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  • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
  • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
  • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
  • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • G—PHYSICS
  • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
  • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
  • G16B30/00—ICT specially adapted for sequence analysis involving nucleotides or amino acids
• • G—PHYSICS
  • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
  • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
  • G16B30/00—ICT specially adapted for sequence analysis involving nucleotides or amino acids
  • G16B30/10—Sequence alignment; Homology search
• • G—PHYSICS
  • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
  • G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
  • G16C99/00—Subject matter not provided for in other groups of this subclass
• • G—PHYSICS
  • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
  • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
  • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
  • G16H50/30—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for calculating health indices; for individual health risk assessment
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
  • C12Q2600/00—Oligonucleotides characterized by their use
  • C12Q2600/156—Polymorphic or mutational markers
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A90/00—Technologies having an indirect contribution to adaptation to climate change
  • Y02A90/10—Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Definitions

• the present invention relates to risk markers ibr suicide. More specifically, the present invention relates to genetic markers associated with suicide risk.
• Suicide has a prominent genetic component (reviewed in 3). Suicide attempts tend to occur more often within families (Johnson et al. 1998; Brent et al.2002). Greater concordance was observed between monozygotic twins than between dizygotic twins (4, 5). The concordant phenotype includes both completed and attempted suicides (4). A review of twin studies estimated the heritability of suicidal behavior to be up to 55% (6).
• German with their replication bipolar disorder sample (STEP-BD. WTCCC, UCL), the most significantly associated marker was rs300774 in an intergenie region at chromosomal region 2p25. which contains the SII3YL1. ACPI, and FAM150B genes.
• the association finding was supported by post-mortem prefrontal cortical gene , ⁇ -. expression analysis, where suicide completers were found to have significantly higher ACPI expression than non-suicide victims (12).
• the strongest association signal from another GWAS of suicide attempt on the bipolar disorder (STEP-BD, WT ' CCC, UCL) came from the iniergenic chromosome 10 marker rs 1466846; this finding was not replicated in the replication sample (GAIN.
• the present invention relates to risk markers for suicide. More specifically, the present invention relates to genetic risk markers for suicide and use thereof.
• a method of identifying a subject at risk for suicide comprising identifying in a biological sample from the subject one or more genetic markers associated with suicide, at least one marker being defined by rs2491144 (SEQ IDMO:l), wherein the presence of the G allele in marker rs2491144 identifies the subject is at increased risk for suicide.
• the biological sample is a sample from blood, saliva, spinal fluid, brain biopsy, cultured cells obtained from the subject stool, urine, autopsy samples, or frozen sections taken for histological purposes.
• the step of identifying in a biological sample from the subject one or more genetic markers associated with suicide comprises PCR analysis, sequencing, 5'exonuclease fluorescence assay, probe hybridization or a combination thereof.
• the subject is a subject diagnosed with a mental illness.
• the mental illness is selected from the group consisting of depression, schizophrenia, schizoaffective disorder, bipolar disorder, personality disorder, seasonal affective disorder, anxiety disorder, and post traumatic stress disorder.
• processors to receive a subject's genotype for one or more genetic markers associated with suicide selected from the group consisting of rs2491144 (SCQ ID NO:l), rs9315639 (SCQ ID O:2). rsl 1082138 (SEQIDNO:3). rsl 1697517 (SCQ ID NO:4), and rs2186437 (SEQ IDKO:5); identify the presence of any of the G allele in 5 marker rs24 1144 (SCQ ID O:l), the C allele in marker rs931 639 (SEQ ID NO:2). the C allele in marker rsl 1082138 (SEQ ID NO:3).
• a method for reducing the risk of suicide in a subject identilied a.s being at increased risk for suicide comprising one or more of a) treating the subject with medication, non-medicinal therapy or a combination thereof; b) monitoring the subject;
• treating the subject with medication comprises administering one or more antipsychotics, mood stabilizers, antidepressants, anticonvulsants, antianxiolytics. or any combination thereof.
