2.36
GPR135 rsl0136708 rsl253103 ( ).54 C 0.280 0.04103 0.49
GPR135 rslO138199 rsl253103 ( ).88 C 0.280 0.04103 0.49
GPR135 rsl253181 rsl253103 ( ).71 C 0.280 0.04103 0.49
GPR135 rsl 7255731 rsl253103 ( ).57 C 0.280 0.04103 0.49
GPR135 rs4898989 rsl253103 ( ).88 C 0.280 0.04103 0.49
GPR135 rs9323348 rsl253103 ( ).88 C 0.280 0.04103 0.49
RTNl rsl0145080 rsl7731838 ( ).65 T 0.100 0.008147 0.28
RTNl rsl 2717467 rsl7731838 ( ).52 T 0.100 0.008147 0.28
RTNl rsl 7310036 rsl7731838 ( ).81 T 0.100 0.008147 0.28
EMLl rs2273704 rsl2590861 ( ).61 C 0.500 0.001846 2.84
EMLl rs7143905 rsl2590861 ( ).7O C 0.500 0.001846 2.84
EMLl rs2273704 rs2273704 N/A C 0.520 0.01052 2.34
EVL rs3206354 rsl2431406 ( ).58 C 0.140 0.007758 4.53
UNC13C rs9920139 rsl961635 ( ).55 T 0.200 0.03866 2.52
UNC13C rs9920150 rsl961635 ( ).61 T 0.200 0.03866 2.52
Gcoml rs986868 rsl 1071337 ( ).59 C 0.640 0.003757 2.64
AKAP13 rsl 053992 rsl 2440599 ( ).61 T 0.460 0.04784 1.94
AKAP13 rsl 1073502 rs2291048 ( ).53 A 0.174 0.03896 0.42
AKAP13 rs2061821 rsl 2440599 ( ).96 T 0.460 0.04784 1.94 Table 6: Alleles Affecting Positive Response to Quetiapine
2
Gene Name Table B Test SNP in r Allele Frequency P ( JR
SNP linkage in disequilibrium responders
AKAPU rs2061822 rs 12440599 0.89 T 0.460 0.04784 [.94
AKAP13 rs2061824 rs 12440599 0.96 T 0.460 0.04784 [.94
AKAPU rs338523 rs 12440599 0.96 T 0.460 0.04784 [.94
AKAPU rs4075254 rs 12440599 0.96 T 0.460 0.04784 [.94
AKAPU rs4075256 rs 12440599 0.96 T 0.460 0.04784 [.94
AKAPU rs4842895 rs 12440599 0.76 T 0.460 0.04784 [.94
AKAPU rs4843074 rs 12440599 0.96 T 0.460 0.04784 [.94
AKAPU rs4843075 rs 12440599 0.96 T 0.460 0.04784 [.94
AKAPU rs7162168 rs 12440599 0.96 T 0.460 0.04784 [.94
SV2B rs 1075840 rs 1079535 0.87 A 0.480 0.02175 _ U5
SV2B rs2301665 rs 1079535 0.74 A 0.480 0.02175 _ U5
SV2B rs8027498 rs 1079535 0.60 A 0.480 0.02175 _ U5
RGMA rsl3167 rsl 1074130 0.59 T 0.180 0.003617 <■ 1.30
IGFlR rs 11247380 rsl521481 0.73 C 0.240 0.02095 ( ).43
IGFlR rs2684808 rs951715 0.51 G 0.260 0.02238 ( ).44
IGFlR rs8030950 rsl879612 0.66 C 0.188 0.02051 ( ).4O
BEAN rs4247350 rsl 1645280 0.61 G 0.417 0.02122 : 1.22
FUSSEL18 rs892583 rs2164098 0.95 G 0.420 0.01515 _ 130
FUSSEL18 rs892583 rs892583 N/A G 0.391 0.04015 _ >.08
KIAA0427 rs2175565 rsl 2456253 0.68 G 0.220 0.03731 ( ).46
KIAA0427 rs4939813 rsl 994559 0.53 A 0.240 0.006482 : 5.18
KIAA0427 rs937021 rsl2458062 0.52 T 0.600 0.03871 [.98
DCC rs 12457407 rs7506909 0.93 A 0.520 0.01922 : U7
DCC rsl393331 rsl 7504520 0.78 G 0.587 0.02781 _ U2
DCC rs2229080 rs9966074 0.60 T 0.340 0.01745 ( ).45
DCC rs4940251 rs7506909 0.67 A 0.520 0.01922 : U7
DCC rs6508145 rsl 454731 0.82 C 0.320 0.01176 _ 1.57
DCC rs6508235 rsl 0515959 0.77 T 0.340 0.03565 _ >.13
DCC rs7506904 rs7506909 0.83 A 0.520 0.01922 : U7
DCC rs950278 rs9966074 0.87 T 0.340 0.01745 ( ).45
Table 7: Alleles Affecting Negative Side Effects for Quetiapine
Gene Name Table B Test SNP in r2 Allele Frequency in P OR
SNP linkage discontinuers disequilibrium
CAMTAl rs845197 rs845265 0.91 T 0.095 0.02848 0.31
RERE rs7530745 rs6577499 1.00 G 0.273 0.03893 0.46
RERE rs7554486 rs6577499 0.65 G 0.273 0.03893 0.46
SLC16A4 rsl0857820 rs3768458 0.65 T 0.318 0.04016 0.48
SLC16A4 rsl334882 rs3768458 1.00 T 0.318 0.04016 0.48
KCNAlO rs3768456 rs7543509 1.00 G 0.182 0.0001722 8.1 1
CACNAlE rs 17494681 rsl 7494681 N/A T 0.296 0.0268 2.40
CACNAlE rs3856090 rs7534913 0.50 G 0.381 0.04817 0.50
KCNHl rs4620600 rs4951495 0.79 A 0.068 0.01863 0.25
ANK3 rs2393596 rslO761451 0.78 G 0.159 0.04472 0.41 Table 7: Alleles Affecting Negative Side Effects for Quetiapine
Gene Name Table B Test SNP in r2 Allele Frequency in P OR
SNP linkage discontinuers disequilibrium
DEAFl rs7109335 rs7123677 0.84 T 0.227 0.03893 2.46
DEAFl rs7121608 rs7123677 0.92 T 0.227 0.03893 2.46
DEAFl rs7935419 rs7123677 0.92 T 0.227 0.03893 2.46
USHlC rs 10766408 rs2041032 0.51 T 0.568 0.01695 2.27
USHlC rs2041027 rs2041032 0.78 T 0.568 0.01695 2.27
USHlC rs2237957 rs2041032 0.69 T 0.568 0.01695 2.27
KCNCl rs 10766434 rs2299637 0.66 A 0.455 0.01364 2.37
KCNCl rs2299637 rs2299637 N/A A 0.455 0.01364 2.37
KCNCl rs757514 rs2299637 0.66 A 0.455 0.01364 2.37
NAV2 rsl0833202 rsl 1025328 0.61 A 0.727 0.001805 3.13
SLC17A6 rs 11026523 rs 1562445 0.79 A 0.068 0.008164 0.22
SLC17A6 rs 1155821 rsl 562445 0.96 A 0.068 0.008164 0.22
SLC17A6 rs2078352 rsl 562445 1.00 A 0.068 0.008164 0.22
SLC17A6 rs2246710 rsl 562445 1.00 A 0.068 0.008164 0.22
SLC17A6 rs2078352 rs2078352 N/A T 0.068 0.01127 0.23
LRRC4C rsl0837367 rsl0501225 0.69 A 0.023 0.03099 0.14
RTN4RL2 rs2511986 rs2649667 0.87 T 0.409 0.04498 2.04
KIAA1853 rs7297606 rs4075945 1.00 T 0.023 0.04399 0.16
CHFR rs2306536 rsl l l47101 1.00 G 0.091 0.04245 0.34
CHFR rs4758954 rsl l l47101 1.00 G 0.091 0.04245 0.34
GPR135 rsl0136708 rsl253103 0.54 C 0.546 0.02737 2.13
GPR135 rslO138199 rs2774052 0.72 A 0.614 0.01223 2.38
GPR135 rsl253181 rs2774052 0.89 A 0.614 0.01223 2.38
GPR135 rs 17255731 rs2774052 0.70 A 0.614 0.01223 2.38
GPR135 rs4898989 rs2774052 0.72 A 0.614 0.01223 2.38
GPR135 rs9323348 rs2774052 0.72 A 0.614 0.01223 2.38
EMLl rs2273704 rsl2590861 0.61 C 0.182 0.02262 0.39
EMLl rs7143905 rsl2590861 0.70 C 0.182 0.02262 0.39
EVL rs 1190954 rsl 190967 0.96 G 0.182 0.02583 0.40
EVL rs 1190956 rsl 190967 0.60 G 0.182 0.02583 0.40
EVL rs 1190974 rsl 190967 0.96 G 0.182 0.02583 0.40
WDR25 rslO873518 rs7492607 0.97 C 0.523 0.01011 2.43
UNC13C rs 11856476 rs8023723 0.53 G 0.477 0.04506 2.00
UNC13C rsl2914912 rs8023723 0.86 G 0.477 0.04506 2.00
UNC13C rs4776216 rs8023723 1.00 G 0.477 0.04506 2.00
NEDD4 rs 17238461 rs2175104 0.53 A 0.048 0.04132 0.24
AKAP13 rs338556 rs870689 0.91 A 0.136 0.009364 4.58
KLHL25 rs2430838 rs870689 1.00 A 0.136 0.009364 4.58
KLHL25 rs2430838 rs2430838 N/A T 0.114 0.03635 3.67
SLCO3A1 rs2176452 rs8027160 0.58 G 0.136 0.01379 0.33 Table 7: Alleles Affecting Negative Side Effects for Quetiapine
Gene Name Table B Test SNP in r2 Allele Frequency in P OR
SNP linkage discontinuers disequilibrium
NETO2 rsl 1859615 rs9928466 0.85 C 0.000 0.03539 0.00
NETO2 rsl6952126 rs9928466 0.85 C 0.000 0.03539 0.00
NETO2 rs7184206 rs9928466 1.00 C 0.000 0.03539 0.00
NETO2 rs9923731 rs9928466 0.85 C 0.000 0.03539 0.00
ZNF423 rsl2924119 rs2883977 0.51 C 0.341 0.005838 2.86
NDRG4 rsl3333449 rsl6960170 0.80 C 0.341 0.03824 2.18
NDRG4 rs7202037 rsl6960170 0.67 C 0.341 0.03824 2.18
CDH8 rsl397131 rsl 6964164 0.90 T 0.523 0.02822 2.13
CDH8 rs8057338 rsl 6964164 0.93 T 0.523 0.02822 2.13
CDH8 rs9302540 rsl 6964164 0.93 T 0.523 0.02822 2.13
CDHIl rs35144 rs40115 1.00 T 0.477 0.03109 2.12
CDHIl rs35148 rs40115 0.68 T 0.477 0.03109 2.12
CDHIl rs35186 rs40115 0.56 T 0.477 0.03109 2.12
CDHIl rs35195 rs35195 N/A A 0.477 0.04506 2.00
CDHIl rs35186 rs35186 N/A T 0.619 0.03313 2.13
BEAN rs4247350 rslO63438 0.59 A 0.182 0.006152 0.32
KIAA 0427 rs2306514 rs2306514 N/A G 0.500 0.02294 2.19
KIAA 0427 rs752151 rs2337099 0.83 G 0.136 0.003807 5.76
KIAAO 427 rs937021 rsl2458062 0.52 T 0.341 0.044 0.49
TMEPAI rs427278 rs203386 0.51 C 0.250 0.02943 0.44
Example 5: Novel Markers Associated with Perphenazine Response
To assess drug response, the last observation for each patient in treatment Phase 1 of the CATIE trial was used as a primary assessment of efficacy. The standard FDA registration trial definition of response of >20% decrease in Positive and Negative Syndrome Scale (PANSS Total Score) was used to assign subjects to a response category. Individuals having composite ordinal effectiveness outcome (COMPEFF) scores of 1 of 2, indicating efficacy, were combined as were those with scores of 3 or 4, indicating lack of efficacy (Davis et al., Schizophr. Bull. 29:73-80 (2003)). The side effects category consisted of individuals discontinued for safety concerns (COMPEFF score 5).
Genetic analysis to document the influence of haplotypes on perphenazine response was performed using as described in Example 2 with the PLINK 1.03 whole genome analysis toolset developed by Purcell and coworkers (Purcell et al., Am. J. Hum. Genet. 81 :559-575 (2007)). PLINK calculates P values for the allele-specific chi-squared test and the odds ratio (OR; or relative risk) associated with the minor allele. Confirmation of SNP effects on perphenazine response and side effects:
Tables 8 and 9 report the minor allele frequencies, P values, and ORs for SNPs, in Tables B and C that affect perphenazine response and side effect rates, respectively. Note in Tables 8 and 9 that haplotype blocks result in the same Test SNP being in linkage disequilibrium with multiple SNPs in Table B. Similarly, haplotype blocks result in multiple Test SNPs that can be used for each SNP listed in Table B, though such redundant examples are not presented in Tables 8 and 9.
Tables 8 and 9, provide numerous examples of SNP-based alleles that predict altered response to perphenazine. For Table 8, ORs of > 1.0 indicate that the minor SNP allele is associated with greater clinical improvement, and ORs of < 1.0 indicate that the minor SNP allele is associated with lesser clinical improvement. For Table 9 ORs of > 1.0 indicate that the minor SNP allele is associated with an increase in study ending side effects, and ORs of < 1.0 indicate that the minor SNP allele is associated a decrease in study ending side effects.
