WO2017033886A1 - Marqueur de prédiction de la sensibilité à l'ocytocine - Google Patents

Marqueur de prédiction de la sensibilité à l'ocytocine Download PDF

Info

Publication number
WO2017033886A1
WO2017033886A1 PCT/JP2016/074371 JP2016074371W WO2017033886A1 WO 2017033886 A1 WO2017033886 A1 WO 2017033886A1 JP 2016074371 W JP2016074371 W JP 2016074371W WO 2017033886 A1 WO2017033886 A1 WO 2017033886A1
Authority
WO
WIPO (PCT)
Prior art keywords
oxytocin
sensitivity
gene
subject
seq
Prior art date
Application number
PCT/JP2016/074371
Other languages
English (en)
Japanese (ja)
Inventor
英典 山末
喬光 渡部
Original Assignee
国立大学法人東京大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 国立大学法人東京大学 filed Critical 国立大学法人東京大学
Publication of WO2017033886A1 publication Critical patent/WO2017033886A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • 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
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor

Definitions

  • the present invention relates to a biomarker capable of predicting the sensitivity of a subject to oxytocin, a method of predicting oxytocin sensitivity using the biomarker, and a method of estimating the therapeutic effect of oxytocin administration in patients with autism spectrum disease from the prediction result of oxytocin sensitivity About.
  • ASD Autism spectrum disorder
  • ASD patients even if they are intelligent, cannot adapt to work or school life due to social communication disabilities, resulting in unproductive life at home, violence or Many people suffer from various social failures such as crime. As a result, ASD is not only a serious problem for patients and their families, but also a great social and economic loss.
  • Non-Patent Documents 1 to 3 The frequency of ASD appearance is very high, at least 1 in 100, and no regional differences have been reported (Non-Patent Documents 1 to 3). Therefore, ASD is not a disease, but a form of behavioral characteristics in human individuals. However, as described above, there is a demand for a method for alleviating or improving the symptoms because it can bring disadvantages to the parties themselves and their surroundings in conducting social life. However, in spite of such a high degree of disability, no effective drug or intervention has been developed for the core symptoms of ASD.
  • Non-patent Document 4 Non-patent Document 4
  • Non-Patent Document 5 a cognitive rehabilitation method in early childhood has been proposed for the treatment of social disorders.
  • the effect is undecided, and furthermore, the number of psychologists who have received specialized training is extremely small, and it requires a lot of labor, so that there has been a problem that it has hardly spread.
  • Oxytocin is an endogenous peptide hormone composed of nine amino acids, and is known to promote lactation and contract uterine smooth muscle in women.
  • Oxytocin is an endogenous peptide hormone composed of nine amino acids, and is known to promote lactation and contract uterine smooth muscle in women.
  • adolescent behavior such as the formation of a mother-child relationship is impaired, and conversely, administration of oxytocin improves this disorder.
  • Non-patent Document 7 it is also known to be involved in the formation of attachments and other behaviors in the central nervous system.
  • non-patent Documents 8 to 10 many studies have revealed that nasal administration of oxytocin to healthy individuals significantly enhances facial memory and facial expression reading and trusting behavior with peers.
  • Non-patent Documents 11 and 12 Furthermore, it has been reported that interpersonal cognition has improved by administration of oxytocin even among ASD parties (Non-patent Documents 11 and 12). In recent years, there have been reports that nasal administration of oxytocin has improved the ability to guess the other's emotions from the eyes (Non-Patent Document 13) and promoted cooperative behavior (Non-Patent Document 14). These findings suggest the possibility of therapeutic intervention for ASD by administration of oxytocin, but on the other hand, the cause of ASD is abnormal brain development from fetal to early childhood, so acquired drug therapy It is considered that the effectiveness of oxytocin as an ASD therapeutic agent is limited.
  • Non-patent Document 15 The inventors subsequently scientifically demonstrated the pharmacological effects of oxytocin on a large number of ASD patients at both the behavioral level and the neurological level, and proved the potential of oxytocin as an ASD therapeutic agent (Non-patent Document 15). ).
  • a new problem was revealed that the sensitivity to oxytocin varies greatly between individuals. Individual differences in oxytocin sensitivity cause variations in the therapeutic effects of ASD due to oxytocin administration. It may also cause delays in setting appropriate dosages and dosages for the development of oxytocin as an ASD treatment. Therefore, technology for accurately predicting oxytocin sensitivity in subjects prior to oxytocin administration has been essential for the development of ASD therapeutics.