• the medication comprises clozapine, lithium, or ketamine.
• the non-medicinal therapy comprises
• electroconvulsive or electroshock therapy magnetic seizure therapy, transcranial magnetic stimulation, cognitive behavioral therapy, dialectical behavioral therapy, risk dissipation group therapy, deep brain stimulation, or a combination thereof.
• testing or screening the subject for mental illness or one or more symptoms associated with suicide or mental illness comprises testing or screening the subject for depression, schizophrenia, schizoaffective disorder, bipolar disorder, obsessive compulsive disorder, personality disorder, seasonal affective disorder, addiction, drug abuse, alcoholism, problem gambling, increased anxiety, anxiety disorder, feelings of worthlessness. psychotic symptoms, delusions, hallucinations, agitation, restlessness, irritability, aggression or anger.
• kits comprising, a) one or more primers to amplify a nucleotide sequence that comprises the polymorphism as defined in: rs24 1144 (SEQ ID NO: 1) or a fragment thereof comprising the polymorphic site, or the complement of SEQ ID NO: I or a fragment thereof comprising the polymorphic sire; rs9315639 (SEQ ID NO:2) or a fragment thereof comprising the polymorp ic site, or the complement of SEQ ID NO:2 or a fragment thereof comprising the polymorphic site.
• rsl 1082138 SEQ ID NO:3 or a fragment thereof comprising the polymorphic site, or the complement of SEQ ID NO:3 or a fragment thereo comprising the
• rsl 1 97517 (SEQ ID NO:4) or a fragment thereof comprising the polymorphic site, or the complement of SEQ ID O:4 or a fragment thereof comprising the polymorphic site.
• rs21 6437 (SEQ ID KO:5) or a fragment thereof comprising the polymorphic site, or the complement of SEQ ID NO:5 or a fragment thereof comprising the polymorphic site, or any combination thereof;
• polymorphisms of SEQ ID NO:l, 2, 3 ; 4, 5, their complements or any combination thereof e) one or more reagents, components and/or products for performing a DNA sequencing react ion that determines the sequence of SEQ ID NO: 1, 2.3, 4, 5, their complements or any combination thereof, f) a gene chip or nucleotide sequence array comprising a plurality of nucleotide sequences comprising or consisting of any one or combination of SEQ ID NOs: 1-5.
• a fragment thereof comprising the polymorphic site or their complements; g) one or more instructions for using the components as described herein, practicing the methods as described herein, interpreting the data obtained from practicing the methods, or any combination thereof; h) a scale, reference or the like that may be used to test, diagnose, monitor or determine symptoms of the subject; or any combination or sub-combination of a) through h).
• kits as defined above and herein comprising. a) one or more primers to amplify a nucleotide sequence that comprises the polymorphism as defined in rs2491144 (SHQ ID NO: I), rs9315639 (SEQ ID O:2), rsl 1082138 (SEQ ID O:3), rsl 1697517 (SEQ ID NO:4),rs2186437 (SEQ IDN " 0:5) or any combination thereof; b) one or more probes that hybridi/e to SEQ ID KOs: 1, 2, 3, 4, or 5.
• polymorphisms of SHQ ID NO: 1, 2, 3.4.5. or a combination thereof e) one or more reagents, components and/or products for performing a DNA sequencing reaction that determines the sequence of SEQ ID NO: 1.2.3, 4, 5, or a combination thereof. f) a gene chip or nucleotide sequence array comprising a plurality of nucleotide sequences comprising or consisting of SEQ ID NOs: I -5.
• FIGURE i shows the nucleotide sequences of rs24 1144 (SEQ ID NO: 1), rs9315639 (SEQ IDNQ:2), rsl 1082138 (SEQ ID NO:3), rsl 1697517 (SEQ !DNQ:4) and rs2186437 (SEQ ID NO: 5).