Table 8: Alleles Affecting Positive Response to Perphenazine
Gene Name Table B Test SNP in r^ Allele Frequency P OR
SNP linkage in disequilibrium responders
CAMTAl rs6577393 rs6657847 0.51 T 0.391 0.04251 2.04
CAMTAl rs6577401 rs6698901 0.59 G 0.641 0.03272 2.03
RP1-21O18.1 rs4661572 rs4501834 0.60 C 0.242 0.02391 2.68
CACNAlE rs 199960 rs 1953690 0.81 A 0.422 0.04061 2.01
CAMKlG rs9430004 rs9430004 N/A T 0.563 0.01262 2.27
KCNHl rs 1393026 rs7529770 0.52 G 0.323 0.01484 0.44
KCNHl rs 1770220 rs 1777256 1.00 A 0.266 0.007082 0.39
ANK3 rs3750800 rs3750800 N/A A 0.281 0.03529 0.48
TOLLIP rs3168046 rs2672812 0.85 G 0.375 0.03841 0.51
TOLLIP rs3750920 rs2672812 0.85 G 0.375 0.03841 0.51
HCCA2 rs7396514 rs 10734456 0.55 C 0.141 0.03102 0.41
DUSP8 rs 10734456 rs 10734456 N/A C 0.141 0.03102 0.41
DUSP8 rs902224 rs 10734456 0.74 C 0.141 0.03102 0.41
KCNCl rs 10766434 rs 10766426 0.78 G 0.484 0.01735 2.21
KCNCl rs2299637 rs 10766426 0.56 G 0.484 0.01735 2.21
KCNCl rs757514 rs 10766426 0.78 G 0.484 0.01735 2.21
SERGEF rs 172424 rs2299628 0.65 G 0.281 0.02554 0.46
SERGEF rs211130 rs2299628 0.65 G 0.281 0.02554 0.46
SERGEF rs211137 rs2299628 0.65 G 0.281 0.02554 0.46
SERGEF rs211146 rs2299628 1.00 G 0.281 0.02554 0.46
SERGEF rs2283233 rs2299628 1.00 G 0.281 0.02554 0.46
SERGEF rsl528 rsl528 N/A C 0.188 0.007483 4.11
SERGEF rs2283233 rs2283233 N/A C 0.274 0.02958 0.47
NAV2 rs2585788 rs2625312 0.84 A 0.203 0.04449 0.47
SLC17A6 rs 1979072 rs 11026546 1.00 A 0.250 0.009104 3.15
SLC17A6 rs 1979073 rs 11026546 1.00 A 0.250 0.009104 3.15
SLC17A6 rs2593644 rs 11026546 0.88 A 0.250 0.009104 3.15
SLC17A6 rs764021 rs721840 0.97 C 0.242 0.02368 0.44
PHACS rs3107275 rs3134907 0.79 C 0.203 0.02318 0.43
KIAA1853 rs 1568923 rsl0851061 0.58 G 0.188 0.03528 0.45
KIAA1545 rs 10870551 rs4418881 1.00 G 0.234 0.0243 0.44 Table 8: Alleles Affecting Positive Response to Perphenazine
Gene Name Table B Test SNP in r2 Allele Frequency P OR
SNP linkage in disequilibrium responders
KIAA1545 rs4883513 rs4883513 N/A T 0.233 0.01119 0.40
RTNl rs 17255975 rsl884737 0.75 G 0.234 0.01716 2.89
UNC13C rs 11856476 rs8024165 0.84 T 0.438 0.01674 2.27
UNC13C rsl2914912 rs8024165 0.63 T 0.438 0.01674 2.27
UNC13C rs4776216 rs8024165 0.52 T 0.438 0.01674 2.27
UNC13C rs9920139 rs9920150 0.91 G 0.047 0.04211 0.28
UNC13C rs9920150 rs9920150 N/A G 0.047 0.04211 0.28
NEDD4 rs 1509408 rsl 509408 N/A C 0.281 0.03119 2.38
GRINLlA rs 16977631 rsl l638184 0.52 A 0.063 0.004306 0.22
GCOMl rs2733619 rs2733619 N/A C 0.016 0.04231 0.15
AKAP13 rs338556 rs8025135 0.71 G 0.297 0.0149 2.63
KLHL25 rs2430838 rs8025135 0.64 G 0.297 0.0149 2.63
SLCO3A1 rs2286355 rsl 1630872 0.85 T 0.422 0.01222 2.39
SLCO3A1 rs6496893 rsl 1638063 1.00 A 0.047 0.04211 0.28
CBLNl rs 11076478 rs893175 0.53 C 0.484 0.007589 2.46
CBLNl rs3743777 rs8052939 0.89 G 0.094 0.01269 9.62
CBLNl rs9935379 rs893175 0.69 C 0.484 0.007589 2.46
CDHIl rs35144 rs35164 0.68 T 0.145 0.04592 0.43
CDHIl rs35148 rs35164 1.00 T 0.145 0.04592 0.43
BEAN rs 11644279 rsl 1075635 0.59 C 0.266 0.02787 2.47
COXlO rs4792434 rs8077302 0.55 G 0.597 0.01289 2.28
COXlO rs8077302 rs8077302 N/A G 0.597 0.01289 2.28
KATNAL2 rs2247221 rs4986203 0.53 A 0.468 0.04996 1.95
KATNAL2 rs2571030 rs4986203 0.53 A 0.468 0.04996 1.95
KATNAL2 rs9961383 rs4986203 0.53 A 0.468 0.04996 1.95
FUSSEL18 rsl0502880 rsl 1082575 0.55 G 0.339 0.01242 0.43
FUSSEL18 rs 17785419 rsl 1082575 0.55 G 0.339 0.01242 0.43
FUSSEL18 rs2668771 rs9965170 0.56 A 0.406 0.02724 0.49
FUSSEL18 rs7236105 rs9965170 0.88 A 0.406 0.02724 0.49
DCC rs 12457407 rs9949949 0.83 A 0.453 0.03236 2.06
DCC rs 1893572 rs7228674 0.77 T 0.156 0.03404 0.42
DCC rs4940251 rs9949949 0.82 A 0.453 0.03236 2.06
DCC rs7506904 rs9949949 0.93 A 0.453 0.03236 2.06
BMP7 rs230198 rs230191 0.97 T 0.406 0.02724 0.49
TMEPAI rs6015068 rs6015068 N/A T 0.484 0.01161 2.33
Table 9: Alleles Affecting Negative Side Effects i for Perphenazine
2
Gene Name Table B Test SNP in r Allele Frequency in P OR
SNP linkage discontinuers disequilibrium
CAMTAl rsl2070592 rs9434833 1.00 T 0.333 0.02671 2.92
SLC6A17 rs924181 rsl 571346 0.64 G 0.583 0.03113 2.59
KCNC4 rsl 1578913 rsl 1578913 N/A A 0.167 0.04276 0.33
SLC16A4 rsl0857820 rs3768458 0.65 T 0.625 0.04343 2.47
SLC16A4 rsl334882 rs3768458 1.00 T 0.625 0.04343 2.47 Table 9: Alleles Affecting Negative Side Effects for Perphenazine
Gene Name Table B Test SNP in r2 Allele Frequency in P OR
SNP linkage discontinuers disequilibrium
CAMKlG rsl l l l9315 rs 11119315 N/A A 0.292 0.02755 3.04
CAMKlG rs6690557 rs713075 0.80 A 0.500 0.02324 2.72
KCNHl rs 1770220 rsl0863854 0.65 T 0.292 0.04383 0.39
TOLLIP rs3168046 rs2014486 0.85 A 0.667 0.0345 2.62
TOLLIP rs3750920 rs2014486 0.85 A 0.667 0.0345 2.62
OTOG rs2041028 rs734640 0.55 G 0.083 0.03774 0.23
OTOG rs2355466 rs734640 0.55 G 0.083 0.03774 0.23
OTOG rs4757548 rs734640 0.50 G 0.083 0.03774 0.23
OTOG rs7111528 rs734640 0.55 G 0.083 0.03774 0.23
SERGEF rs 172424 rs4141243 0.65 C 0.625 0.009037 3.19
SERGEF rs211130 rs4141243 0.65 C 0.625 0.009037 3.19
SERGEF rs211137 rs4141243 0.65 C 0.625 0.009037 3.19
SERGEF rs211146 rs4141243 1.00 C 0.625 0.009037 3.19
SERGEF rs2283233 rs4141243 1.00 C 0.625 0.009037 3.19
SERGEF rs2283233 rs2283233 N/A C 0.583 0.02427 2.71
PTPN5 rs4274187 rs4075664 0.67 C 0.667 0.04808 2.47
HSDl 7Bl 2 rsl061810 rsl0768983 0.87 G 0.455 0.03089 2.72
HSDl 7Bl 2 rs4755744 rsl0768983 1.00 G 0.455 0.03089 2.72
ZFP91-CNTF rsl938596 rs2509920 0.97 C 0.625 0.04343 2.47
ZFP91-CNTF rs4319530 rs2509920 0.90 C 0.625 0.04343 2.47
KIAA1545 rsl0870551 rs4418881 1.00 G 0.542 0.01977 2.80
EMLl rs2250718 rs3783322 0.70 G 0.250 0.02801 0.34
UNC13C rsl 1639005 rs7163424 0.62 T 0.167 0.03824 0.32
UNC13C rsl2914912 rsl 2912762 0.71 A 0.591 0.0436 2.53
UNC13C rs4776216 rsl 2912762 0.77 A 0.591 0.0436 2.53
UNC13C rs9302181 rs7163424 0.64 T 0.167 0.03824 0.32
AKAP13 rsl6977252 rsl 7623915 0.75 C 0.375 0.005111 3.73
KLHL25 rs2554 rsl 7623915 0.62 C 0.375 0.005111 3.73
SLCO3A1 rsl2912997 rsl 2912997 N/A G 0.542 0.02862 2.62
IGFlR rsl 1247380 rs7165181 0.55 G 0.292 0.04586 2.74
IGFlR rsl879613 rs7165181 0.96 G 0.292 0.04586 2.74
CDH8 rsl 1075445 rsl 1075445 N/A G 0.208 0.02023 0.31
CDH8 rsl369918 rsl 1075445 1.00 G 0.208 0.02023 0.31
CDH8 rsl978796 rsl 1075445 1.00 G 0.208 0.02023 0.31
CDH8 rs6498807 rsl 1075445 0.80 G 0.208 0.02023 0.31
CDH8 rs9939991 rs4784163 0.55 G 0.167 0.04276 0.33
KIAA0513 rs3794684 rs3794682 0.69 A 0.250 0.03871 0.36
KIAA0513 rs4783121 rs715707 1.00 A 0.125 0.01543 6.24
KIAA0513 rs4783121 rs4783121 N/A A 0.125 0.03696 4.64
COXlO rs2302107 rsl 003060 0.89 T 0.042 0.0156 0.12
FUSSEL18 rsl0502880 rsl 7785419 1.00 A 0.292 0.02612 0.35
FUSSEL18 rsl7785419 rsl 7785419 N/A A 0.292 0.02612 0.35
FUSSEL18 rs2668771 rsl 7785419 0.54 A 0.292 0.02612 0.35
FUSSEL18 rs7236105 rsl 7785419 0.85 A 0.292 0.02612 0.35
FUSSEL18 rs892583 rs892583 N/A G 0.500 0.001787 3.96
DYM rs8096141 rsl 6950298 0.61 C 0.167 0.04251 3.63
DCC rs6508145 rsl 031062 0.67 G 0.250 0.02271 3.39 Example 6: Novel Markers Associated with Ziprasidone Response
To assess drug response, the last observation for each patient in treatment Phase 1 of the CATIE trial was used as a primary assessment of efficacy. The standard FDA registration trial definition of response of >20% decrease in Positive and Negative Syndrome Scale (PANSS Total Score) was used to assign subjects to a response category. Individuals having composite ordinal effectiveness outcome (COMPEFF) scores of 1 of 2, indicating efficacy, were combined as were those with scores of 3 or 4, indicating lack of efficacy (Davis et al., Schizophr. Bull. 29:73-80 (2003)). The side effects category consisted of individuals discontinued for safety concerns (COMPEFF score 5).
Genetic analysis to document the influence of haplotypes on ziprasidone response was performed using as described in Example 2 with the PLINK 1.03 whole genome analysis toolset developed by Purcell and coworkers (Purcell et al., Am. J. Hum. Genet. 81 :559-575 (2007)). PLINK calculates P values for the allele-specific chi-squared test and the odds ratio (OR; or relative risk) associated with the minor allele.
Confirmation of SNP effects on ziprasidone response and side effects:
Tables 10 and 11 report the minor allele frequencies, P values, and ORs for SNPs, in Tables B and C that affect ziprasidone response and side effect rates, respectively. Note in Tables 10 and 11 that haplotype blocks result in the same Test SNP being in linkage disequilibrium with multiple SNPs in Table B. Similarly, haplotype blocks result in multiple Test SNPs that can be used for each SNP listed in Table B, though such redundant examples are not presented in Tables 10 and 11.
Tables 10 and 11 , provide numerous examples of SNP -based alleles that predict altered response to ziprasidone. For Table 10, ORs of > 1.0 indicate that the minor SNP allele is associated with greater clinical improvement, and ORs of < 1.0 indicate that the minor SNP allele is associated with lesser clinical improvement. For Table 11 ORs of > 1.0 indicate that the minor SNP allele is associated with an increase in study ending side effects, and ORs of < 1.0 indicate that the minor SNP allele is associated a decrease in study ending side effects.
Table 10: Alleles Affecting Positive Response to Ziprasidone
Gene Name Table B Test SNP in r2 Allele Frequency P OR
SNP linkage in disequilibrium responders
RP1-21O18.1 rs2073091 rs761288 0.69 C 0.235 0.0481 0.40
RP1-21O18.1 rs4661572 rs761288 0.56 C 0.235 0.0481 0.40
KCND3 rs4838924 rsl373291 0.86 T 0.147 0.03358 0.32
RABGAPlL rs 16847624 rslO912854 0.84 C 0.125 0.03253 0.29
RABGAPlL rs6425302 rslO912854 0.96 C 0.125 0.03253 0.29
CACNAlE rs 199960 rs3856093 0.51 C 0.206 0.0147 0.31
CACNAlE rs3856090 rs3856093 1.00 C 0.206 0.0147 0.31
CACNAlE rs506947 rsl6857457 0.93 G 0.219 0.009356 5.69
DPH3 rs2245721 rs842264 0.57 T 0.618 0.03373 2.49 Table 10: Alleles Affecting Positive Response to Ziprasidone
Gene Name Table B Test SNP in r2 Allele Frequency P OR
SNP linkage in disequilibrium responders
DPH3 rs842257 rs842264 0.57 T 0.618 0.03373 2.49
DPH3 rs859703 rs842264 0.57 T 0.618 0.03373 2.49
EXOC2 rs2294660 rs2073008 0.54 T 0.000 0.008039 0.00
EXOC2 rs998777 rs2073008 0.74 T 0.000 0.008039 0.00
BRSK2 rsl554857 rs7396009 0.81 T 0.529 0.04022 2.41
HCCA2 rs7396514 rs7396009 1.00 T 0.529 0.04022 2.41
HCCΛ2 rs7945160 rs7396009 0.55 T 0.529 0.04022 2.41
HCCA2 rs9440 rs7396009 0.55 T 0.529 0.04022 2.41
DUSP8 rs 10734456 rs7396009 0.55 T 0.529 0.04022 2.41
D USP 8 rs902224 rs7396009 0.81 T 0.529 0.04022 2.41
KCNQl rs231348 rs231348 N/A T 0.294 0.003769 5.08
OTOG rs 11024357 rsl 1024357 N/A C 0.353 0.03601 2.73
OTOG rs 11024358 rsl 1024357 1.00 C 0.353 0.03601 2.73
PTPN5 rs4757707 rsl 1024786 0.64 T 0.471 0.01003 3.18
NΛV2 rs7125647 rs2119981 0.61 A 0.618 0.01558 2.83
SLC6A5 rs2001982 rs7950354 0.57 C 0.147 0.02376 0.30
LRRC4C rs2953310 rs2953310 N/A C 0.235 0.01582 0.33
HSDl 7Bl 2 rsl061810 rsl7596617 0.54 T 0.147 0.02376 0.30
HSDl 7Bl 2 rsl0838160 rs938942 0.59 T 0.618 0.04616 2.36
HSDl 7Bl 2 rs3802891 rs938942 0.59 T 0.618 0.04616 2.36
HSDl 7Bl 2 rs4755744 rsl7596617 0.65 T 0.147 0.02376 0.30
ZFP91-CNTF rsl938596 rs2509920 0.97 C 0.559 0.04351 2.37
ZFP91-CNTF rs4319530 rs2509920 0.90 C 0.559 0.04351 2.37
DTX4 rs 1048444 rs544864 0.55 T 0.147 0.03358 0.32
DTX4 rs2211912 rs2211912 N/A A 0.353 0.03477 0.40
DTX4 rs3847 rs544864 0.55 T 0.147 0.03358 0.32
DTX4 rs5029315 rs2211912 1.00 A 0.353 0.03477 0.40
DTX4 rs544864 rs544864 N/A T 0.147 0.03358 0.32
DTX4 rs621162 rs544864 1.00 T 0.147 0.03358 0.32
DTX4 rs656163 rs2211912 0.88 A 0.353 0.03477 0.40
TTC5 rsl0873395 rs8022565 0.77 C 0.441 0.02702 2.68
TTC5 rs2318864 rs8022565 0.73 C 0.441 0.02702 2.68
TTC5 rs3742945 rs8022565 0.73 C 0.441 0.02702 2.68
TTC5 rs2318864 rs2318864 N/A G 0.441 0.04178 2.47
TEPl rsl713449 rsl760909 0.96 T 0.059 0.01999 0.19
TEPl rs7150689 rsl760909 0.87 T 0.059 0.01999 0.19
TEPl rs938886 rsl760909 1.00 T 0.059 0.01999 0.19
TEPl rs938887 rsl760909 0.67 T 0.059 0.01999 0.19
TEPl rsl713449 rsl 713449 N/A T 0.059 0.02358 0.20
DAAMl rsl252989 rsl957409 0.94 A 0.250 0.01917 0.33
DAAMl rsl253005 rsl957409 1.00 A 0.250 0.01917 0.33
DAAMl rsl268579 rs2053298 1.00 T 0.441 0.04178 2.47
DAAMl rs4901909 rsl957409 0.62 A 0.250 0.01917 0.33
DAAMl rs8022614 rsl957409 0.71 A 0.250 0.01917 0.33
DAAMl rs941884 rsl957409 0.72 A 0.250 0.01917 0.33
EMLl rsl 1160553 rs8013843 0.71 T 0.059 0.0113 0.17
EMLl rsl 1160563 rs8020741 0.68 T 0.235 0.02281 0.35
EMLl rsl2433613 rs8013843 0.60 T 0.059 0.0113 0.17
EMLl rs6575751 rs8013843 0.71 T 0.059 0.0113 0.17
WDR25 rslO873518 rsl 1160589 1.00 A 0.529 0.03593 2.48
UNC13C rsl2910912 rsl2910912 N/A G 0.382 0.001068 5.22 Table 10: Alleles Affecting Positive Response to Ziprasidone
Gene Name Table B Test SNP in r2 Allele Frequency P OR
SNP linkage in disequilibrium responders
ADAMlO rs4775086 rs7161889 0.55 C 0.382 0.02825 2.79
ADAMlO rs514049 rs7161889 0.70 C 0.382 0.02825 2.79
ADAMlO rs653765 rs7161889 0.79 C 0.382 0.02825 2.79
AKAPU rs2291049 rsl0520596 0.59 G 0.206 0.0113 5.44
AKAPU rs338556 rs8025135 0.71 G 0.059 0.02358 0.20
KLHL25 rs2430838 rs8025135 0.64 G 0.059 0.02358 0.20
KLHL25 rs2554 rs 10520595 0.50 T 0.353 0.02633 2.95
SV2B rsl l630131 rs6496778 0.55 G 0.441 0.01303 3.10
SV2B rs2073967 rs6496778 0.87 G 0.441 0.01303 3.10
IGFlR rs 11247380 rs4966036 0.55 C 0.265 0.02113 3.60
IGFlR rs 1879613 rs4966036 0.96 C 0.265 0.02113 3.60
IGFlR rs8030950 rsl879612 0.66 C 0.559 0.005 3.38
CBLNl rs 11076478 rs 1469906 0.72 A 0.206 0.004634 0.26
CBLNl rs9935379 rs 1469906 0.90 A 0.206 0.004634 0.26
CBLNl rs9935379 rs9935379 N/A G 0.206 0.02119 0.33
CDH8 rs 11075445 rs 11075445 N/A G 0.559 0.02987 2.53
CDH8 rs 1369918 rs 11075445 1.00 G 0.559 0.02987 2.53
CDH8 rs 1978796 rs 11075445 1.00 G 0.559 0.02987 2.53
CDH8 rs6498807 rsl397126 0.51 G 0.281 0.007855 4.62