  • Non-patent Document 16 Single gene polymorphism of the gene of CD38 protein involved in oxytocin secretion was studied in healthy subjects. No relevance has been found (Non-patent Document 16). On the other hand, SNP of oxytocin receptor was similarly examined in healthy subjects, and there was a report that there was a weak but significant correlation between SNP and the effect of oxytocin administration on amygdala activation during gaze treatment ( Non-patent document 17).
  • An object of the present invention is to develop a biomarker that correlates closely with the sensitivity of oxytocin and can predict the sensitivity, and to provide a method for predicting oxytocin sensitivity in a subject using the biomarker.
  • Another object of the present invention is to provide a method for estimating the therapeutic effect of oxytocin on ASD patients before oxytocin administration based on the results of the oxytocin sensitivity prediction method.
  • the present inventors studied the development of a biomarker that strongly correlates with the pharmacological effect of oxytocin on the core symptoms of ASD.
  • the present invention is based on the above findings and provides the following.
  • the oxytocin sensitivity prediction marker according to (1) wherein cytosine at the methylation target site shown is a methylated gene and can predict high sensitivity to oxytocin.
  • (3) The genes encoding the proteins consisting of the amino acid sequences represented by SEQ ID NOs: 2, 4, 6, 8, and 10 described in (a) are represented by SEQ ID NOs: 1, 3, 5, 7, and 9, respectively.
  • predicting hyposensitivity to oxytocin wherein the SNP selected from the group consisting of rs53576, rs11706648, rs17049528, rs4686300, and rs237900 is not GG, AA, GG, CC, or GG, respectively.
  • the SNP selected from the group consisting of rs2254298, rs11131149, rs2268495, rs237887, and rs237878 is a gene that is not GG, GG, GG, GG, and TT, and can predict high sensitivity to oxytocin.
  • the oxytocin sensitivity prediction marker according to (4). (7) Any one of (1) and (4) to (6), wherein the gene encoding the protein consisting of the amino acid sequence represented by SEQ ID NO: 12 described in (b) is composed of the base sequence represented by SEQ ID NO: 11 The oxytocin sensitivity prediction marker described in 1.
  • a method for predicting the sensitivity of a subject to oxytocin the step of extracting genomic DNA from the sample derived from the subject, and the amino acid sequences represented by SEQ ID NOs: 2, 4, 6, 8, and 10 in the extracted genomic DNA Detecting the presence or absence of methylation of a methylation target site represented by cg12513795, cg27278382, cg19104656, cg16553574, and cg04861640, respectively, of a gene encoding one or more proteins selected from the group consisting of: Predicting that the subject is significantly more sensitive to oxytocin when the target site is methylated.
  • the genes encoding the proteins consisting of the amino acid sequences shown in SEQ ID NOs: 2, 4, 6, 8, and 10 have the base sequences shown in SEQ ID NOs: 1, 3, 5, 7, and 9, respectively (8) The method described in 1.
  • a method for estimating a therapeutic effect of oxytocin administration in a patient with autism spectrum disease wherein the subject is a step of predicting sensitivity in the oxytocin sensitivity prediction method according to (8), (9) or (13),
  • the method includes the step of estimating that a therapeutic effect of oxytocin administration on a subject with autism spectrum disorder can be expected.
  • the oxytocin sensitivity prediction method using the oxytocin sensitivity prediction marker of the present invention it is possible to improve the clinical trial success rate by selecting an ASD patient highly sensitive to oxytocin. It can also significantly accelerate the development rate of oxytocin as an ASD therapeutic agent. Furthermore, it is possible to make a custom-made medical treatment in which an appropriate usage and dose that bring about the maximization of the drug effect by administration of oxytocin and the minimization of the risk of side effects are set according to individual ASD patients.
  • the horizontal axis shows the frequency of each SNP set included in the SNP group.
  • “*” and “**” are Bonferroni-corrected P values (P Bonferroni-corrected ), and the values in the residual test after the chi-square test are P, respectively. ⁇ 0.05, P ⁇ 0.01.
  • the horizontal axis shows the prediction effect of oxytocin calculated by SVR (Support Vector Regression) when the SNPs indicated by black bars in FIG. 3 are used in combination.
  • the vertical axis shows the actual measurement value normalized for the experimentally observed effect.
  • (A) to (f) show the results of each of the six oxytocin response indices.
  • B is a four-quadrant diagram showing binomial classification. Based on the regression analysis indicated by A, patients were classified into oxytocin response groups and relatively weak response groups. Patients plotted in quadrants II and III were considered correctly classified, and patients plotted in quadrants I and IV were considered not.