• the polymorphic site is shown underlined in square brackets.
• the present invention provides a method of identifying a subject that is at risk for suicide comprising, testing a biological sample comprising genomic DNA of the subject to determine if the genomic DNA comprises one or more polymorphic markers associated with suicide defined by 1) rs2491144 (SEQ ID NO:l) or a fragment thereof com prising the polymorphic site, or a nucleotide sequence which is the complement of SEQ ID NQ:1 or the fragment thereof comprising the polymorphic site; 2) rs931 639 (SEQ ID NO:2) or a fragment thereof comprising the polymorphic site, or a nucleotide sequence which is the complement of rs9315639 (SEQ ID NO:2) or a fragment thereof comprising the polymorphic site; 3) rs 11082138 (SEQ ID Ts ' 0:3) or a fragment thereofcomprising the polymorphic site, or a nucleotide sequence which is the complement of rsl 10821 8 (SEQ ID NO:3) or
• the fragments of the markers are at least 7 consecutive nucleotides, for example 7.8.9. 10. 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21,22,23, 24, 25,26, 27, 28.29, 30, 31.32.33, 34.35.36, 37.38.39, 40.41.42.43.44, 45.46.47, 48.49, or 50 consecutive nucleotides of the markers described in SEQ ID NO: 1-5 or the complement " thereof.
• the present invention also provides a method of identifying a subject that is at risk for suicide comprising, testing a biological sample comprising genomic DNA of the subject to determine if the genomic DNA comprises one or more polymorphic markers associated with suicide defined by rs2491144 (SEQ ID NO; 1 ). rs931 639 (SEQ ID O:2), rsl 1082138 (SEQ ID NO;3), rsl 1697517 (SEQ 1DN0:4).
• the marker is rs2491144.
• the one or more markers is rs2491144 and at least one of rs9315639. rsl 1082138, rsl 1697517. and rs2186437.
• the marker is rs2491144 and this marker is employed in combination with one or more additional genetic markers that are known in the art to be predictive of suicide risk and/or mental illness.
• j 0037] In a further embodiment of the present invention. Lhe method may be practiced as described above, but lhe testing a biological sample comprises testing the biological sample for genomic DKA of the subject to determine if the genomic DNA comprises one or more markers comprising the polymorphism that exhibits between 90% and
• sequence identity 5 100%) sequence identity to the markers described, for example, but not lim ited to 90%, 91 %.92%, 93%.94%, 95%, 96%.97%.98%, 99%.99.5%.99.9% or 100%> sequence identity with SFQ ID NO: I , SEQ ID KO:2.
• the first nucleotide shown in SEQ ID NO: 1 is a " The present invention is meant to include a sequence that is substantially identical to SEQ ID NO: I but that comprises a different
• nucleotide for example, a ' "G" at position number 1, as the variant nucleotide
• sequence exhibits more than 90% sequence identity with SEQ ID NO-.l and comprises the polymorphism shown in underlined brackets.
• oligonucleotide alignment To determine whether a nucleic acid or DNA exhibits similarity or a percentage identity with the sequences presented herein, oligonucleotide alignment
• BLAST GeneBank URL: vvww.ncbi.nlm.nih.gov/cgi-bin/BLASiy, using default parameters: Program: blastn; Database: nr; Expect 10; filter: default; Alignment: pairwise; Query genetic Codes: Standard(l)).
• BLAS ' 1 EMBL URL: http://www.embl-heidelberg.de/Services/ index.html using default parameters: Matrix BLOSUM62; Filter: default, echofilter:
• LxpecLlO cutoff: default; Strand: both; Descriptions: 50. Alignments: 50), or FASTA. search, using default parameters.