CDH8 rs9939991 rs6498806 0.65 A 0.294 0.004701 4.92
CDHIl rs35144 rs4967886 0.65 A 0.265 0.007512 0.30
CDHIl rs35148 rs35164 1.00 T 0.177 0.02306 0.32
CDHIl rs35186 rs35216 0.56 G 0.250 0.03882 0.38
KIAA05U rsl2597135 rs8063083 0.53 C 0.559 0.04351 2.37
KIAA05U rs3751756 rs8063083 0.60 C 0.559 0.04351 2.37
KIAA0182 rs3815794 rslO53328 0.73 T 0.382 0.04528 2.52
FUSSEL18 rs892583 rs 11877471 0.68 G 0.441 0.04178 2.47
KIAAO 427 rs4939813 rs9959212 0.66 A 0.294 0.03491 0.39
DCC rs 1431748 rs7504750 0.63 C 0.412 0.03518 2.60
TMEPAI rs427278 rs203386 0.51 C 0.294 0.01685 0.35
Table 11: Alleles Affecting Negative Side Effects for Ziprasidone
Gene Table B Test SNP in r2 Allele Frequency in P OR
Name SNP linkage discontinuers disequilibrium
RERE rs3753275 rs4581300 0.72 T 0.292 0.01404 4.06
SLC6A17 rsl010892 rsl7671169 0.70 A 0.708 0.02545 3.02
SLC6A17 rs6689641 rsl7671169 0.82 A 0.708 0.02545 3.02
SLC6A17 rs877068 rsl7671169 0.60 A 0.708 0.02545 3.02
SLC6A17 rs924181 rsl7671169 0.53 A 0.708 0.02545 3.02
DNM3 rs 10752946 rs9425598 1.00 A 0.583 0.01857 3.03
CACNAlE rs 199960 rs3856093 0.51 C 0.542 0.04571 2.56
CACNAlE rs3856090 rs3856093 1.00 C 0.542 0.04571 2.56
KCNHl rsl 1119658 rsl875438 0.59 C 0.292 0.04465 0.37
KCNHl rs 1393026 rs7529770 0.52 G 0.625 0.01287 3.27 Table 11: Alleles Affecting Negative Side Effects for Ziprasidone
Gene Table B Test SNP in r2 Allele Frequency in P OR
Name SNP linkage discontinuers disequilibrium
KCNHl rs 1501569 rsl 501555 0.56 G 0.667 0.01802 3.14
OTOG rs2073582 rs972676 0.71 A 0.250 0.04192 0.35
NΛV2 rs 1372989 rsl 982265 0.54 G 0.000 0.02984 0.00
SLC6A5 rs2001982 rs7950354 0.57 C 0.458 0.0371 2.73
SYT13 rs4992029 rs7117240 0.55 C 0.542 0.03343 2.72
SYT13 rs8929 rs7117240 0.54 C 0.542 0.03343 2.72
CHFR rs2306536 rs4758911 0.94 C 0.458 0.005139 3.97
CHFR rs4758954 rs4758911 0.94 C 0.458 0.005139 3.97
RTNl rs 17255975 rsl884737 0.75 G 0.333 0.04006 2.96
UNC13C rs 11639005 rs8025195 0.81 G 0.208 0.04687 0.34
UNC13C rsl2594549 rsl 864416 0.85 A 0.250 0.004958 6.00
UNC13C rs8025195 rs8025195 N/A G 0.208 0.04687 0.34
UNC13C rs9302181 rs8025195 0.78 G 0.208 0.04687 0.34
AKAP13 rs 16977252 rsl 6949988 0.56 T 0.583 0.01303 3.23
AKAP13 rs338556 rs2241269 0.54 T 0.458 0.0371 2.73
SV2B rs 1075840 rs6496780 0.74 G 0.167 0.04248 0.31
SV2B rsl l630131 rsl 7516708 0.66 T 0.000 0.02337 0.00
SV2B rs2073967 rsl 7516708 0.55 T 0.000 0.02337 0.00
SV2B rs2301665 rs6496780 0.87 G 0.167 0.04248 0.31
NETO2 rsl 1859615 rs9928466 0.85 C 0.125 0.01646 10.43
NETO2 rs 16952126 rs9928466 0.85 C 0.125 0.01646 10.43
NETO2 rs7184206 rs9928466 1.00 C 0.125 0.01646 10.43
NETO2 rs9923731 rs9928466 0.85 C 0.125 0.01646 10.43
CBLNl rsl 1076478 rsl2598711 0.89 G 0.458 0.004068 4.10
CBLNl rs9935379 rsl2598711 0.72 G 0.458 0.004068 4.10
CDHIl rs35144 rs4967886 0.65 A 0.625 0.04807 2.56
PMP22 rsl 79521 rs2323653 0.88 A 0.458 0.0371 2.73
FUSSEL18 rsl0502880 rsl 1663646 0.55 T 0.583 0.04765 2.54
FUSSEL18 rsl 7785419 rsl 1663646 0.55 T 0.583 0.04765 2.54
DCC rs4940251 rs4940259 0.51 A 0.500 0.03013 2.80
DCC rs6508235 rs4940259 1.00 A 0.500 0.03013 2.80
Example 7: Novel Markers Associated with Overall Response
To assess drug response, the last observation for each patient in treatment Phase 1 of the CATIE trial was used as a primary assessment of efficacy. The standard FDA registration trial definition of response of >20% decrease in Positive and Negative Syndrome Scale (PANSS Total Score) was used to assign subjects to a response category. Individuals having composite ordinal effectiveness outcome (COMPEFF) scores of 1 of 2, indicating efficacy, were combined as were those with scores of 3 or 4, indicating lack of efficacy (Davis et al., Schizophr. Bull. 29:73-80 (2003)). The side effects category consisted of individuals discontinued for safety concerns (COMPEFF score 5).
Genetic analysis to document the influence of haplotypes on overall response regardless of the drug used was performed using as described in Example 2 with the PLINK 1.03 whole genome analysis toolset developed by Purcell and coworkers (Purcell et al., Am. J. Hum. Genet. 81 :559-575 (2007)). PLINK calculates P values for the allele-specifϊc chi-squared test and the odds ratio (OR; or relative risk) associated with the minor allele.
Confirmation of SNP effects on overall response and side effects for all drugs:
Tables 12 and 13 report the minor allele frequencies, P values, and ORs for SNPs, in Tables B and C that affect overall response for all drugs combined and side effect rates for all drugs combined, respectively; for a combined sample set of patients treated with the drugs described in Examples 2 through 6. Note in Tables 12 and 13 that haplotype blocks result in the same Test SNP being in linkage disequilibrium with multiple SNPs in Table B. Similarly, haplotype blocks result in multiple Test SNPs that can be used for each SNP listed in Table B, though such redundant examples are not presented in Tables 12 and 13.
Tables 12 and 13, provide numerous examples of SNP-based alleles that predict altered response for all drugs combined (see Examples 2 through 6). For Table 12, ORs of > 1.0 indicate that the minor SNP allele is associated with greater clinical improvement, and ORs of < 1.0 indicate that the minor SNP allele is associated with lesser clinical improvement. For Table 13 ORs of > 1.0 indicate that the minor SNP allele is associated with an increase in study ending side effects, and ORs of < 1.0 indicate that the minor SNP allele is associated a decrease in study ending side effects.
Table 12: Alleles Affecting Positive Response to For All Drugs Combined
Gene Table B Test SNP in r2 Allele Frequency P (
Name SNP linkage in disequilibrium responders
PRDM2 rsl203682 rsl203682 N/A C 0.159 0.04025 ( ).67
SLC6A17 rsl010892 rs6689641 0.87 A 0.387 0.02751 ( ).72
SLC6A17 rs6689641 rs6689641 N/A A 0.387 0.02751 ( ).72
SLC6A17 rs877068 rs6689641 0.75 A 0.387 0.02751 ( ).72
KCND3 rsl 1102342 rsl538388 0.90 A 0.451 0.0118 [.45
DNM3 rsl0752946 rs9425598 1.00 A 0.468 0.02928 [.38
DNM3 rs4382763 rs6701929 0.84 C 0.199 0.01233 ( ).64
KCNHl rsl 770220 rsl 777256 1.00 A 0.331 0.03394 ( ).72
EXOC2 rs2493037 rs2473484 1.00 C 0.171 0.02535 [.58
USHlC rslO55574 rs4756895 0.52 T 0.518 0.02037 [.40
USHlC rslO55577 rs4756895 0.52 T 0.518 0.02037 [.40
USHlC rsl 6770 rs2237961 0.92 C 0.067 0.01527 ( ).52
USHlC rs2072225 rs4756895 0.64 T 0.518 0.02037 [.40
USHlC rs4756895 rs4756895 N/A T 0.518 0.02037 [.40
LRRC4C rs2953310 rs2953310 N/A C 0.338 0.02054 ( ).7O
HSDl 7Bl 2 rsl061810 rslO838184 0.65 C 0.222 0.04552 ( ).71
HSDl 7Bl 2 rsl0838160 rs7482725 0.62 A 0.514 0.03771 [.36
HSDl 7Bl 2 rs3802891 rs7482725 0.62 A 0.514 0.03771 [.36
HSDl 7Bl 2 rs4755744 rslO838184 0.72 C 0.222 0.04552 ( ).71
KIAA1853 rs6490226 rs7966721 0.53 G 0.436 0.01646 [.43
KIΛΛ1545 rs7294615 rs4242909 0.60 C 0.407 0.03532 ( ).73
JPH4 rsl 2897422 rsl 2897422 N/A A 0.159 0.02094 [.64
DAAMl rsl252989 rs8004164 0.91 A 0.372 0.02642 ( ).72 Table 12: Alleles Affecting Positive Response to For All Drugs Combined
Gene Table B Test SNP in r2 Allele Frequency P (
Name SNP linkage in disequilibrium responders
DAAMl rsl253005 rs8004164 0.97 A 0.372 0.02642 ( ).72
DAAMl rs4901909 rs8004164 0.60 A 0.372 0.02642 ( ).72
DAAMl rs8022614 rs8004164 0.74 A 0.372 0.02642 ( ).72
DAAMl rs941884 rs8004164 0.69 A 0.372 0.02642 ( ).72
GPR135 rsl0136708 rs4898989 0.61 A 0.450 0.02522 [.40
GPR135 rslO138199 rs4898989 1.00 A 0.450 0.02522 [.40
GPR135 rsl253181 rs4898989 0.81 A 0.450 0.02522 [.40
GPR135 rs 17255731 rs4898989 0.51 A 0.450 0.02522 [.40
GPR135 rs4898989 rs4898989 N/A A 0.450 0.02522 [.40
GPR135 rs9323348 rs4898989 1.00 A 0.450 0.02522 [.40
RTNl rsl0145080 rsl 7731838 0.65 T 0.187 0.02742 ( ).67
RTNl rs 12717467 rsl 7731838 0.52 T 0.187 0.02742 ( ).67
RTNl rs 17310036 rsl 7731838 0.81 T 0.187 0.02742 ( ).67
EMLl rslO144785 rsl 7099031 0.63 C 0.197 0.0419 [.48
UNC13C rsl2910912 rsl2910912 N/A G 0.229 0.004504 [.68
NEDD4 rs2271289 rsl2916104 0.86 T 0.458 0.03201 [.37
NEDD4 rs2303579 rslO518831 0.51 G 0.183 0.01556 [.62
NEDD4 rs2303580 rslO518831 0.51 G 0.183 0.01556 [.62
GRINLlA rs4774275 rsl 873995 0.51 G 0.416 0.02634 ( ).72
GRINLlA rs986868 rs9302201 0.90 C 0.405 0.003219 [.56
AKAP13 rs 11073502 rs2291048 0.53 A 0.232 0.02934 ( ).69
AKAP13 rs745191 rs745191 N/A T 0.248 0.04875 ( ).72
SV2B rs 1075840 rs2106692 0.52 A 0.324 0.03372 [.40
SV2B rsl 117388 rs2106692 0.61 A 0.324 0.03372 [.40
SV2B rsl l630131 rs6496778 0.55 G 0.309 0.002113 [.66
SV2B rs2073967 rs6496778 0.87 G 0.309 0.002113 [.66
SV2B rs2301665 rs2106692 0.56 A 0.324 0.03372 [.40
SV2B rsl l630131 rsl l630131 N/A A 0.211 0.03028 [.50
RGMA rsl3167 rsl 1074130 0.59 T 0.121 0.02593 [.72
IGFlR rs2684808 rs951715 0.51 G 0.303 0.0154 ( ).69
CDHIl rs35144 rs4967886 0.65 A 0.335 0.001908 ( ).62
CDHIl rs35148 rs35140 0.68 G 0.264 0.002194 ( ).61
CDHIl rs35186 rs35140 0.56 G 0.264 0.002194 ( ).61
CDHIl rs35195 rs35195 N/A A 0.271 0.003523 ( ).63
CDHIl rs35144 rs35144 N/A C 0.279 0.006589 ( ).65
CDHIl rs35186 rs35186 N/A T 0.419 0.02642 ( ).72
FUSSEL18 rs892583 rsl 1877471 0.68 G 0.377 0.01138 [.48
FUSSEL18 rs892583 rs892583 N/A G 0.323 0.02405 [.44
SMAD2 rsl 2457664 rsl 0502890 1.00 T 0.433 0.04215 ( ).74
SMAD2 rsl 787176 rsl 0502890 0.82 T 0.433 0.04215 ( ).74
SMAD2 rsl 792666 rsl 0502890 0.62 T 0.433 0.04215 ( ).74
SMAD2 rsl 792682 rsl 0502890 0.79 T 0.433 0.04215 ( ).74
SMAD2 rs2000709 rsl 0502890 0.94 T 0.433 0.04215 ( ).74
SMAD2 rs7228393 rsl 0502890 0.94 T 0.433 0.04215 ( ).74
SMAD 7 rs736839 rs2337153 0.73 A 0.433 0.003271 [.55
SMAD4 rsl2458752 rs7243135 0.97 G 0.451 0.04012 [.35
SMAD4 rsl2958604 rs7243135 0.97 G 0.451 0.04012 [.35
SMAD4 rs2276163 rs7243135 0.97 G 0.451 0.04012 [.35
SMAD4 rs2298617 rs7243135 0.97 G 0.451 0.04012 [.35
SMAD4 rs3764465 rs7243135 0.97 G 0.451 0.04012 [.35
SMAD4 rs620898 rs7243135 0.97 G 0.451 0.04012 [.35 Table 12: Alleles Affecting Positive Response to For All Drugs Combined
Gene Table B Test SNP in Allele Frequency OR Name SNP linkage in disequilibrium responders
DCC rs 12457407 rs9949949 0.83 A 0.426 0.00489 [.53
DCC rsl393331 rs8088048 0.78 C 0.436 0.02862 [.39
DCC rs 1431748 rs7504750 0.63 C 0.329 0.005512 [.57
DCC rs2229080 rsl2605899 0.53 C 0.422 0.03279 ( ).73
DCC rs4940251 rs9949949 0.82 A 0.426 0.00489 [.53
DCC rs6508235 rs9954344 0.62 G 0.418 0.01342 [.45
DCC rs7506904 rs9949949 0.93 A 0.426 0.00489 [.53
DCC rs950278 rsl2605899 0.97 C 0.422 0.03279 ( ).73
Table 13: Alleles Increasing Negative Side Effects for All Drugs Combined
Gene Table B Test SNP in r Allele Frequency in P OR
Name SNP linkage discontinuers disequilibrium
CAMTAl rs228651 rsl 1121029 0.51 A 0.154 0.0369 0.61
RERE rs6698830 rs 12024032 0.90 C 0.364 0.01972 0.66
RERE rs7530745 rsl 2024032 0.55 C 0.364 0.01972 0.66
RERE rs7554486 rsl 2024032 0.80 C 0.364 0.01972 0.66
KCNAlO rsl281174 rsl281177 0.60 A 0.413 0.04816 1.43
KCNAlO rsl281177 rsl281177 N/A A 0.413 0.04816 1.43
CACNAlE rs506947 rs593413 1.00 A 0.082 0.0313 0.52
SYT14 rs4609425 rsl2029138 0.96 G 0.414 0.03589 1.46
EXOC2 rs2493049 rs 12154040 0.54 C 0.488 0.03739 1.44
NAV2 rs2028570 rsl867116 0.90 T 0.500 0.02091 1.50
NAV2 rs7125647 rs2119981 0.61 A 0.380 0.04636 0.70
SLC17A6 rs 11026523 rs2078352 0.79 T 0.138 0.01 0.53
SLC17A6 rs 1155821 rs2078352 0.96 T 0.138 0.01 0.53
SLC17A6 rs2078352 rs2078352 N/A T 0.138 0.01 0.53
SLC17A6 rs2246710 rs2078352 1.00 T 0.138 0.01 0.53
DAAMl rsl252989 rs8004164 0.91 A 0.513 0.01324 1.55
DAAMl rsl253005 rs8004164 0.97 A 0.513 0.01324 1.55
DAAMl rsl268579 rs2053298 1.00 T 0.253 0.02417 0.64
DAAMl rs4127823 rsl2589351 0.61 C 0.338 0.02459 0.66
DAAMl rs4901909 rs8004164 0.60 A 0.513 0.01324 1.55
DAAMl rs8022614 rs8004164 0.74 A 0.513 0.01324 1.55
DAAMl rs941884 rs8004164 0.69 A 0.513 0.01324 1.55
GPR135 rsl0136708 rsl 253170 0.67 T 0.319 0.01197 0.63
GPR135 rslO138199 rsl 253170 0.54 T 0.319 0.01197 0.63
GPR135 rsl253181 rsl 253170 0.74 T 0.319 0.01197 0.63
GPR135 rs4898989 rsl 253170 0.54 T 0.319 0.01197 0.63
GPR135 rs9323348 rsl 253170 0.54 T 0.319 0.01197 0.63 Table 13: Alleles Increasing Negative Side Effects for All Drugs Combined
Gene Table B Test SNP in r2 Allele Frequency in P ( JR
Name SNP linkage discontinuers disequilibrium I
EVL rs 1190956 rslO136836 0.71 T 0.049 0.02337 ( ).43
WDR25 rslO873518 rs8005782 1.00 A 0.468 0.007603 1.61
HERC2 rs 1635168 rs6497292 0.87 G 0.130 0.01823 1.91
HERC2 rs2238289 rs6497292 0.51 G 0.130 0.01823 1.91
HERC2 rs7495174 rs6497292 0.58 G 0.130 0.01823 1.91
UNC13C rs 11856476 rs8024165 0.84 T 0.352 0.01767 [.55
UNC13C rsl2914912 rs8024165 0.63 T 0.352 0.01767 [.55
UNC13C rs4776216 rs8024165 0.52 T 0.352 0.01767 [.55
ADAMlO rs3764196 rs7164844 0.51 C 0.074 0.00561 ( ).42
ADAMlO rs4775086 rs605928 0.59 G 0.222 0.03434 ( ).65
ADAMlO rs514049 rs605928 0.73 G 0.222 0.03434 ( ).65
ADAMlO rs653765 rs605928 0.89 G 0.222 0.03434 ( ).65
CDHIl rs 1520233 rs 1520233 N/A A 0.309 0.03062 ( ).67
CDHIl rs35144 rs40115 1.00 T 0.438 0.001518 [.77
CDHIl rs35148 rs40115 0.68 T 0.438 0.001518 [.77
CDHIl rs35186 rs40115 0.56 T 0.438 0.001518 [.77
CDHIl rs35195 rs35195 N/A A 0.438 0.002584 1.71
CDHIl rs35144 rs35144 N/A C 0.430 0.009028 [.60
CDHIl rs35186 rs35186 N/A T 0.544 0.04441 [.43
BEAN rs4247350 rslO63438 0.59 A 0.265 0.01355 ( ).62
KIAA0182 rs3815794 rs7195186 0.75 G 0.488 0.009922 [.57
KIAA0182 rs736845 rs736845 N/A T 0.231 0.01238 ( ).6O
C16orf74 rs2305357 rs394623 0.55 C 0.321 0.04089 ( ).69
C16orf74 rs373835 rs394623 0.68 C 0.321 0.04089 ( ).69
C16orf74 rs386061 rs394623 0.68 C 0.321 0.04089 ( ).69
Example 8: Novel Markers Associated with Overall Psychiatric Endophenotypes in SZ
Genotype and PANNS phonotype data were evaluated for 417 SZ patients enrolled in the CATIE trial. Following a period of drug wash-out, the CATIE study investigators rated each participant at baseline for psychopathology using the PANSS.