  • C shows the classification result regarding the therapeutic effect of oxytocin in each oxytocin response index.
  • a to f correspond to the response indices (a) to (f) shown in A. 0.01 and 0.05 on the right side are Bonferroni corrected P values (Pcorrected). It is a figure which shows the oxytocin effect by the administration order of oxytocin and a placebo. The regression analysis result when a placebo is administered after oxytocin administration is shown. It is a figure which shows the oxytocin effect by the administration order of oxytocin and a placebo. The regression analysis result when oxytocin is administered after placebo administration is shown. It is a figure which shows the weighted value of SNP used as the parameter
  • the 1st aspect of this invention is an oxytocin sensitivity prediction marker.
  • the oxytocin sensitivity prediction marker of the present invention is a biomarker composed of a gene having a site that significantly correlates with sensitivity to oxytocin. By detecting the marker from the subject, it is possible to predict the sensitivity of the subject to oxytocin, and it is possible to predict the therapeutic effect of oxytocin on ASD in the subject from the prediction result of the sensitivity.
  • oxytocin sensitivity prediction marker refers to a biomarker that can predict the sensitivity of a subject to oxytocin. The entity is composed of a gene having a specific structure described later.
  • Oxytocin (OXT) is an endogenous peptide hormone composed of 9 amino acids as described above, and is secreted from the posterior pituitary gland. It is known to promote milk secretion and contraction of uterine smooth muscle in women. In Japan, it is approved for induction of labor, promotion of labor and abortion.
  • “Sensitivity” in this specification means sensitivity of a cell or an individual to a drug. Accordingly, “oxytocin sensitivity” in this specification refers to the sensitivity of cells or individuals to oxytocin. For example, “highly sensitive to oxytocin” means that it can be responsive to a small amount of oxytocin. On the other hand, “low sensitivity to oxytocin” means that responsiveness is not exhibited or there is almost no responsiveness unless a large amount of oxytocin is present. As described later, oxytocin sensitivity is strongly related to the drug effect of oxytocin, that is, the therapeutic effect in ASD patients.
  • oxytocin sensitivity is to estimate the subject's oxytocin sensitivity when the subject's oxytocin sensitivity is not clear.
  • estimate means determining an event that cannot be known based on the obtained information. In this specification, it uses, when determining the therapeutic effect of the oxytocin administration to an ASD patient mainly based on the prediction result information of the oxytocin sensitivity in a test subject.
  • ASD Abbreviations: Autism spectrum disorder
  • ASD patient “Autism spectrum patient” (ASD patient) means a person diagnosed with ASD by a doctor or a person suspected of having ASD. As described above, ASD is understood as a form of behavioral characteristics in human individuals rather than diseases. Therefore, regarding ASD, “patient”, “affected”, “symptom”, “treatment” and the like used on the premise of a disease are not appropriate expressions. However, from the viewpoint of eliminating the life and economic disadvantages of ASD parties and related parties by mitigating or improving the behavior of those diagnosed with ASD and adapting them to human social life. For convenience, those who have been diagnosed with ASD are referred to as ASD patients.
  • ASD affected by ASD
  • ASD symptoms are behavioral and / or physical characteristics observed in ASD patients.
  • ASD treatment means that ASD patients themselves and their related people can live a social life without burden by alleviating or improving the symptoms of ASD.
  • the “subject” refers to a human individual to which a prediction method using the oxytocin sensitivity prediction marker of this embodiment is applied.
  • the oxytocin sensitivity predictive marker of the present invention includes five methylation indicator genes that use methylation as an index at a specific methylation target site, and an SNP that uses an SNP at a specific position as a base sequence of a specific allele. It consists of two groups of indicator genes. Hereinafter, each group of genes will be specifically described. 1-3-1. Methylation index genes The first group of oxytocin sensitivity prediction markers is composed of methylation index genes.
  • Methods oflation indicator gene consists of five genes, namely C3orf59 gene, UQCRC1 gene, VARS2 gene, ZNF92 gene, and ZSCAN26 gene.
  • the “methylation indicator gene” means not only a substantial gene region consisting of exons and introns, but also a transcription region including an untranslated region (including 5′UTR and 3′UTR), and expression control thereof. It means one gene expression unit that includes a region (including enhancer, promoter, CpG island, and shore region).
  • the “shore region” refers to a region of up to 2000 bp located on both sides of the CpG island.