• Polypeptide alignment algorithms are also available, for example, without limitation, BLAST 2 Sequences
• hybridisation to filter-bound sequences under moderately stringent conditions may, lor example, be performed in 0.5 M Nal IPCu, 7% sodium dodecyl sulfate (SDS), I m EDTA at 65°C, and washing in 0.2 x SSC/0.1% SDS at 42°C for at least I hour (see Ausubcl, et al. (eds), 1989, Current Protocols in Molecular Biology. Vol. 1. Green Publishing Associates. Inc., and John Wiley & Sons. Inc., New York, at p.2.10.3).
• hybridization to filter- bound sequences under stringent conditions may, for example, be performed in 0.5 NaMPOi, 7% SDS, 1 mivl EDTA at 65°C f and washing in 0.1 x SSC/0.1% SDS at 6K C for at least 1 hour.
• Hybridization conditions may be modified in accordance with known methods depending on the sequence of interest (see Tijssen, 1 93, Laboratory Techniques in Biochemistry and Molecular Biology ⁇ Hybridization with Nucleic Acid Probes, Part l. Chapter 2 "Overview of principles of hybridization and the strategy of nucleic acid probe assays". Elsevier, New York).
• stringent conditions are selected to be about 5°C lower than the thermal melting point for the specific sequence at a defined ionic strength and pH.
• the method as described herein may be employed to identify, treat or treat preventative!' a subject that is at risk for suicide wherein at the time of testing or screening the subject appears healthy.
• This information may be important when testing/screening subjects that have a familial history of suicide or suicide attempts or mental illness, lor example, but not limited to bipolar disease, schizophrenia or another mental illness, even though at the time of testing/screening, the subject may have little or no symptoms of disease or has not exhibited symptoms associated with suicide.
• Knowledge that the subject has one or more genetic markers associated with a higher risk of suicide may be useful in many ways, for example, by implementing proactive measures to reduce suicide risk at the earliest time possible or developing treatment regimens if for example, the subject later develops a mental illness such as. without limitation, bipolar disease, schizophrenia or another mental illness and requires treatment.
• the present invention also contemplates a method as described above that further comprises one or more steps to reduce the subject's risk ofsuicide.
• Such steps may comprise , but are not limited to treating the subject with medication such as, for example one or more antipsychotics, including typical and atypical antipsychotics, mood stabilizers, antidepressants, anticonvulsants, or other type(s) of medication, for example, but not wishing to be limiting, lithium, clozapine or ketamine.
• medication such as, for example one or more antipsychotics, including typical and atypical antipsychotics, mood stabilizers, antidepressants, anticonvulsants, or other type(s) of medication, for example, but not wishing to be limiting, lithium, clozapine or ketamine.
• antipsychotics or “antipsychotic medication” it is meant any drug, pharmaceutical, natural product, composition or the like that may be employed to prevent and/or treat psychosis, schizophrenia, schizoaffective disorder, disruptive behavior, disorganized thinking, symptoms of mania, or any combination thereof in a subject.
• Antipsychotic medication may comprise, but is not limited to, drugs that affect dopamine signaling, for example, drugs that bind reversibly or irreversibly to one or more dopamine receptors, drugs that act as competitive or non-competitive inhibitors to down regulate dopamine receptor signaling, or that block the dopamine D2 receptor (see for example Seeman et al, 1976 and Seeman et al, 2005).
• antipsychotic drugs comprise clozapine, olanzapine, trifluoperazine, thioridazine, haloperidol, haloperidol decanoate, thiothixene, chlorpromazine, fluphenazine, loxapine, perphenazine, perphenazine decanoate, pe ihenazine-atnitriptyline, acetophenazine, molindone, mesoridazme, fluphenazine decanoate. methotrime razine, risperidone, aripiprazole or a combination thereof.
• the antipsychotic drug comprises clozapine or a combinaiion therapy comprising clozapine.
• the antipsychotic drug comprises clozapine or a combinaiion therapy comprising clozapine.
• the antipsychotic drug comprises clozapine or a combinaiion therapy comprising clozapine.