Each of the individual and composite scores is a quantitative trait that can be assessed using quantitative statistical genetics methods. Genetic analysis to determine the influence of haplotypes on quantitative PANSS values was performed using the PLINK 1.03 whole genome analysis toolset developed by Purcell and coworkers (Purcell et al., Am. J. Hum. Genet. 81 :559-575 (2007)). Confirmation of SNP effects on psychiatric endopheno types:
Tables 14 and 15 show numerous examples of novel alleles that affect the values obtained for specific psychiatric endophenotypes. Note in Tables 14 and 15 that haplotype blocks result in the same Test SNP being in linkage disequilibrium with multiple SNPs in Table B. Similarly, haplotype blocks result in multiple Test SNPs that can be used for each SNP listed in Table B, though such redundant examples are not presented in Tables 12 and 13 unless different test SNPs influence different psychiatric endophenotypes.
Tables 14 and 15 report results for specific SNP alleles that affect quantitative endophenotypes for SZ, along with Beta values and P values for the particular alleles of SNPs listed in Tables B and C. The Beta, beta weight from the regression, measures the impact of the SNP allele on the particular scale. A positive Beta means that the allele for the test SNP increases the score for that measure of psychopathology by the Beta value, while a negative Beta means that the allele for the test SNP decreases the score that for that measure of psychopathology by the Beta value.
Table 14 shows selected examples for PANSS Total score, Positive Symptoms subscale, Negative Symptoms subscale, and the General Psychopathology subscale, analyzed as quantitative traits in PLINK using linear regression.
Table 15 shows selected examples for the individual PANSS components. The component evaluated in each row is identified by one of the following abbreviations: Positive Symptoms: Pl- delusions, P2-conceptual disorganization, P3 -hallucinatory behavior, P4-exitement, P5-grandiosity, P6-suspiciousness, P7-hostility; Negative Symptoms: Nl-blunted affect, N2-emotional withdrawal, N3-poor rapport, N4-passive/appathetic social withdrawal, N5-difficultiy in abstract thinking, N6-lack of spontaneity and flow of conversation, N7-steryotyped thinking; General Psychopathology Symptoms: Gl-somatic concern, G2-anxiety, G3-guilt feelings, G4-tension, G5-mannerisms and posturing, Gό-depression, G7-motor retardation, G8-uncooperativeness, G9-unusual thought content, G10-disorentation, GI l -poor attention, G12-lack of judgment and insight, G 13 disturbance of volition, G14-poor impulse control, G15-preoccupation, G16-active social avoidance.
Table 14: Alleles Influencing Composite Psychiatric Endophenotypes
2
Gene Name Table B Test SNP in r Allele PANSS Beta P
SNP linkage disequilibrium
CAMTAl rsl2070592 rs9434833 1.00 T Positive [.25 0.02983
CAMTAl rsl2070592 rs2071918 1.00 T General [.83 0.0474
CAMTAl rslO11124 rsl616122 0.63 C General [.60 0.01229
CAMTAl rsl417986 rs2301488 0.54 T Negative [.05 0.02118
PER3 rs707463 rs228688 0.75 T Negative [.02 0.0273
PER3 rs707465 rs228688 0.81 T Negative [.02 0.0273
RP1-21O18.1 rs938249 rs4661563 0.66 G Negative -0.90 0.0453
DNM3 rs4382763 rsl2410416 1.00 C Positive 0.97 0.04342
DNM3 rs4382763 rs7550558 0.84 G Total 3.38 0.01491
DNM3 rs4382763 rs2586389 0.84 A Negative 1.24 0.01611
FASLG rsl0458360 rsl0458360 N/A C General -1.85 0.005609 Table 14: Alleles Influencing Composite Psychiatric Endophenotypes
2
Gene Name Table B Test SNP in r Allele PANSS Beta P
SNP linkage disequilibrium
FASLG rsl2135884 rsl0458360 0.56 C General -1.85 0.005609
FASLG rsl0458360 rsl0458360 N/A C Total -2.67 0.03637
FASLG rsl2135884 rsl0458360 0.56 C Total -2.67 0.03637
CACNAlE rs 17494681 rs 17494681 N/A T Negative -1.60 0.006522
CACNAlE rs 199960 rs 1953690 0.81 A General 1.39 0.04994
CACNAlE rs3856090 rs7534913 0.50 A General 1.31 0.04178
CACNAlE rs4652678 rs 17693196 0.50 T General 2.21 0.01456
CACNAlE rs704326 rs704331 0.64 G Negative -1.27 0.005535
CAMKlG rs2356933 rs6683256 1.00 T General -1.45 0.03081
CAMKlG rs2356933 rs6683256 1.00 T Total -3.00 0.019
CAMKlG rsl7014820 rsl0489339 0.70 G Total 3.79 0.0419
KCNHl rs 1770213 rs7546472 0.89 C General 1.91 0.01334
KCNHl rs 1770213 rs7546472 0.89 C Positive 1.31 0.006236
KCNHl rs 1770213 rs7546472 0.89 C Total 3.93 0.007621
KCNHl rs4620600 rs4951495 0.79 A Negative 1.37 0.01718
KCNHl rs4620600 rsl 1119679 0.83 A Positive -1.16 0.0231
EXOC2 rs2493037 rs2473484 1.00 C Positive -1.24 0.03906
ANK3 rsl0733757 rsl 0761446 0.90 C Negative -1.13 0.03077
ANK3 rs4568956 rsl 0761446 0.57 C Negative -1.13 0.03077
ANK3 rs7907721 rsl 0761446 0.50 C Negative -1.13 0.03077
RHOG rs 1055640 rsl055640 N/A G Positive -0.87 0.03465
RHOG rs 11030008 rsl 1030008 N/A G General 1.44 0.02802
RHOG rs 1451722 rsl 1030008 0.76 G General 1.44 0.02802
RHOG rs 11030008 rsl 1030008 N/A G Positive 1.35 0.000922
RHOG rs 1451722 rsl 1030008 0.76 G Positive 1.35 0.000922
RHOG rs 11030008 rsl 1030008 N/A G Total 3.22 0.01005
RHOG rs 1451722 rsl 1030008 0.76 G Total 3.22 0.01005
USHlC rs 1064074 rsl 064074 N/A C Negative 0.88 0.04895
USHlC rs2072225 rsl 064074 0.54 C Negative 0.88 0.04895
USHlC rs 16770 rs2237961 0.92 C Positive 1.61 0.014
OTOG rs 10832824 rs7111528 0.75 T Total -2.73 0.04189
OTOG rs2023483 rs7111528 0.70 T Total -2.73 0.04189
OTOG rs2041028 rs7111528 1.00 T Total -2.73 0.04189
OTOG rs7111528 rs7111528 N/A T Total -2.73 0.04189
OTOG rs 1003490 rsl 1024348 0.77 T General -1.65 0.03189
OTOG rs 10832824 rsl 1024348 0.52 T General -1.65 0.03189
OTOG rs2023483 rsl 1024348 0.50 T General -1.65 0.03189
SERGEF rs4757589 rsl 1024415 0.63 C General 1.28 0.04742
PTPN5 rsl550870 rs7950091 0.84 T General -1.57 0.01419
PTPN5 rs6483524 rs7950091 0.50 T General -1.57 0.01419
PTPN5 rs 10766500 rsl 1024782 0.93 T General -1.82 0.009458
PTPN5 rs 10766500 rsl 1024782 0.93 T Negative -0.98 0.04673
PTPN5 rs 10766500 rsl 1024782 0.93 T Total -2.97 0.0268
NAV2 rsl0833202 rsl 1025328 0.61 G General -1.66 0.01012
NAV2 rs6483629 rsl2099330 0.59 T Positive -1.61 0.01255
SLC6A5 rs1443547 rsl 6906507 0.54 A General 1.51 0.0386
SLC6A5 rs894750 rsl 6906507 0.77 A General 1.51 0.0386
SLC6A5 rs1443547 rsl 6906507 0.54 A Total 2.97 0.03352
SLC6A5 rs894750 rsl 6906507 0.77 A Total 2.97 0.03352
LRRC4C rsl0837367 rsl 0501227 1.00 G Positive -1.66 0.04454
SYT13 rs2863172 rs4755941 0.80 A General 2.40 0.02256 Table 14: Alleles Influencing Composite Psychiatric Endophenotypes
2
Gene Name Table B Test SNP in r Allele PANSS Beta P
SNP linkage disequilibrium
SYT13 rs2863174 rs4755941 0.88 A General 2.40 0.02256
SYT13 rs4755941 rs4755941 N/A A General 2.40 0.02256
SYT13 rs7103871 rs4755941 0.84 A General 2.40 0.02256
KIAA1853 rs6490226 rs 1568922 0.91 C General -1.83 0.01852
KIAA1853 rs6490226 rs 1568922 0.91 C Positive -1.07 0.02697
KIAA1853 rs6490226 rs 1568922 0.91 C Total -3.74 0.0115
KIAA1853 rs7136574 rs4298970 0.72 A General 1.46 0.03329
KIAA1853 rs7136574 rs4075946 0.82 T Positive -0.91 0.02171
KIAA1853 rs7136574 rs4075946 0.82 T Total -2.54 0.03892
KIAA1853 rs 1541764 rs 1541764 N/A G General 1.52 0.01871
KIAA1853 rs2555269 rs 1541764 0.51 G General 1.52 0.01871
KIAA1853 rs2723880 rs 1541764 0.74 G General 1.52 0.01871
KIAA1853 rs2723882 rs 1541764 0.55 G General 1.52 0.01871
KIAA1853 rs 1541764 rs 1541764 N/A G Negative 1.18 0.009674
KIAA1853 rs2555269 rs 1541764 0.51 G Negative 1.18 0.009674
KIAA1853 rs2723880 rs 1541764 0.74 G Negative 1.18 0.009674
KIAA1853 rs2723882 rs 1541764 0.55 G Negative 1.18 0.009674
KIAA1853 rs 1541764 rs 1541764 N/A G Total 3.21 0.009581
KIAA1853 rs2555269 rs 1541764 0.51 G Total 3.21 0.009581
KIAA1853 rs2723880 rs 1541764 0.74 G Total 3.21 0.009581
KIAA1853 rs2723882 rs 1541764 0.55 G Total 3.21 0.009581
STX2 rsl236 rs7956851 0.81 C Negative -0.99 0.04055
STX2 rs4759517 rs7956851 1.00 C Negative -0.99 0.04055
STX2 rs6486600 rs7956851 0.97 C Negative -0.99 0.04055
STX2 rs6486602 rs7956851 1.00 C Negative -0.99 0.04055
TTC5 rs2318864 rs4981148 0.52 T General -1.69 0.04301
TTC5 rs3737220 rs4981148 0.51 T General -1.69 0.04301
TTC5 rs3742945 rs4981148 0.52 T General -1.69 0.04301
TTC5 rs2318864 rs4981148 0.52 T Total -3.18 0.04708
TTC5 rs3737220 rs4981148 0.51 T Total -3.18 0.04708
TTC5 rs3742945 rs4981148 0.52 T Total -3.18 0.04708
TEPl rsl713449 rsl713448 0.96 A General 1.55 0.0488
TEPl rs7150689 rsl713448 0.87 A General 1.55 0.0488
TEPl rs938886 rsl713448 1.00 A General 1.55 0.0488
TEPl rs938887 rsl713448 0.67 A General 1.55 0.0488
JPH4 rs 12897422 rsl2897422 N/A A General -2.40 0.0136
JPH4 rs 12897422 rs 12897422 N/A A Negative -2.00 0.003322
JPH4 rs 12897422 rs 12897422 N/A A Total -5.10 0.00594
DAAMl rslO143918 rs 10483710 0.58 A Negative -1.48 0.01586
DAAMl rs 12147707 rs 10483710 0.86 A Negative -1.48 0.01586
DAAMl rs 17095965 rs 10483710 0.86 A Negative -1.48 0.01586
DAAMl rsl252989 rs4901909 0.62 T Positive 0.83 0.04088
DAAMl rsl253005 rs4901909 0.62 T Positive 0.83 0.04088
DAAMl rs4901909 rs4901909 N/A T Positive 0.83 0.04088
DAAMl rs8022614 rs4901909 0.60 T Positive 0.83 0.04088
DAAMl rs941884 rs4901909 0.85 T Positive 0.83 0.04088
DAAMl rslO143918 rs6573250 0.69 T General -1.52 0.01672
DAAMl rs 11626926 rs 1547199 0.85 T General 1.37 0.03582
DAAMl rs4127823 rsl271513 0.65 C General -1.57 0.02025
DAAMl rs941886 rsl271513 1.00 C General -1.57 0.02025
EMLl rs2250718 rs3783322 0.70 G General 1.54 0.01544 Table 14: Alleles Influencing Composite Psychiatric Endophenotypes
2
Gene Name Table B Test SNP in r Allele PANSS Beta P
SNP linkage disequilibrium
EMLl rs2250718 rs3783322 0.70 G Nesative 1.10 0.01418
EMLl rs2250718 rs3783322 0.70 G Total 2.62 0.03153
EMLl rsl 1160553 rsl 1160554 1.00 C Negative -1.83 0.000141
EMLl rsl 1160563 rsl 1160554 0.56 C Negative -1.83 0.000141
EMLl rsl2433613 rsl 1160554 0.88 C Negative -1.83 0.000141
EMLl rs6575751 rsl 1160554 1.00 C Negative -1.83 0.000141
EMLl rs746698 rslO131519 0.91 C Positive 1.07 0.03808
EMLl rs746698 rslO131519 0.91 C Total 3.17 0.04577
EMLl rs2273707 rs2250718 0.53 T General 1.29 0.04771
EMLl rs2273704 rs3818279 0.58 G Negative 1.53 0.004398
EMLl rs746698 rs3818279 0.71 G Negative 1.53 0.004398
EMLl rsl 1160553 rs4900447 0.59 A General -2.06 0.002015
EMLl rsl 1160563 rs4900447 0.97 A General -2.06 0.002015
EMLl rsl2433613 rs4900447 0.51 A General -2.06 0.002015