  • Each methylation indicator gene includes a methylation target site having a strong correlation with the sensitivity of oxytocin and the degree of improvement of ASD in the base sequence. Therefore, the sensitivity of the subject to oxytocin can be predicted using the methylation of cytosine at the methylation target site in each gene on the genomic DNA of the subject as an index. Specifically, when the cytosine at the methylation target site is methylated, the subject is predicted to be highly sensitive to oxytocin. Therefore, if a subject is an ASD patient, it can be estimated that the therapeutic effect by oxytocin administration can be expected.
  • C3orf59 gene The C3orf59 (chromosome 3 open reading frame 59) gene is also called MB21D2 (Mab-21 domain containing 2) gene, which is present on the third chromosome in humans and consists of the amino acid sequence shown in SEQ ID NO: 2. Encodes C3orf59 protein of unknown function.
  • the presence or absence of methylation in cytosine at the methylation target site indicated by cg12513795 is an index for predicting oxytocin sensitivity.
  • the C3orf59 gene can be used as a oxytocin hypersensitive predictive marker to indicate that a subject having the gene is highly sensitive to oxytocin.
  • the cytosine represented by cg12513795 is located at position 192636139 on human chromosome 3 (according to the Genome Reference Consortium Human Build 37 patch release 13 assembly. The same applies herein except for the ZSCAN26 gene).
  • the complementary strand of the transcription region of the C3orf59 gene is located at positions 19514604 to 192635950 on chromosome 3.
  • the exons of the cds (coding sequence) indicated by the nucleotide sequence of SEQ ID NO: 1 are positions 192516175 to 192517439 (first exon) ), And 192635419-192635629 (second exon) (1476bases in total).
  • Methylation affecting gene expression is known to be abundant upstream of genes, but recent research results show that most methylation fluctuations occur within the shore region of CpG islands outside of promoters and CpG islands. This has become the norm (Irizarry et al., Nature Genetics, 2009).
  • CMOS complementary metal-oxide-semiconductor
  • SEQ ID NO: 13 shows the sequence information of 500 bases before and after the methylation target site. This base sequence corresponds to the complementary strand sequence at positions 192636539 to 192636639 on human chromosome 3, and the methylation target site is cytosine located at position 501.
  • UQCRC1 ubiquinol-cytochrome c reductase core protein 1
  • Ubiquinol-cytochrome c reductase functions as the third complex (complex III) in the mitochondrial electron transport system, and the UQCRC1 protein constitutes one of its subunits.
  • the presence or absence of methylation in cytosine indicated by cg27278382 is an index for predicting oxytocin sensitivity.
  • the UQCRC1 gene can be used as a oxytocin hypersensitive predictive marker to indicate that a subject having the gene is highly sensitive to oxytocin.
  • cytosine shown by cg27278382 is located at the position 46486622 on the human chromosome 3.
  • the complementary strand of the transcription region of UQCRC1 gene is located at positions 4863432-48647391 on chromosome 3.
  • the exons of cds indicated by the nucleotide sequence of SEQ ID NO: 3 are positions 4863661-48636625 (1st exon), 48386868- 48637143 (exon 2), 48637496-48637584 (exon 3), 4883915-48638000 (exon 4), 48638113-48638273 (exon 5), 48638408-48638551 (exon 6), 48638785- 48638900 (7th exon), 48640997-48641076 (8th exon), 48641666-48641864 (9th exon), 48642084-48642213 (10th exon), 48643203-48643289 (11th exon), 48646595- 48646735 (exon 12) and 48646985-48647053 (exon 13) (1443 bases).
  • a known CpG island (NBCI CpG island location 48646317-48647776; UCSC CpG island name chr3: 48646620-48647404; Hidden Markov Model Island 3: 48621506- 48622400), and the methylation target site is present in the CpG island.
  • SEQ ID NO: 14 shows sequence information of 500 bases including the methylation target site. This base sequence corresponds to positions 4862622 to 4486222 on human chromosome 3, and the methylation target site is cytosine located at position 501.
  • VARS2 gene VARS2 (valyl-tRNA Synthetase 2) gene is present on chromosome 6 in humans, and is a VARS2 protein consisting of the amino acid sequence represented by SEQ ID NO: 6, ie, mitochondrial aminoacyl-tRNA synthetase 2 (mitochondrial aminoacyl-tRNA) code synthetase2).
  • Mitochondrial aminoacyl tRNA synthetase 2 catalyzes a reaction of esterifying valine to tRNA (Val) to synthesize aminoacyl tRNA (Val).
  • the presence or absence of methylation in cytosine indicated by cg19104656 is an index for predicting oxytocin sensitivity.