• non-medicinal therapies include, but are not limited to electroconvulsive therapy or electroshock therapy, transcranial magnetic stimulation, cognitive behavioral therapy, dialectical behavioral therapy, risk dissipation group therapy or a combination thereof.
• the subject may be subjected to monitoring, for example more frequent or intensive monitoring by a physician, clinician, health care provider or family member.
• the subject may be subjected to counseling by a physician, psychologist, health care provider or the like.
• the method also contemplates embodiments wherein the subject is further tested or screened for one or more mental illnesses or one or more symptoms that are associated with mental illness or suicide.
• mental illnesses may include, but are not limited to depression, schizophrenia, schizoaffective disorder, bipolar disorder, obsessive compulsive disorder, personality disorder, seasonal affective disorder, mood disorder, post traumatic stress disorder, addiction, drug abuse, alcoholism, problem gambling and the like.
• Symptoms that are associated with mental illness are well known in the art and may be obtained from psychiatric diagnostic manuals known in the art.
• DSM IV Diagnostic and Statistical Manual of Mental Disorders
• Symptoms that can be associated with suicide include, among others, increased anxiety, feelings of worthlessness. psychotic symptoms, delusions, hallucinations, agitation, restlessness, irritability, aggression or anger.
• the subject that is tested may comprise an individual that has been diagnosed with a mental illness or exhibits one or more symptoms of a mental illness such as, without limitation, depression, bipolar symptoms, psychotic symptoms, schizophrenia symptoms, schizoaffective disorder symptoms or a combination thereof, for example, but not limited to as described in DSM-IV which is hereby incorporated by reference.
• Psychotic symptoms may comprise positive symptoms such as. but not limited to distortions or exaggerations of inferential thinking (i.e. delusions), perception (i.e. hallucinations), language and communication (disorganised speech) and behavior (grossly disorganized or catatonic behavior) or any combination thereof.
• the positive ymptoms may comprise distinct dimensions, for example, psychotic dimensions including, but not limited to delusions and hallucinations and
• disorganization dimensions including, but not limited to disorganized speech and behavior.
• the symptoms may comprise one or more negative symptoms, for example, but not limited to symptoms that reflect a diminution or loss of normal function.
• the subject may exhibit a combination of both positive and negative symptoms.
• the subject that is tested has been diagnosed or is suspected of having bipolar disorder, schizophrenia or schizoaffective disorder.
• the method described above also contemplates testing the biological sample comprising DNA or a second biological sample obtained from the subject for one or more additional genetic markers, nucleotide sequences, proteins, metabolites or any combination thereof.
• the same or a different biological sample from the subject may be tested for other genetic markers known in the art that are associated with suicide ideation or mental illness including, but not limited to bipolar disease, schizophrenia, schizoaffective disorder and the like.
• the subject also may be tested for markers that predict drug treatment outcome or that assist in determining drug treatment.
• the subject may be tested to determine the presence of alcohol or drugs in blood or to determine the level of alcohol or drugs in blood, as it is known that alcohol and drug use may be contributing factors to suicidal tendencies and may also interact with drug treatment regimens.
• the method as described herein also contemplates removing or reducing access to compounds, compositions, articles or cues such as alcohol, drugs and the like which may increase suicide risk.
• the present invention provides:
• a method of identifying a subject who is diagnosed with a mental illness or who exhibits one or more symptoms of a mental illness for suicide risk comprising, testing a biological sample comprising genomic DMA of the subject to determine if the genomic DNA comprises one or more markers defined by rs249] 144 (SEQ ID NO:l), rs9315639 (SEQ ID NO:2). rsl 1082138 (SEQ 1DN0:3), rs 11697517 (SEQ ID O;4). rs2186437 (SEQ ID NO:5) or a combination thereof wherein the presence of the G allele in marker rs249l 144 identifies the subject is at increased risk for suicide.
• the presence of the C allele in marker rs93 i 5639 identifies the subject is at increased risk for suicide.