EMLl rs6575751 rs4900447 0.59 A General -2.06 0.002015
EMLl rsl 1160553 rs4900447 0.59 A Total -4.44 0.000493
EMLl rsl 1160563 rs4900447 0.97 A Total -4.44 0.000493
EMLl rsl2433613 rs4900447 0.51 A Total -4.44 0.000493
EMLl rs6575751 rs4900447 0.59 A Total -4.44 0.000493
HERC2 rsl 1631797 rs916977 0.86 T Negative 1.26 0.01939
HERC2 rs2238289 rs916977 0.79 T Negative 1.26 0.01939
HERC2 rs916977 rs916977 N/A T Negative 1.26 0.01939
UNC13C rsl 7731958 rsl7731958 N/A T General -3.74 0.01791
UNC13C rs2163195 rs8024845 1.00 G Negative 0.97 0.04595
UNC13C rs489526 rs573320 0.70 A Negative -1.04 0.04416
UNC13C rs489526 rs500853 1.00 G Total -2.76 0.03901
UNC13C rsl 6974691 rsl 6974712 0.96 T General -1.57 0.04754
UNC13C rsl 6974691 rsl 6974712 0.96 T Negative -1.39 0.01224
UNC13C rsl 6974691 rsl 6974712 0.96 T Total -3.83 0.01099
Gcoml rs4774275 rs9806498 1.00 T Positive 0.98 0.01975
GCOMl rsl 6977629 rsl 6977629 N/A T Negative 2.21 0.01041
Gcoml rsl 6977631 rsl 6977629 0.56 T Negative 2.21 0.01041
GRINLlA rs986868 rs7176042 0.75 A Positive -0.99 0.01843
AKAP13 rs745191 rs745191 N/A T Positive 0.99 0.02393
AKAP13 rsl 1073502 rs2291048 0.53 A Positive 1.22 0.006071
AKAP13 rs2241268 rs2241268 N/A A Positive 1.04 0.01761
KLHL25 rsl 1637212 rsl l637212 N/A G Positive 1.07 0.01597
SV2B rsl l630131 rsl l631712 0.55 C Negative -1.50 0.002999
SV2B rs2073967 rsl l631712 0.87 C Negative -1.50 0.002999
SLCO3A1 rs2286355 rsl 1630872 0.85 T Negative -0.99 0.04033
IGFlR rs7170035 rs4966012 0.55 C Negative -1.04 0.03039
IGFlR rs4965436 rsl 1634874 0.76 C Positive 1.43 0.02266
IGFlR rs2684792 rs7173377 0.96 C Positive 1.22 0.0019
CBLNl rsl 1076478 rsl 469906 0.72 A Negative -1.15 0.01235
CBLNl rs9935379 rsl 469906 0.90 A Negative -1.15 0.01235
ZNF423 rsl2924119 rs4785185 0.50 T Positive -1.04 0.03187
CDH8 rs4131634 rsl 1862752 0.51 A General -2.74 0.006021
CDH8 rs4131634 rsl 1862752 0.51 A Total -4.07 0.03321
CDH8 rs9939991 rsl3336134 0.55 C Positive -0.99 0.01792
CDH8 rsl 1075445 rs7189354 1.00 G Positive -1.23 0.002488
CDH8 rsl 369918 rs7189354 1.00 G Positive -1.23 0.002488 Table 14: Alleles Influencing Composite Psychiatric Endophenotypes
2
Gene Name Table B Test SNP in r Allele PANSS Beta P
SNP linkage disequilibrium
CDH8 rs 1978796 rs7189354 1.00 G Positive -1.23 0.002488
CDH8 rs6498807 rs7189354 0.80 G Positive -1.23 0.002488
CDH8 rsl397131 rs 16964164 0.90 T Negative 0.91 0.04219
CDH8 rs8057338 rs 16964164 0.93 T Negative 0.91 0.04219
CDH8 rs9302540 rs 16964164 0.93 T Negative 0.91 0.04219
CDHIl rs 1520233 rs4625747 0.67 T General -1.51 0.02769
CDHIl rs35148 rs35162 1.00 A General 1.73 0.01682
CDHIl rs35144 rs35162 0.68 A Positive 1.14 0.01107
CDHIl rs35148 rs35162 1.00 A Positive 1.14 0.01107
CDHIl rs35144 rs35162 0.68 A Total 3.04 0.02738
CDHIl rs35148 rs35162 1.00 A Total 3.04 0.02738
CDHIl rs35186 rs35140 0.56 G Positive 0.91 0.0272
CDHIl rs35195 rs35195 N/A A General 1.45 0.02761
CDHIl rs35195 rs35195 N/A A Positive 0.87 0.03339
CDHIl rs35144 rs35186 0.56 T General 1.58 0.0137
CDHIl rs35186 rs35186 N/A T General 1.58 0.0137
CDHIl rs35186 rs35186 N/A T Total 2.57 0.03558
KIAAOl 82 rs 1049868 rs732460 0.58 T Negative 1.11 0.03822
KIAAOl 82 rs3815795 rs732460 0.59 T Negative 1.11 0.03822
PMP22 rs 13422 rs 192046 0.93 T General 1.28 0.03702
PMP22 rs230938 rs 192046 0.67 T General 1.28 0.03702
PMP22 rs 179521 rs 11656487 0.83 C General -1.41 0.02417
PMP22 rs231018 rs 11656487 0.52 C General -1.41 0.02417
PMP22 rs 179521 rs 11656487 0.83 C Total -2.48 0.03766
PMP22 rs231018 rs 11656487 0.52 C Total -2.48 0.03766
KATNAL2 rs2187092 rs2010834 0.97 A General 2.27 0.0008
KATNAL2 rs2247221 rs2010834 0.56 A General 2.27 0.0008
KATNAL2 rs2571030 rs2010834 0.56 A General 2.27 0.0008
KATNAL2 rs2576042 rs2010834 0.59 A General 2.27 0.0008
KATNAL2 rs7233515 rs2010834 0.69 A General 2.27 0.0008
KATNAL2 rs9304340 rs2010834 0.97 A General 2.27 0.0008
KATNAL2 rs2187092 rs2010834 0.97 A Negative 1.18 0.01344
KATNAL2 rs2247221 rs2010834 0.56 A Negative 1.18 0.01344
KATNAL2 rs2571030 rs2010834 0.56 A Negative 1.18 0.01344
KATNAL2 rs2576042 rs2010834 0.59 A Negative 1.18 0.01344
KATNAL2 rs7233515 rs2010834 0.69 A Negative 1.18 0.01344
KATNAL2 rs9304340 rs2010834 0.97 A Negative 1.18 0.01344
KATNAL2 rs2187092 rs2010834 0.97 A Total 4.45 0.000588
KATNAL2 rs2247221 rs2010834 0.56 A Total 4.45 0.000588
KATNAL2 rs2571030 rs2010834 0.56 A Total 4.45 0.000588
KATNAL2 rs2576042 rs2010834 0.59 A Total 4.45 0.000588
KATNAL2 rs7233515 rs2010834 0.69 A Total 4.45 0.000588
KATNAL2 rs9304340 rs2010834 0.97 A Total 4.45 0.000588
KATNAL2 rs9961383 rs2571034 0.60 G General 1.61 0.01919
KATNAL2 rs9961383 rs2571034 0.60 G Total 2.68 0.04215
KATNAL2 rs2187092 rs2576040 0.57 T Positive -1.02 0.01334
KATNAL2 rs2247221 rs2576040 0.61 T Positive -1.02 0.01334
KATNAL2 rs2571030 rs2576040 0.61 T Positive -1.02 0.01334
KATNAL2 rs2576042 rs2576040 1.00 T Positive -1.02 0.01334
KATNAL2 rs7233515 rs2576040 0.51 T Positive -1.02 0.01334
KATNAL2 rs9304340 rs2576040 0.57 T Positive -1.02 0.01334 Table 14: Alleles Influencing Composite Psychiatric Endophenotypes
Gene Name Table B Test SNP in r2 Allele PANSS Beta P
SNP linkage disequilibrium
FUSSEL18 rsl0502880 rs9304344 0.85 T General -1.48 0.02048
FUSSEL18 rs 17785419 rs9304344 0.85 T General -1.48 0.02048
FUSSEL18 rs2668771 rs9304344 0.64 T General -1.48 0.02048
FUSSEL18 rs7236105 rs9304344 1.00 T General -1.48 0.02048
FUSSEL18 rsl0502880 rs9304344 0.85 T Positive -0.87 0.02914
FUSSEL18 rs 17785419 rs9304344 0.85 T Positive -0.87 0.02914
FUSSEL18 rs2668771 rs9304344 0.64 T Positive -0.87 0.02914
FUSSEL18 rs7236105 rs9304344 1.00 T Positive -0.87 0.02914
FUSSEL18 rsl0502880 rs9304344 0.85 T Total -2.69 0.02795
FUSSEL18 rs 17785419 rs9304344 0.85 T Total -2.69 0.02795
FUSSEL18 rs2668771 rs9304344 0.64 T Total -2.69 0.02795
FUSSEL18 rs7236105 rs9304344 1.00 T Total -2.69 0.02795
DCC rs6508145 rs 1031062 0.67 G Negative -1.36 0.02919
DCC rs6508145 rs 1031062 0.67 G Total -3.34 0.04901
DCC rs 1893572 rs7228674 0.77 T Negative 1.68 0.000333
DCC rs 1893572 rs9807201 0.65 A General 1.73 0.01191
DCC rs 1893572 rs9807201 0.65 A Total 3.16 0.01642
DCC rs 1431748 rs4998815 0.61 G General -1.47 0.02576
DCC rs 1431748 rs9953016 0.81 C Negative -1.13 0.0172
DCC rs 1431748 rs7504750 0.63 C Total -2.97 0.02854
TMEPAI rs427278 rs203386 0.51 C General 1.51 0.02214
TMEPAI rs427278 rs203386 0.51 C Total 2.78 0.02738
Table 15: Alleles Influencing Specific Psychiatric Endophenotypes
Gene Name Table B Test SNP in r2 Allele PANSS Beta P
SNP linkage disequilibrium
CAMTAl rs7554752 rs4908575 0.96 C GlO 0.18 0.002944
CAMTAl rs 12070592 rs2071918 1.00 T G6 -0.42 0.002692
CAMTAl rs 12070592 rs2071918 1.00 T G9 -0.38 0.003607
CAMTAl rs707455 rs697686 0.66 T N7 -0.27 0.002057
PER3 rs707463 rs707463 N/A T N7 -0.25 0.004339
PER3 rs707465 rs697686 0.93 T N7 -0.27 0.002057
PER3 rs707463 rs697686 1.00 T N7 -0.27 0.002057
PER3 rs2640909 rs228652 0.70 A N5 -0.34 0.002229
RP1-21O18.1 rs 12057431 rsl0803343 1.00 C G14 0.95 0.0002941
RP1-21O18.1 rs4661572 rs 1000313 0.63 G G14 0.28 0.0003008
KCND3 rs3738298 rs584096 0.70 G GlO -0.28 0.0003434
DNM3 rs4382763 rs2586392 0.84 C N7 0.27 0.003464
CACNAlE rs 17494681 rs 17494681 N/A T N4 -0.37 0.003546
CACNAlE rs3856090 rs 10797729 0.70 A G7 0.34 0.0001445
CACNAlE rs 199960 rs 10797729 0.77 A G7 0.34 0.0001445
CACNAlE rs 199960 rs7513540 0.61 T Gl -0.32 0.001712
CACNAlE rs4652678 rs 17693196 0.50 T Gl 0.40 0.002089
CACNAlE rs704326 rs704331 0.64 G G7 -0.28 0.0005166
CACNAlE rs704326 rs704331 0.64 G Nl -0.32 0.00162
CACNAlE rs704326 rs704331 0.64 G N3 -0.28 0.001365
CACNAlE rs704326 rs704331 0.64 G N6 -0.32 0.0008968
CAMKlG rs 17014820 rs7512091 0.91 A G5 0.29 0.001812 Table 15: Alleles Influencing Specific : Psychiatric Endophenotypes
Gene Name Table B Test SNP in i J- Allele PANSS Beta P
SNP linkage disequilibrium
CAMKlG rs6690557 rs713075 ( ).80 A G5 -0.23 0.003493
CAMKlG rs 17014820 rs7516885 [.00 T N7 0.38 0.0007187
CAMKlG rs 17014820 rsl0489339 ( ).7O G G4 0.43 0.0006328
KCNHl rs 1770213 rs7546472 ( ).89 C Pl 0.39 0.003181
DPH3 rs2245721 rs842264 ( ).57 T P5 0.30 0.0005309
DPH3 rs842257 rs842264 ( ).57 T P5 0.30 0.0005309
DPH3 rs859703 rs842264 ( ).57 T P5 0.30 0.0005309
DPH3 rs2245708 rs842261 ( ).67 A P5 0.27 0.004185
DPH3 rs2245721 rs842251 [.00 G GlO 0.20 0.000734
DPH3 rs842257 rs842251 [.00 G GlO 0.20 0.000734
DPH3 rs859703 rs842251 [.00 G GlO 0.20 0.000734
DPH3 rs2245721 rs842259 [.00 T G7 -0.23 0.004115
DPH3 rs842257 rs842259 [.00 T G7 -0.23 0.004115
DPH3 rs859703 rs842259 [.00 T G7 -0.23 0.004115
EXOC2 rsl473909 rs9405242 ( ).97 A N5 -0.35 0.0008412
TOLLIP rs3168046 rs2014486 ( ).85 A G7 -0.24 0.001849
TOLLIP rs3750920 rs2014486 ( ).85 A G7 -0.24 0.001849
BRSK2 rsl554857 rs 1554857 N/A A G5 -0.23 0.002684
BRSK2 rsl554857 rsl 108991 ( ).81 G G5 -0.25 0.001173
HCCA2 rs7945160 rsl 108991 ( ).55 G G5 -0.25 0.001173
HCCA2 rs9440 rsl 108991 ( ).55 G G5 -0.25 0.001173
HCCA2 rs7396514 rsl 108991 [.00 G G5 -0.25 0.001173
DUSP8 rs 10734456 rsl 108991 ( ).55 G G5 -0.25 0.001173
DUSP8 rs902224 rsl 108991 ( ).81 G G5 -0.25 0.001173
RHOG rs 1055640 rsl 055640 N/A G G4 -0.25 0.003073
RHOG rs 1451722 rsl 1030008 ( ).76 G Pl 0.32 0.00439
RHOG rs 11030008 rsl 1030008 N/A G Pl 0.32 0.00439
RHOG rs 1451722 rsl 1030008 ( ).76 G P6 0.33 0.001515
RHOG rs 11030008 rsl 1030008 N/A G P6 0.33 0.001515
USHlC rs2072225 rsl 064074 ( ).54 C G16 0.28 0.002619
USHlC rs 1064074 rsl 064074 N/A C G16 0.28 0.002619
USHlC rs 16770 rs2237961 ( ).92 C P4 0.42 0.0007385
OTOG rs2041028 rs757982 ( ).64 A G12 -0.32 0.0007194
OTOG rs7111528 rs757982 ( ).64 A G12 -0.32 0.0007194
OTOG rs2023483 rs7111528 ( ).7O T P2 -0.27 0.008232
OTOG rs 10832824 rs7111528 ( ).75 T P2 -0.27 0.008232
OTOG rs2041028 rs7111528 [.00 T P2 -0.27 0.008232
OTOG rs7111528 rs7111528 N/A T P2 -0.27 0.008232
OTOG rs2023483 rs4757560 ( ).52 C P5 -0.25 0.008921
PTPN5 rs 10766500 rsl 1024782 ( ).93 T G16 -0.31 0.002084
PTPN5 rs 10766500 rs755796 ( ).93 G GlO -0.19 0.004029
NA V2 rs 10833202 rsl 1025328 ( ).61 G G15 -0.25 0.003892
NA V2 rs7125647 rsl0833228 ( ).65 C GI l 0.30 0.0007124
LRRC4C rs2953310 rs2953310 N/A C P4 -0.21 0.004729
LRRC4C rsl0837367 rsl 0501227 [.00 G Pl -0.67 0.003309
HSDl 7Bl 2 rsl061810 rslO838186 ( ).87 C G5 0.21 0.003535
HSDl 7Bl 2 rs4755744 rslO838186 [.00 C G5 0.21 0.003535
HSDl 7Bl 2 rs 11037691 rsl 1037691 N/A A G5 0.39 0.004419
SYT13 rs 12362429 rsl 2362444 [.00 G GlO 0.21 0.0007107
SYT13 rs 12362429 rsl 2362444 [.00 G P2 0.29 0.002839
SYT13 rs4992029 rsl 075778 ( ).61 G P2 0.27 0.009285 Table 15: Alleles Influencing Specific Psychiatric Endophenotypes
Gene Name Table B Test SNP in r2 Allele PANSS Beta P
SNP linkage disequilibrium
SYT13 rs2863182 rsl 075778 0.84 G P2 0.27 0.009285
SYT13 rsl 1038382 rsl 075778 1.00 G P2 0.27 0.009285
SYT13 rs4992029 rs6485608 0.50 C GlO 0.20 0.002462
SYT13 rsl 1038382 rs6485608 0.84 C GlO 0.20 0.002462
SYT13 rs2863182 rs6485608 1.00 C GlO 0.20 0.002462
DTX4 rsl 048444 rs2211912 0.77 A N6 0.32 0.0006063
DTX4 rs3847 rs2211912 0.77 A N6 0.32 0.0006063
DTX4 rs656163 rs2211912 0.88 A N6 0.32 0.0006063
DTX4 rs5029315 rs2211912 1.00 A N6 0.32 0.0006063
DTX4 rs2211912 rs2211912 N/A A N6 0.32 0.0006063
DTX4 rs3847 rs3847 N/A A N6 0.30 0.003075
DTX4 rs621162 rs544864 1.00 T N6 0.35 0.0008417
DTX4 rs544864 rs544864 N/A T N6 0.35 0.0008417
KIAA1853 rs6490226 rs7966721 0.53 G Nl -0.32 0.00181
KIAA1853 rs7136574 rs4298970 0.72 A Gl 0.28 0.004999
RIMBP2 rs4237817 rsl 877978 0.55 C G4 0.25 0.003266
TTC5 rs3737220 rs4981148 0.51 T G15 -0.32 0.004087
TTC5 rs2318864 rs4981148 0.52 T G15 -0.32 0.004087
TTC5 rs3742945 rs4981148 0.52 T G15 -0.32 0.004087
NDRG2 rsl 243444 rsl 243446 0.58 G G15 0.23 0.004573
NDRG2 rsl 243446 rsl 243446 N/A G G15 0.23 0.004573
JPH4 rsl 2897422 rsl 2897422 N/A A G2 -0.45 0.0009928
JPH4 rsl 2897422 rsl 2897422 N/A A G6 -0.44 0.002891
JPH4 rsl 2897422 rsl 2897422 N/A A N4 -0.43 0.003217
DACTl rs464582 rs464582 N/A C G14 -0.19 0.0041
DACTl rs464582 rs464582 N/A C P4 -0.22 0.004041
DACTl rs464582 rs464582 N/A C P7 -0.21 0.001554
DAAMl rs 12147707 rsl 0483710 0.86 A G13 -0.36 0.0009634
DAAMl rsl 7095965 rsl 0483710 0.86 A G13 -0.36 0.0009634
DAAMl rslO143918 rsl 0483710 0.58 A G5 -0.28 0.003772
DAAMl rs 12147707 rsl 0483710 0.86 A G5 -0.28 0.003772
DAAMl rsl 7095965 rsl 0483710 0.86 A G5 -0.28 0.003772
DAAMl rslO143918 rs6573250 0.69 T G13 -0.28 0.0003461
DAAMl rs941886 rs941886 N/A C G13 -0.24 0.003883
DAAMl rsl 1626926 rsl 547199 0.85 T G13 0.23 0.004418
DAAMl rs4127823 rsl271513 0.65 C G13 -0.25 0.003443
DAAMl rs941886 rsl271513 1.00 C G13 -0.25 0.003443
GPR135 rsl 7255731 rs4898989 0.51 A P6 -0.29 0.005506
GPR135 rsl0136708 rs4898989 0.61 A P6 -0.29 0.005506
GPR135 rsl253181 rs4898989 0.81 A P6 -0.29 0.005506
GPR135 rslO138199 rs4898989 1.00 A P6 -0.29 0.005506
GPR135 rs9323348 rs4898989 1.00 A P6 -0.29 0.005506
GPR135 rs4898989 rs4898989 N/A A P6 -0.29 0.005506
GPR135 rsl0136708 rsl 253103 0.54 C G16 -0.27 0.003698
GPR135 rsl 7255731 rsl 253103 0.57 C G16 -0.27 0.003698
GPR135 rsl253181 rsl 253103 0.71 C G16 -0.27 0.003698
GPR135 rslO138199 rsl 253103 0.88 C G16 -0.27 0.003698
GPR135 rs4898989 rsl 253103 0.88 C G16 -0.27 0.003698
GPR135 rs9323348 rsl 253103 0.88 C G16 -0.27 0.003698
RTNl rsl0145080 rsl2878097 0.55 C G12 0.32 0.003522
RTNl rsl 7310036 rsl2878097 1.00 C G12 0.32 0.003522 Table 15: Alleles Influencing Specific Psychiatric Endophenotypes
Gene Name Table B Test SNP in r2 Allele PANSS Beta P
SNP linkage disequilibrium
RTNl rs 17310036 rsl 951366 0.79 A N3 0.26 0.002511
RTNl rsl0145080 rsl 7256003 0.55 C G8 0.20 0.0032
RTNl rs 17310036 rsl 7256003 1.00 C G8 0.20 0.0032
EMLl rs2250718 rs3783322 0.70 G G7 0.29 0.0002896
EMLl rsl 1160563 rsl 1160554 0.56 C Nl -0.35 0.001551
EMLl rsl 1160563 rsl 1160554 0.56 C N6 -0.30 0.003367
EMLl rsl2433613 rsl 1160554 0.88 C N6 -0.30 0.003367
EMLl rsl 1160553 rsl 1160554 1.00 C N6 -0.30 0.003367
EMLl rs6575751 rsl 1160554 1.00 C N6 -0.30 0.003367
EMLl rsl 1160563 rsl 957509 0.56 A G7 -0.29 0.0006263
EMLl rsl2433613 rsl 957509 0.88 A G7 -0.29 0.0006263
EMLl rsl 1160553 rsl 957509 1.00 A G7 -0.29 0.0006263
EMLl rs6575751 rsl 957509 1.00 A G7 -0.29 0.0006263
EMLl rsl 1160553 rsl l91109 0.51 A Nl -0.37 0.0002563
EMLl rs6575751 rsl l91109 0.51 A Nl -0.37 0.0002563
EMLl rsl 1160553 rsl l91109 0.51 A N3 -0.28 0.001132
EMLl rs6575751 rsl l91109 0.51 A N3 -0.28 0.001132
EMLl rsl2433613 rsl 005766 0.77 G Nl -0.35 0.001409
EMLl rsl2433613 rsl 005766 0.77 G N4 -0.30 0.003513
EMLl rsl 1160553 rsl 005766 0.88 G N4 -0.30 0.003513
EMLl rs6575751 rsl 005766 0.88 G N4 -0.30 0.003513
EMLl rs2273707 rs975252 0.59 T G7 0.26 0.001636
EMLl rs2273707 rs2250718 0.53 T G2 0.31 0.0005703
EMLl rs2250718 rs2250718 N/A T G2 0.31 0.0005703
EMLl rs2273704 rs3818279 0.58 G Nl 0.41 0.0006622
EMLl rs746698 rs3818279 0.71 G Nl 0.41 0.0006622
EMLl rsl 1160563 rs8020741 0.68 T G5 -0.22 0.00144
EMLl rsl2433613 rs4900447 0.51 A G15 -0.31 0.0004618
EMLl rsl 1160553 rs4900447 0.59 A G15 -0.31 0.0004618
EMLl rs6575751 rs4900447 0.59 A G15 -0.31 0.0004618
EMLl rsl 1160563 rs4900447 0.97 A G15 -0.31 0.0004618
EMLl rsl2433613 rs4900447 0.51 A G5 -0.22 0.002755
EMLl rsl 1160553 rs4900447 0.59 A G5 -0.22 0.002755
EMLl rs6575751 rs4900447 0.59 A G5 -0.22 0.002755
EMLl rsl2433613 rs4900447 0.51 A N7 -0.25 0.003313
EMLl rsl 1160553 rs4900447 0.59 A N7 -0.25 0.003313
EMLl rs6575751 rs4900447 0.59 A N7 -0.25 0.003313
EMLl rsl 1160563 rs4900447 0.97 A N7 -0.25 0.003313
EVL rsl 190956 rs2400848 0.51 C G16 -0.54 0.004824
BEGAIN rs7140556 rsl 190862 0.65 T G14 -0.23 0.001153
HERC2 rs2238289 rs916977 0.79 T N3 0.37 0.0003766
HERC2 rsl 1631797 rs916977 0.86 T N3 0.37 0.0003766
HERC2 rs916977 rs916977 N/A T N3 0.37 0.0003766
HERC2 rs2238289 rs916977 0.79 T N6 0.37 0.001355
HERC2 rsl 1631797 rs916977 0.86 T N6 0.37 0.001355
HERC2 rs916977 rs916977 N/A T N6 0.37 0.001355
UNC13C rsl7731958 rsl 7731958 N/A T G6 -0.95 0.00007556
UNC13C rs489526 rs500853 1.00 G N7 -0.25 0.004691
UNC13C rs489526 rs500853 1.00 G P2 -0.29 0.004176
UNC13C rsl 6974691 rsl 6974712 0.96 T GlO -0.21 0.0047
UNC13C rsl 6974691 rsl 6974712 0.96 T P2 -0.34 0.003461 Table 15: Alleles Influencing Specific Psychiatric Endophenotypes
Gene Name Table B Test SNP in r2 Allele PANSS Beta P
SNP linkage disequilibrium
Gcoml rs 16977631 rsl 6977629 0.56 T G16 0.52 0.003424
Gcoml rs 16977629 rsl 6977629 N/A T G16 0.52 0.003424
GRINLlA rs986868 rsl 425948 0.97 A P7 -0.21 0.001524
AKAPU rs745191 rs745191 N/A T G9 0.29 0.003429
AKAPU rs 11073502 rs2291048 0.53 A G9 0.30 0.002606
AKAPU rs 11073502 rs2291048 0.53 A Pl 0.37 0.002475
AKAPU rs2241268 rs2241268 N/A A G9 0.28 0.004651
KLHL25 rsl 1637212 rsl 1637212 N/A G P5 0.26 0.009632
SV2B rsl l630131 rsl l631712 0.55 C N4 -0.31 0.003964
SV2B rs2073967 rsl l631712 0.87 C N4 -0.31 0.003964
SLCOMl rs4294800 rs8032981 0.67 A Gl -0.35 0.001287
SLCO3A1 rs4294800 rs975721 0.51 G P5 -0.26 0.004699
SLCO3A1 rs2176452 rs975721 0.53 G P5 -0.26 0.004699
IGFlR rs4965436 rsl 1634874 0.76 C P5 0.40 0.005139
IGFlR rsl 1247380 rsl 879613 0.53 A Gl 0.39 0.0005785
IGFlR rsl879613 rsl 879613 N/A A Gl 0.39 0.0005785
IGFlR rs2684792 rs7173377 0.96 C G9 0.26 0.004224
IGFlR rs2684792 rs7173377 0.96 C P3 0.33 0.003003
IGFlR rs2684792 rs7173377 0.96 C P5 0.27 0.002108
NDRG4 rs42945 rs40359 0.66 C G12 -0.28 0.002966
GOT2 rs2042445 rs7204324 0.51 T P5 -0.41 0.008799
CDH8 rs4636897 rsl 1641508 1.00 A G2 0.44 0.0009623
CDH8 rs4131634 rs4416006 0.96 C G5 -0.25 0.002379
CDH8 rs4131634 rsl 1862752 0.51 A G4 -0.39 0.002652
CDH8 rs6498807 rs7189354 0.80 G Pl -0.32 0.004743
CDH8 rsl 1075445 rs7189354 1.00 G Pl -0.32 0.004743
CDH8 rsl369918 rs7189354 1.00 G Pl -0.32 0.004743
CDH8 rsl 978796 rs7189354 1.00 G Pl -0.32 0.004743
CDHIl rs35144 rs35165 0.68 A G6 0.35 0.001477
CDHIl rs35148 rs35165 1.00 A G6 0.35 0.001477
CDHIl rs35144 rs35162 0.68 A G2 0.29 0.00496
CDHIl rs35148 rs35162 1.00 A G2 0.29 0.00496
KIAA05U rs4783121 rsl 6975240 0.87 G G6 -0.70 0.002637
PMP22 rsl 3422 rs231020 0.64 T P3 -0.36 0.0008073
PMP22 rs231021 rs231020 0.67 T P3 -0.36 0.0008073
PMP22 rs231018 rs231020 0.93 T P3 -0.36 0.0008073
PMP22 rs231018 rsl0852830 0.52 C G13 -0.24 0.001942
PMP22 rsl 79521 rsl0852830 0.83 C G13 -0.24 0.001942
KATNAL2 rs2247221 rs2010834 0.56 A N7 0.33 0.0001519
KATNAL2 rs2571030 rs2010834 0.56 A N7 0.33 0.0001519
KATNAL2 rs2576042 rs2010834 0.59 A N7 0.33 0.0001519
KATNAL2 rs7233515 rs2010834 0.69 A N7 0.33 0.0001519
KATNAL2 rs2187092 rs2010834 0.97 A N7 0.33 0.0001519
KATNAL2 rs9304340 rs2010834 0.97 A N7 0.33 0.0001519
KIAAO 427 rs2175565 rs9952398 1.00 C Gl -0.31 0.00361
KIAA 0427 rs937021 rs937021 N/A G N5 0.30 0.003682
DYM rs357894 rs357894 N/A C G9 -0.33 0.0006157
DYM rs498929 rsl 6950465 0.54 T G9 -0.36 0.001734
DCC rsl 7753970 rsl 6954731 0.87 G G4 0.27 0.004839
DCC rs8089980 rs8089980 N/A T G16 0.27 0.003432
DCC rs8089980 rs8089980 N/A T G7 0.24 0.002252 Table 15: Alleles Influencing Specific Psychiatric Endophenotypes
Gene Name Table B Test SNP in r2 Allele PANSS Beta P
SNP linkage disequilibrium
DCC rs8089980 rslO853621 0.76 T G7 0.25 0.001494
DCC rs8089980 rs 10853622 0.76 A G12 -0.27 0.004596
DCC rs 1893572 rs7228674 0.77 T G16 0.28 0.004286
DCC rs 1893572 rs7228674 0.77 T Nl 0.32 0.002084
DCC rs 1893572 rs7228674 0.77 T N2 0.26 0.004955
DCC rs 1893572 rs7228674 0.77 T N6 0.28 0.004787
DCC rs 1893572 rs9807201 0.65 A G7 0.32 0.000156
DCC rs 1893572 rs9807201 0.65 A N3 0.30 0.001024
DCC rs 1431748 rs4998815 0.61 G G12 -0.28 0.004202
DCC rs950278 rs 12967277 0.60 G G12 0.28 0.002738
DCC rs950278 rsl2455180 0.53 T P2 -0.25 0.008191
DCC rs2229080 rsl2455180 0.64 T P2 -0.25 0.008191
DCC rs 1431748 rs9953016 0.81 C N2 -0.29 0.001508
DCC rs 1431748 rs7504750 0.63 C G2 -0.32 0.001379
DCC rs8096519 rs 11082964 0.95 G N2 0.30 0.004634
DCC rs 12457407 rs9954344 0.61 G P2 -0.27 0.004541
DCC rs6508235 rs9954344 0.62 G P2 -0.27 0.004541
DCC rs7506904 rs9954344 0.69 G P2 -0.27 0.004541
DCC rs4940251 rs9954344 0.86 G P2 -0.27 0.004541
DCC rs2270954 rs2270954 N/A A P6 -0.46 0.002603
BMP7 rs 10375 rs6123669 0.91 C G14 -0.21 0.001474
BMP7 rs6014947 rs6123669 0.97 C G14 -0.21 0.001474
BMP7 rs230198 rs230198 N/A G G15 -0.25 0.004865
OTHER EMBODIMENTS
It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:
1. A method of obtaining information regarding a human subject's risk of developing schizophrenia (SZ) the method comprising: obtaining a test haplotype for the subject by determining the genotype of at least one test marker listed in Table B, or a test marker that lies between a pair of delimiting markers listed in Table A and that is in linkage disequilibrium with markers listed in Table B, wherein the test haplotype indicates the subject's risk of developing SZ.