• the presence of the C allele in marker rsl 1082138 ideniifies the subject is at increased risk for suicide
• the presence of the T allele in marker rsl 1697517 identifies the subject is at increased risk for suicide
• the presence of the C allele in marker rs2186437 identifies the subject is at increased risk for suicide.
• the method as described herein may further comprise selecting a subject thai is diagnosed with a mental illness or that exhibits one or more symptoms associated with suicide or mental illness and obtaining the biological sample from the subject.
• tissue sample may be used for genotyping the polymorphisms in SEQ ID NO: 1 -5 5 including but not limited to. blood, saliva, spinal fluid, brain biopsy, cultured cells obtained from the subject, stool, urine, autopsy samples, or frozen sections taken for histological purposes.
• blood is obtained from a subject for assaying with respect to above mentioned polymorphisms.
• venous blood is obtained from a subject using standard venipuncture techniques.
• Polymorphisms may be genotyped using conventional techniques. For example, PGR using primers incorporating fluorescent probes is one suitable technique. Further, but not wishing to be considered limiting, primers having appropriate sequences upstream and downstream of the polymorphic site may be used to amplify the nucleotide regions comprising the polymorphisms.
• Single nucleotide polymorphism (SNP) analysis is useful for detecting di ferences between alleles of a. gene or nucleotide sequence.
• SNP single nucleotide polymorphism
• various methods exist in the art for genotyping nucleotide sequences including, but not limited to 5 " exonuclease assays, nucleotide sequencing, probe hybridization and the like. All such methods are meant to be encompassed herein.
• various realtime PGR methods that can be used to detect S Ps. including, e.g., Taqman or molecular beacon-based assays (U.S. Pat.
• Nos.5,210,015: 5,487.972: and PCT WO 95/13399 arc useful to monitor for the presence or absence of a SNP.
• Still other SNP detection methods are known in the art including, without limitation, DNA sequencing, sequencing by hybridization, dot blotting, and oligonucleotide array (DNA Chip) hybridization analysis.
• Applied Biosystems, Inc hosier City, CA has developed several aspects of SNP genotyping technology. In one well-used protocol, PCR amplification of a desired SNP region is conducted using targeting primers, including two allcle-specific fluoro genie probes, each consisting of a different fluorescent reporter dye and a fluorescent quencher.
• FRPT fluorescence resonance energy transfer
• the presence of a particular allele at the polymorphic site is determined in relation to the adjacent nucleotide sequence upstream and downstream from the polymorphic site, for example, but not limited to, about 3, 4.5, 6,7, 8, 9, 10.11, 12. 13, 14 or 15 nucleotides upstream and/or about 3, 4, 5, 6, 7, 8, 9 : 10. 11, 12, 13 : 14 or 15 nucleotides downstream of t lie polymorphic site.
• the present invention also contemplates that the presence of a particular allele may be determined in relation to the nucleotide sequence comprising about 20.25, 30, 50 or more nucleotides upstream (or any number therein between) and about 20, 25, 30, 50 and/or more nucleotides downstream (or any number therein between) of the polymorphic site as provided by SEQ ID NOs: 1 -5, respectively.
• the term "and/or" is used to specifically indicate that the number of continuous upstream and downstream nucleotides does not need to be the same.
• nucleotide sequences to determine if a particular polymorphism or group of polymorphisms is present in a subject, as would be known to a person of skill in the art may be employed in the practice of the present invention.
• the method of obtaining a sample and analyzing its nucleotide sequence or DNA is not critical to the present invention and any methods may be used (e.g. Ausubef et al. (eds), 1 89, Current Protocols in Molecular Biology. Green Publishing Associates, Inc.. and John Wiley & Sons, Inc., New York, at p.2.10.3. or Maniatis et al., in Molecular Cloning ( ⁇ Laboratory Manual), Cold Spring Harbor Laboratory. 1982. p.387389).