2. The method of claim 1 , wherein the at least one test marker is in a KIAAO 182 gene or KIAA0427 gene, and further is selected from the group consisting of: rs736845; rs994060; rs381579; rs217556; rs8095199; or is a test marker in LD with these markers; wherein the genotype of the test marker indicates the subject's risk of developing SZ
3. The method of claim 1 , wherein the at least one test marker is are selected from the group consisting of: rsl0864639; rs845197; rs2071986; rsl2136689; rs8627; rs7546786; rs2073091; rs4661572; rsl2057431; rs4838924; rsl0913530; rsl2096984; rs2073484; rs6672082; rsl5655; rs2093184; rs7554526; rs9425287; rsl0458360; rsl2135884; rs553042; rsl7494681; rs506947; rs638132; rs6690557; rs9429830; rsl770220; rsl050745; rs2393607; rsl 1596260; rs2241540; rsl551684; rs2283174; rs231348; rsl 1030008; rs2237965; rsl0766408; rsl0766410; rs2041027; rs2073582; rs2237957; rs4757589; rsl0766590; rs2042600; rs2278132; rs7119267; rs2028570; rs2289566; rsllO26532; rsl551833; rsl0837367; rsl061810; rs4755744; rsl0838160; rs3802891; rsl6937817; rs7950395; rsl2362429; rsllO38382; rs2863182; rs4992029; rsl938596; rs4319530; rs7945889; rs948562; rslO48444; rs2211912; rs3847; rs5029315; rs544864; rs621162; rs656163; rsl568923; rs7134748; rs7969288; rs7297606; rs4237817; rs2306541; rs3737220; rs2318864; rs3742945; rsl l541; rsl60472; rs863091; rs4127823; rslO138199; rsl253181; rsl7255731; rs4898989; rs9323348; rs2273704; rs7143905; rs746698; rsll l60553; rsl2433613; rs6575751; rs3206354; rsl 1074322; rsl635168; rs2238289; rs7495174; rsl 1631797; rs916977; rs2115827; rs2163195; rsl2594549; rsl897069; rsl2910912; rsll856476; rs4424863; rs8028559; rsl7238461; rsl509408; rs2291049; rs2430838; rs338556; rsl075840; rsl 117388; rs2301665; rs8027498; rs3743444; rsl2912997; rs4965436; rsl 1247380; rsl879613; rslO39342; rsll20276; rsl224; rs2354580; rs3826176; rs9937623; rsl3333449; rs7202037; rs736845; rs9940601; rs3815794; rsll644122; rs2305357; rs373835; rs386061; rsl3422; rs230938; rs231021; rsl0502880; rsl7785419; rs2668771; rs7236105; rsl2457664; rsl787176; rsl792666; rsl792682; rs2000709; rs7228393; rs2175565; rs8095199; rsl2458752; rsl2958604; rs2276163; rs2298617; rs3764465; rsl893572; rsl62316; or is a test markers in LD with one of these markers; wherein the genotype of the test marker indicates the subject's risk of developing SZ.
4. A method of predicting a human subject's likely response to an antipsychotic medication, the method comprising: obtaining a test haplotype for the subject by determining the genotype for at least one test marker listed in Table B, or at least one test marker that lies between the delimiting markers in Table A and that is in linkage disequilibrium (LD) with a marker listed in Table B, wherein the test haplotype indicates the subject's likely response to an antipsychotic medication.
5. The method of Claim 4, wherein the treatment is administration of olanzapine, and the at least one test marker is in a gene selected from the group consisting of C16orf74, synaptic vesicle glycoprotein 2B (SV2B), calmodulin binding transcription activator 1 (CAMTAl), otogelin (OTOG), ras homolog gene family, member G (RHOG) and further is selected from the group consisting of: rsl 16301; rs230535; rs373835; rs386061; rs449250; rs657739; rs657740; rs755475; rs755475; rsl41798; rsllO3OO; rsl45172; rsl00349; rslO8328; rs202348; rsl lO243; rsl 1024358; or is a test markers in LD with one of these markers, wherein the test haplotype indicates the subject's likely response to administration of olanzapine.
6. The method of Claim 4, wherein the treatment is administration of olanzapine, and the at least one test marker is selected from the group consisting of: rs277675; rs6657847; rs4243823; rsl0864255; rs228652; rslOOO313; rs6665012; rsl97412; rs544941; rsl0910966; rslO63412; rsl0910966; rsl0910966; rs6701631; rs2470508; rs842254; rs842254; rs842254; rslO761446; rslO761446; rslO761446; rs2237961; rs2625312; rs6573250; rs7143953; rs7143953; rsl7096088; rsl2589351; rs7143953; rs7143953; rs7143953; rsl253170; rsl253170; rsl253170; rsl273156; rsl253170; rsl253170; rsll623084; rsl l623084; rsl0150225; rsl0150225; rsll623084; rs8041209; rs8041209; rs8041209; rsl2900128; rslO518831; rslO518831; rsl002556; rsl002556; rs207954; rs8027160; rsll633717; rsll633717; rsll633717; rslO58132; rslO58132; rslO58132; rs442069; rs442069; rs442069; rslO23943; rsl2953717; rs2337153; rs577979; rs577979 or is a test marker that is in linkage disequilibrium with one of these markers, wherein the test haplotype indicates the subject's likely response to administration of olanzapine.
7. The method of Claim 4, wherein the treatment is administration of risperidone, and the at least one test marker is in a gene selected from the group consisting of neural precursor cell expressed, developmentally down-regulated 4 (NEDD4), cadherin 8, type 2 (CDH8), deformed epidermal autoregulatory factor 1 (DEAFl), hect domain and RLD 2 (HERC2) and further is selected from the group consisting of: rs230357; rs230358; rsl39713; rs805733; rs930254; rsllO754; rsl36991; rsl97879; rs649880; rs993999; rs496314; rs659799; rs936465; rs659799; rsl 10743; rsl63516; rs223828; rs7495174; or is a test marker that is in linkage disequilibrium with one of these markers, wherein the test haplotype indicates the subject's likely response to administration of risperidone.
8. The method of Claim 4, wherein the treatment is administration of risperidone, and the at least one test marker is selected from the group consisting of: rs228651 ; rs2640909; rs2073091; rs4661572; rsl2133992; rs534276; rsl97422; rs4382763; rsl3932; rsl770213; rs2245708; rs2493049; rsl551684; rs4963145; rs6597996; rs936465; rs6597990; rs4345940; rs7932938; rsl 1026532; rs4992029; rs8929; rs2511986; rs7297606; rs2277356; rsl243444; rsl243446; rsl7833769; rsl958180; rsl0136708; rslO138199; rsl253181; rsl7255731; rs4898989; rs9323348; rsllO74322; rsl635168; rs2238289; rs7495174; rsl6974691; rslll7388; rs3743444; rs2176452; rsll247380; rsl879613; rs3743777; rsllO75445; rsl369918; rsl978796; rs6498807; rs9939991; rs35144; rs35148; rs35186; rs35195; rsl393331; rs4940251; rs6508235; rsl2136689; rs8627; rs6425302; rsl99960; rs3856090; rs2393607; rsllO38382; rs2863182; rs3741494; rsl2897422; rs4898983; rs2303579; rs2303580; rs4774275; rs986868; rs2286355; rslO39342; rsl 120276; rsl224; rs2354580; rs3826176; rs9937623; rsllO76478; rs9935379; rsl397131; rs8057338; rs9302540;
no rs736839; rs8096141; rs427278; or is a test marker that is in linkage disequilibrium with one of these markers, wherein the test haplotype indicates the subject's likely response to administration of risperidone.
9. The method of Claim 4, wherein the treatment is administration of quetiapine, and the at least one test marker is in a gene selected from the group consisting of catenin (cadherin-associated protein), delta 1 (CTNNDl), reticulon 1 (RTNl), A kinase (PRKA) anchor protein 13 (AKAP 13), potassium voltage-gated channel, shaker-related subfamily, member 10 (KCNAlO), solute carrier family 17 (sodium- dependent inorganic phosphate cotransporter), member 6 (SLC 17A6), and further is selected from the group consisting of: rs207835; rsllO265; rsll5582; rs207835; rs224671; rs376845; rs708228; rslO8966; rsll5701; rs215663; rs652908; rslO5399; rs206182; rs206182; rs206182; rs338523; rs407525; rs407525; rs484289; rs484307; rs484307; rs716216; rsl 10735; rsl01450; rsl27174; rsl7310036; or is a test marker that is in linkage disequilibrium with one of these markers, wherein the test haplotype indicates the subject's likely response to administration of quetiapine.
10. The method of Claim 4, wherein the one or more test markers is selected from the group consisting of: rs845197; rs7530745; rs7554486; rsl0857820; rsl334882; rs3768456; rsl7494681; rs3856090; rs4620600; rs2393596; rs7109335; rs7121608; rs7935419; rsl0766408; rs2041027; rs2237957; rsl0766434; rs2299637; rs757514; rsl0833202; rs2078352; rsllO26523; rsll55821; rs2246710; rsl0837367; rs2511986; rs7297606; rs2306536; rs4758954; rslO138199; rsl253181; rsl7255731; rs4898989; rs9323348; rsl0136708; rs2273704; rs7143905; rsl 190954; rsl 190956; rsl 190974; rslO873518; rsll856476; rsl2914912; rs4776216; rsl7238461; rs338556; rs2430838; rs2176452; rsl l859615; rsl6952126; rs7184206; rs9923731; rsl2924119; rsl3333449; rs7202037; rsl397131; rs8057338; rs9302540; rs35144; rs35148; rs35186; rs35195; rs4247350; rs2306514; rs937021; rs752151; rs427278; rs7546786; rs638132; rs2356933; rs2294660; rs998777; rsl798177; rs7947357; rs708228; rsl0896644; rsl 1570176; rs2156638; rs652908; rsl236; rs4759517; rs6486600; rs6486602; rs464582; rslO143918; rsl2147707; rsl7095965; rsl 1626926; rs4127823; rsl0145080; rsl2717467; rsl7310036; rs3206354; rs9920139; rs9920150; rs986868; rslO53992; rs2061821; rs2061822; rs2061824; rs338523; rs4075254; rs4075256; rs4842895; rs4843074; rs4843075; rs7162168; rsl 1073502; rsl075840; rs2301665; rs8027498; rsl3167; rs8030950; rsl 1247380; rs2684808; rs892583; rs2175565; rs4939813; rs6508145; rs2229080; rs950278; rsl2457407; rs4940251; rs7506904; rs6508235; rsl393331or is a test marker that is in linkage disequilibrium with one of these markers, wherein the test haplotype indicates the subject's likely response to administration of quetiapine.
11. The method of Claim 4, wherein the treatment is administration of perphenazine, and the at least one test marker is in a gene selected from the group consisting of secretion regulating guanine nucleotide exchange factor (SERGEF) potassium voltage-gated channel, subfamily H (eag-related), member 1 (KCNHl), functional smad suppressing element 18 (FUSSELl 8) and further is selected from the group consisting of: rsl77022; rsl39302; rsl528; rsl72424; rs211130; rs211137; rs211146; rs228323; rsl05028; rsl77854; rs266877; rs723610; rs892583; or is a test marker that is in linkage disequilibrium with one of these markers, wherein the test haplotype indicates the subject's likely response to perphenazine.
12. The method of Claim 4, wherein the treatment is administration of perphenazine, and the at least one test marker is selected from the group consisting of: rs6577393; rs6577401; rs4661572; rsl99960; rs9430004; rsl770220; rsl393026; rs3750800; rs3168046; rs3750920; rs7396514; rsl0734456; rs902224; rsl0766434; rs2299637; rs757514; rsl528; rsl72424; rs211130; rs211137; rs211146; rs2283233; rs2585788; rsl979072; rsl979073; rs2593644; rs764021; rs3107275; rsl568923; rsl0870551; rs4883513; rsl7255975; rsl l856476; rsl2914912; rs4776216; rs9920139; rs9920150; rsl509408; rsl6977631; rs2733619; rs338556; rs2430838; rs2286355; rs6496893; rsl 1076478; rs9935379; rs3743777; rs35144; rs35148; rsll644279; rs4792434; rs8077302; rs2247221; rs2571030; rs9961383; rs2668771; rs7236105; rsl0502880; rsl7785419; rsl893572; rsl2457407; rs4940251; rs7506904; rs230198; rs6015068; rsl2070592; rs924181; rsll578913; rsl0857820; rsl334882; rs6690557; rsl 1119315; rs4963153; rs7946354; rs2041028; rs2355466; rs4757548; rs7111528; rs4274187; rsl061810; rs4755744; rsl938596; rs4319530; rs2250718; rsll639005; rs9302181; rsl6977252; rs2554; rsl2912997; rsll247380; rsl879613; rs9939991; rsllO75445; rsl369918; rsl978796; rs6498807; rs4783121; rs3794684; rs2302107; rs892583; rs8096141; rs6508145 or is a test markers that is in linkage disequilibrium with one of these markers, wherein the test haplotype indicates the subject's likely response to administration of perphenazine.
13. The method of Claim 4, wherein the treatment is administration of ziprasidone, and the at least one test marker is in a gene selected from the group consisting unc-13 homolog C (C. elegans) (UNC13C), cerebellin 1 precurso (CBLNl), checkpoint with forkhead and ring finger domains (CHFR) and is further selected from the group consisting of: rsl29109; rsl 10764; rs993537; rsl25945; rsll6390; rs802519; rs930218; rs230653; rs4758954; or is a test marker that is in linkage disequilibrium with one of these markers, wherein the test haplotype indicates the subject's likely response to administration of ziprasidone.
14. The method of Claim 4, wherein the treatment is administration of ziprasidone, and the at least one test marker is selected from the group consisting of: rs2073091; rs4661572; rs4838924; rsl6847624; rs6425302; rs506947; rsl99960; rs3856090; rs2245721; rs842257; rs859703; rs2294660; rs998777; rsl0734456; rsl554857; rs7396514; rs7945160; rs902224; rs9440; rs231348; rsl 1024357; rsllO24358; rs4757707; rs7125647; rs2001982; rs2953310; rsl061810; rs4755744; rsl0838160; rs3802891; rsl938596; rs4319530; rs2211912; rs5029315; rs656163; rs1048444; rs3847; rs544864; rs621162; rs2318864; rsl0873395; rs3742945; rsl713449; rs7150689; rs938886; rs938887; rsl268579; rsl252989; rsl253005; rs4901909; rs8022614; rs941884; rslll60553; rsl2433613; rs6575751; rslll60563; rslO873518; rsl2910912; rs4775086; rs514049; rs653765; rs2554; rs2291049; rs2430838; rs338556; rsll630131; rs2073967; rs8030950; rsll247380; rsl879613; rsllO76478; rs9935379; rs9939991; rsllO75445; rsl369918; rsl978796; rs6498807; rs35148; rs35186; rs35144; rsl2597135; rs3751756; rs3815794; rs892583; rs4939813; rsl431748; rs427278; rs3753275; rsl010892; rs6689641; rs877068; rs924181; rsl0752946; rsll ll9658; rsl501569; rsl393026; rs2073582; rsl372989; rs4992029; rs8929; rs2306536; rs4758954; rsl7255975; rsl2594549; rsl 1639005; rs8025195; rs9302181; rsl6977252; rsl075840; rs2301665; rsll859615; rsl6952126; rs7184206; rs9923731; rsl79521; rsl0502880; rsl7785419; rs4940251; rs6508235 or is a test marker that is in linkage disequilibrium with one of these markers, wherein the test haplotype indicates the subject's likely response to administration of ziprasidone.
15. The method of Claim 4, wherein the treatment is administration of an antipsychotic drug, and the at least one test marker is in a gene selected from the group consisting cadherin 11, type 2, OB-cadherin (osteoblast) (CDHIl), deleted in colorectal carcinoma (DCC), Usher syndrome 1C (autosomal recessive, severe) (USHlC) and is further selected from the group consisting of: rs35144 ; rs35148 ; rs35186 ; rs35195 ; rs35144 ; rs222908; rs950278; rsl43174; rsl24574; rs494025; rs750690; rs650823; rsl39333; rsl52023; rslO5557; rslO5557; rs207222; rs475689; rs 16770; or is a test markers that is in linkage disequilibrium with one of these markers, wherein the test haplotype indicates the subject's likely response to administration of an antipsychotic.
16. The method of Claim 4, wherein the treatment is administration of an antipsychotic, and the at least one test marker is selected from the group consisting of: rsl203682; rsl010892; rs6689641; rs877068; rsll lO2342; rs4382763; rsl0752946; rsl770220; rs2493037; rslO55574; rslO55577; rs2072225; rs4756895; rsl6770; rs2953310; rsl0838160; rs3802891; rsl061810; rs4755744; rs6490226; rs7294615; rsl2897422; rsl252989; rsl253005; rs4901909; rs8022614; rs941884; rsl0136708; rslO138199; rsl253181; rsl7255731; rs4898989; rs9323348; rsl0145080; rsl2717467; rsl7310036; rslO144785; rsl2910912; rs2271289; rs2303579; rs2303580; rs4774275; rs986868; rs745191; rsll073502; rsll630131; rs2073967; rsl075840; rslll7388; rs2301665; rsl3167; rs2684808; rs35144; rs35148; rs35186; rs35195; rs892583; rsl2457664; rsl787176; rsl792666; rsl792682; rs2000709; rs7228393; rs736839; rsl2458752; rsl2958604; rs2276163; rs2298617; rs3764465; rs620898; rs2229080; rs950278; rsl431748; rsl2457407; rs4940251; rs7506904; rs6508235; rsl393331; rs228651; rs6698830; rs7530745; rs7554486; rsl281174; rsl281177; rs506947; rs4609425; rs2493049; rs7125647; rs2028570; rsl lO26523; rsll55821; rs2078352; rs2246710; rsl268579; rs4127823; rsll90956; rslO873518; rsl635168; rs2238289; rs7495174; rsll856476; rsl2914912; rs4776216; rs4775086; rs514049; rs653765; rs3764196; rsl520233; rs4247350; rs3815794; rs736845; rs2305357; rs373835; rs386061 or is a test marker that is in linkage disequilibrium with one of these markers, wherein the test haplotype indicates the subject's likely response to administration of an antipsychotic.
17. A method of predicting degree of severity of a psychiatric endophenotype in a human subject, the method comprising: obtaining a test haplotype for the subject by determining the genotype for at least one test marker listed in Table B, or at least one test markers that lies between the delimiting markers listed in Table A and that is in linkage disequilibrium (LD) with a marker in Table B, wherein the test haplotype indicates the likely degree of severity of a psychiatric endophenotype in the subject.
18. The method of Claim 17, wherein the psychiatric endophenotype is a quantitative trait that can be measured using one or more of PANSS Total composite score, PANSS Positive composite score, PANSS Negative composite score, and PANSS General Psychopathology composite score.
19. The method of Claim 18, wherein one or more test markers are from calcium channel, voltage-dependent, R type, alpha IE subunit (CACNAlE), echinoderm microtubule associated protein like 1 (EMLl), katanin p60 subunit A-like 2 (KATNAL2) genes and selected from among the group consisting of: rs 174946; rsl99960; rs385609; rs465267; rs704326; rs218709; rs224722; rs257103; rs257604; rs723351; rs930434; rs996138; rs225071; rsll l605; rslll605; rsl24336; rs657575; rs746698; rs227370; rs2273704; or is a test marker in linkage disequilibrium with one of these markers, wherein the test haplotype indicates the likely degree of severity of a psychiatric endophenotype in the subject.
20. The method of Claim 18, wherein the at least one test marker is selected from the group consisting of: rsl2070592; rslO11124; rsl417986; rs707463; rs707465; rs938249; rs4382763; rsl0458360; rsl2135884; rsl7494681; rsl99960; rs3856090; rs4652678; rs704326; rs2356933; rsl7014820; rsl770213; rs4620600; rs2493037; rsl0733757; rs4568956; rs7907721; rsl055640; rsl l030008; rsl451722; rsl064074; rs2072225; rsl6770; rsl0832824; rs2023483; rs2041028; rs7111528; rsl003490; rs4757589; rsl550870; rs6483524; rsl0766500; rsl0833202; rs6483629; rsl443547; rs894750; rsl0837367; rs2863172; rs2863174; rs4755941; rs7103871; rs6490226; rs7136574; rsl541764; rs2555269; rs2723880; rs2723882; rsl236; rs4759517; rs6486600; rs6486602; rs2318864; rs3737220; rs3742945; rsl713449; rs7150689; rs938886; rs938887; rsl2897422; rslO143918; rsl2147707; rsl7095965; rsl252989; rsl253005; rs4901909; rs8022614; rs941884; rsll626926; rs4127823; rs941886; rs2250718; rslll60553; rslll60563; rsl2433613; rs6575751; rs746698; rs2273707; rs2273704; rsl 1631797; rs2238289; rs916977; rsl7731958; rs2163195; rs489526; rsl 6974691; rs4774275; rsl6977629; rsl6977631; rs986868; rs745191; rsll073502; rs2241268; rsll637212; rsl l630131; rs2073967; rs2286355; rs7170035; rs4965436; rs2684792; rsllO76478; rs9935379; rsl2924119; rs4131634; rs9939991; rsllO75445; rsl369918; rsl978796; rs6498807; rsl397131; rs8057338; rs9302540; rsl520233; rs35148; rs35144; rs35186; rs35195; rslO49868; rs3815795; rsl3422; rs230938; rsl79521; rs231018; rs2187092; rs2247221; rs2571030; rs2576042; rs7233515; rs9304340; rs9961383; rsl0502880; rsl7785419; rs2668771; rs7236105; rs6508145; rsl893572; rsl431748; rs427278; or is a test marker that is in linkage disequilibrium with one of these markers, wherein the test haplotype indicates the likely degree of severity of a psychiatric endophenotype.
21. The method of Claim 17, wherein the psychiatric endophenotype comprises one or more of: a Positive Symptom selected from the group consisting of Pl- delusions, P2-conceptual disorganization, P3 -hallucinatory behavior, P4-exitement, P5 -grandiosity, P6-suspiciousness, P7-hostility; a Negative Symptom selected from the group consisting of Nl -blunted affect, N2-emotional withdrawal, N3-poor rapport, N4-passive/appathetic social withdrawal, N5 -difficultly in abstract thinking, N6-lack of spontaneity and flow of conversation, N7-steryotyped thinking; or a general psychopathology symptom selected from the group consisting of Gl -somatic concern, G2-anxiety, G3-guilt feelings, G4-tension, G5-mannerisms and posturing, G6- depression, G7-motor retardation, G8-uncooperativeness, G9-unusual thought content, G10-disorentation, GIl -poor attention, G12-lack of judgment and insight, Gl 3 disturbance of volition, G14-poor impulse control, G15-preoccupation, and G 16- active social avoidance.
22. The method of Claim 21 , wherein the at least one test marker is from a gene selected from the group consisting of DPH3, KTIl 1 homo log (DPH3), insulin- like growth factor I receptor (IGFlR), calcium/calmodulin-dependent protein kinase IG (CAMKlG), neuron navigator 2 (NAV2), bone morphogenetic protein 7 (BMP7), and further is selected from the group consisting ofrs224572; rs842257; rs859703; rs224570; rs496543; rsll2473; rsl 87961; rs268479; rslO8332; rs712564; rslO375 ; rs601494; rs230198; or is a test marker that is in linkage disequilibrium with one of these markers, wherein the test haplotype indicates the likely severity of a psychiatric endophenotype.
23. The method of Claim 22, wherein the at least one test marker is selected from the group consisting of: rs7554752; rsl2070592; rs707463; rs707455; rs707465; rs2640909; rsl2057431; rs4661572; rs3738298; rs4382763; rsl7494681; rs3856090; rsl99960; rs4652678; rs704326; rsl7014820; rs6690557; rsl770213; rs2245721; rs842257; rs859703; rs2245708; rsl473909; rs3168046; rs3750920; rsl554857; rs7945160; rs9440; rsl0734456; rs902224; rs7396514; rsl055640; rsl451722; rsl 1030008; rs2072225; rsl064074; rsl6770; rs2041028; rs7111528; rs2023483; rsl0832824; rsl0766500; rsl0833202; rs7125647; rs2953310; rsl0837367; rsl061810; rs4755744; rsllO37691; rsl2362429; rs4992029; rs2863182; rsl lO38382; rslO48444; rs3847; rs656163; rs5029315; rs2211912; rs621162; rs544864; rs6490226; rs7136574; rs4237817; rs3737220; rs2318864; rs3742945; rsl243444; rsl243446; rsl2897422; rs464582; rsl2147707; rsl7095965; rslO143918; rs941886; rsll626926; rs4127823; rsl7255731; rsl0136708; rsl253181; rslO138199; rs9323348; rs4898989; rsl0145080; rsl7310036; rs2250718; rsll l60563; rsl2433613; rslll60553; rs6575751; rs2273707; rs2273704; rs746698; rsll90956; rs7140556; rs2238289; rsll631797; rs916977; rsl7731958; rs489526; rsl6974691; rsl6977631; rsl6977629; rs986868; rs745191; rsll073502; rs2241268; rsll637212; rsll630131; rs2073967; rs4294800; rs2176452; rs4965436; rsll247380; rsl879613; rs2684792; rs42945; rs2042445; rs4636897; rs4131634; rs6498807; rsl 1075445; rsl369918; rsl978796; rs35144; rs35148; rs4783121; rsl3422; rs231021; rs231018; rsl79521; rs2247221; rs2571030; rs2576042; rs7233515; rs2187092; rs9304340; rs2175565; rs937021; rs357894; rs498929; rsl7753970; rs8089980; rsl893572; rsl431748; rs950278; rs2229080; rs8096519; rsl2457407; rs6508235; rs7506904; rs4940251; rs2270954; rslO375; rs6014947; rs230198; or is a test marker that is in linkage disequilibrium with one of these markers, wherein the test haplotype indicates the likely degree of severity of a psychiatric endophenotype.
24. The method of any of claims 1-3, wherein the test haplotype indicates that the subject has an increased risk of developing SZ.
25. The method of any of claims 1 -23 , wherein obtaining a test haplotype comprises: obtaining a sample comprising DNA from the subject; and determining the genotype for the test marker.
26. The method of any of claims 1-23, further comprising: obtaining a reference haplotype comprising a reference marker that corresponds to the test marker; and comparing the test haplotype to the reference haplotype, wherein the presence of a haplotype in both the test haplotype and a reference haplotype is indicative of likelihood that a subject will develop SZ, likely pharmacological response, or likely severity of a psychiatric endophenotype.
27. The method of claim 26, wherein the reference haplotype is from one or more subjects who have SZ and the presence of a haplotype in both the test haplotype and the reference haplotype indicates that there is an increased likelihood that the subject will develop SZ.
28. The method of claim 26, wherein the reference haplotype comprises a haplotype from at least one of the following relatives of the subject:
(a) a parent who has SZ, SD, or SPD;
(b) a sibling who has SZ, SD, or SPD, and an unaffected parent; or
(c) a second degree relative who has SZ, SD, or SPD and an unaffected parent; wherein sharing of a haplotype between the test haplotype and the reference haplotype from the relative who has SZ, SD, or SPD, is indicative of an increased likelihood that the subject will develop broadly defined SZ.
29. The method of any of claims 1-23, further comprising determining the genotype of one or more additional markers listed in Table B, or one or more test markers that are in linkage disequilibrium with a marker listed in Table B.
30. The method of any of claims 1-23, wherein the subject is a patient having or suspected of having SZ.
31. The method of any of claims 1 -23 , wherein the subj ect has one or more risk factors associated with SZ.
32. The method of claim 31 , wherein the risk factors associated with SZ or BD include one or more of: a relative afflicted with SZ, SPD, SD or Bipolar Disorder; and a genetically based phenotypic trait associated with risk for SZ, SPD, or SD.
33. The method of any of claims 1-23, further comprising selecting or excluding a subject for enrollment in a clinical trial based on the test haplotype.
34. The method of any of claims 1-23, further comprising stratifying a subject population for analysis of a clinical trial based on test haplotypes in the subjects.
35. The method of any of claims 1-23, further comprising confirming a diagnosis of SZ using psychometric instruments.
36. The method of any of claims 1-23, further comprising stratifying patients into biologically similar groups based on test haplotypes in order to determine a differential diagnosis.
37. An array comprising a substrate having a plurality of addressable areas, wherein one or more of the addressable areas comprises a probe that can be used to detect a polymorphism that is listed in Table B or is in linkage disequilibrium with a marker listed in Table B.
38. A method of selecting a subject for administration of a treatment for schizophrenia (SZ), schizotypal personality disorder (SPD), or schizoaffective disorder (SD), the method comprising: obtaining a haplotype for the subject, wherein the haplotype comprises at least one marker that is listed in Table B or is in linkage disequilibrium with a marker listed in Table B; determining whether the haplotype is associated with an improved response profile for a clinical treatment; and selecting the subject if the haplotype indicates that the subject is more likely to have an improved response profile to the clinical treatment in question.
39. A method of selecting a treatment for a subject, the method comprising: obtaining a haplotype for the subject, wherein the haplotype comprises at least one marker that is listed in Table B or is in linkage disequilibrium with a marker listed in Table B; determining whether the haplotype is associated with an improved response profile for a clinical treatment; and selecting the treatment if the haplotype indicates that the subject is more likely to have an improved response profile to the clinical treatment in question.
40. A method of identifying haplotypes associated with altered outcome to a treatment for schizophrenia (SZ), schizotypal personality disorder (SPD), or schizoaffective disorder (SD), the method comprising obtaining a haplotype for a subject, wherein the haplotype comprises at least one marker that is listed in Table B or is in linkage disequilibrium with a marker listed in Table B; obtaining data regarding response to a treatment in the subject; and correlating the haplotype with a response to the clinical treatment.
41. The method of claim 40, wherein the data regarding response to a treatment comprises at least one parameter selected from the group consisting of efficacy, side- effect profile, treatment maintenance and discontinuation rates, return to work status, hospitalizations, suicidality, total healthcare cost, social functioning scales, response to non-pharmacological treatments, and dose response curves.
42. The method of claim 41 , wherein the side-effect profile includes one or more of weight gain, metabolic dysfunction, lipid dysfunction, movement disorders, and extrapyramidal symptoms.
43. The method of claim 40, wherein the information regarding outcome of the treatment is from a clinical trial.
44. A method of providing information regarding one or more of the following: a subject's risk of developing schizophrenia (SZ), clinical response to antipsychotic medications, or severity of psychopathology endophenotypes, the method comprising: obtaining a sample from the subject at a first site, transferring the sample to a second site for analysis, wherein the analysis provides data regarding the identity, presence or absence of at least one test marker that is listed in Table B or is in linkage disequilibrium with a marker listed in Table B; analyzing the data for potential impact on one or more of the following: a subject's risk of developing schizophrenia (SZ); clinical response to antipsychotic medications; and presence or severity of psychiatric endophenotypes; and transferring the results of the analysis to one or more of the following: a health care provider; the subject; a healthcare payer; or a clinical trial sponsor.
45. The method of claim 44, wherein the data is transferred to a healthcare payer and used to decide whether to reimburse a health care provider or subject for medical expenses, including drug costs.
46. The method of any of claims 1-23 or 38-45, wherein obtaining a test haplotype comprises obtaining a sample comprising genomic DNA of the subject, and determining the identity of the alleles at the test markers.
47. The method of any of claims 1-23 or 38-45, wherein obtaining a test haplotype comprises constructing a haplotype using previously determined genotype information, wherein the previously determined genotype information includes at least one test marker that is listed in Table B or is in linkage disequilibrium with a marker listed in Table B.
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