• any methods may be used (e.g. Ausubef et al. (eds), 1 89, Current Protocols in Molecular Biology. Green Publishing Associates, Inc.. and John Wiley & Sons, Inc., New York, at p.2.10.3
• DNA may be extracted using a non-enzymatic high-sak procedure.
• the DNA may be analyzed in situ. Olher methods of DNA analysis that are known to persons skilled in the art may also be used.
• the RNAs that are produced may be isolated and analyzed by well-known methods known in the art and
• K> is meant to be encompassed by the method of the present invention as described
• kits comprising, a) one or more primers to amplify a nucleotide sequence that comprises the polymorphism as defined in rs24 1144 ⁇ SEQ ID NO: I) or a fragment thereof which
• SEQ ID NO:4 amino acid sequence
• rs2186437 SEQ ID NO:5
• primers comprising or consisting of the nucleotide sequence which is the complement of those described above may also be used, as are sequences which exhibit about 90-100% sequence identity, for example, but not limited to 90%, 91%, 92%, 93%, 94%, 95%.96%, 97%, 98%, 99%.99.5%, 99,9% or 100% to those described above or a sequence that is 5 complementary thereto; b) one or more probes that hybridize to SHQ ID NOs: 1 , 2, 3.4, 5, a fragment thereof comprising the polymorphic site or their complementary sequence over a region of nucleotides comprising the polymorphic site, wherein said probe hybridizes to a particular variant of the polymorphism at the polymorphic site.
• the probes may be labeled with an appropriate group, for example, a fluorescent tag, fluorophore, radioactive label or the like.
• the one or more probes may be attached covaleiitly or physically associated with a support for e ample- bill not limited to a bio-chip, array, slide, multiweli plate, bead or the like.
• the probes may comprise an array of nucleic acids; c) one or more reagents and/or products comprising buffers, nucleotides. DNA amplifying enzymes, or any combination thereof: d) one or more reagents, components and/or products for genotyping the
• polymorphisms of SEQ ID NO: 1.2.3, 4, 5, or a combination thereof e) one or more reagents, components and/or products for performing a DNA sequencing reaction that determines the sequence of SEQ ID NO: 1 , 2.3, 4.5, or a combination thereof. f) a gene chip or nucleotide sequence array comprising one or more nucleotide sequences comprising or consisting of SEQ ID NOs: 1 -5.
• Genotyping Sample GBP was genotyped with the lllumina Sentrix Human Hap550 Bead chip (lllumina Inc., San Diego. CA, USA) mostly at lllumina Inc. (San Diego. CA. USA), with 290 subjects being genotyped at the Genome Quebec facility (Montreal, Quebec, Canada).
• rs2491144 One interesting marker that was tested (rs2491144) is mapped to the 3' region of SDC3 coding for the syndecan 3 protein, which is highly expressed in neural cells (18). and maybe important in brain development (1 ). Studies on mice deficient in sdc3 indicated a role of this protein in long-term potentiation and hippocanipal memory (20).
• the rs9315639 marker is mapped to the STOML3 stomatin ( ⁇ 72)- I ike 3 gene, which appears to be important for mechanorcceptor mediated signal transduction in sensory neurons (21 ).
• the rs2186437 marker is located approximately 1.4Mb 3' of the amyloid beta (A4) precursor protein-coding gene API 5 , which has been implicated in Alzheimer's disease.
• codes for the progesterone receptor, which interacts with FKBP5 (24) and regulate F BP5 expression (25), and the FMRl gene (DIANA Lab: rank #3 with miTG Score 0.9909; mirDB: rank #21 with Target
• Score 83) encodes the Fragile X Mental Retardation 1 protein in which expansion of the (CGG)n trinucleotide repeat in the 5' untranslated region causes Fragile X
• Angst F Stassen HhL Clayton PJ. Angst J. Mortality of patients with mood disorders: follow-up over 34-38 years. J Affect Disord 2002; 68(2-3): 167-181.

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