  • the VARS2 gene can be used as a oxytocin hypersensitive predictive marker to indicate that a subject having the gene is highly sensitive to oxytocin.
  • cytosine represented by cg19104656 is located at position 30882087 on human chromosome 6.
  • the transcription region of the VARS2 gene is located at positions 30881982-30894236 on chromosome 6.
  • the exons of cds indicated by the nucleotide sequence of SEQ ID NO: 5 are 30826414-30882814 (first exon), 30882933-30883014 ( Exon 2), 30883132-30883232 (Exon 3), 30835323-30883644 (Exon 4), 30883758-30883824 (Exon 5), 30883929-30884026 (Exon 6), 30884655-30884736 ( 7th exon), 3088882-30885001 (exon 8), 30885472-30885583 (9th exon), 30886604-30886692 (10th exon), 30875535-30887625 (11th exon), 30887866-30887993 ( Exon 12), 30888110-30888213 (Exon 13), 30888445-30888526 (Exon 14), 30888842-30888918 (Exon 15), 30889007-30889082 (Exon 16), 30889366-30889468 ( 17 exons), 308897
  • ZNF92 zinc finger protein 92
  • Zn zinc finger protein 92
  • the presence or absence of methylation in cytosine indicated by cg16553574 is an index for predicting oxytocin sensitivity.
  • the ZNF92 gene can be used as a oxytocin hypersensitive predictive marker to indicate that a subject having the gene is highly sensitive to oxytocin.
  • cytosine at the methylation target site indicated by cg16553574 is located at position 64839175 on human chromosome 7.
  • the transcription region of the ZNF92 gene is located at positions 64838752 to 64866049 on chromosome 7.
  • the cds exons represented by the nucleotide sequence of SEQ ID NO: 7 are positions 64838911 to 64838913 (first exon) and positions 64852815 to 64852941 ( 2nd exon), 64537719-64853814 (3rd exon), and 64863254-64864788 (4th exon) (total 1761 bases).
  • There is a known CpG island (UCSC CpG island name chr7: 64838984-64839213 position; Hidden Markov Model Island 7: 64476127-64476686 position) in the upstream region of cds of ZNF92 gene, and the methylation concerned
  • the target site is within the CpG island.
  • SEQ ID NO: 16 shows the sequence information of 500 bases before and after the methylation target site. This base sequence corresponds to positions 6438875 to 6648975 on human chromosome 7, and the methylation target site is cytosine located at position 501.
  • ZSCAN26 gene ZSCAN26 (zinc finger and SCAN domain containing 26) gene is also called ZNF187 (zinc finger protein 187) gene. In humans, it is present on chromosome 6 and encodes the ZSCAN26 protein consisting of the amino acid sequence shown in SEQ ID NO: 10. Like the ZNF92 protein, the ZSCAN26 protein is one of the proteins that form a complex with zinc (Zn), and methylation of this gene is predicted to be closely related to the pathogenesis of ASD.
  • the presence or absence of methylation in cytosine indicated by cg04861640 is an index for predicting oxytocin sensitivity.
  • the ZSCAN26 gene can be used as a oxytocin hypersensitive predictive marker to indicate that a subject having the gene is highly sensitive to oxytocin.
  • the cytosine represented by cg04861640 is located at position 28234605 on human chromosome 6 (according to the Genome Reference Consortium Human Build 38 patch release 2 assembly).
  • the transcription region of the ZSCAN26 gene is located at positions 28234788 to 28246001 on chromosome 6.
  • the exons of cds indicated by the nucleotide sequence of SEQ ID NO: 9 are 2827920 to 28271934 (first exon) and 28272670 to 28272787 ( 2nd exon) and 28276195-28277096 (3rd exon) (1035 bases in total).
  • the upstream region of cds of the ZSCAN26 gene there is a known CpG island (UCSC CpG island name chr6: 28234842 to 28235124) that is related to its expression, and the methylation target site is present on the N-shore.
  • SEQ ID NO: 17 shows the sequence information of 500 bases including the methylation target site.
  • This base sequence corresponds to positions 28234105 to 28235105 on human chromosome 6, and the methylation target site is cytosine located at position 501.
  • SNP indicator gene oxytocin receptor gene
  • the second group of oxytocin sensitivity prediction markers is composed of SNP indicator genes.
  • the “SNP indicator gene” in the present specification is an oxytocin receptor gene (OXTR) (referred to herein as “OXTR gene” in many cases).
  • OXTR gene is a seven-transmembrane G protein-coupled receptor, and has a function of activating intracellular signaling by binding to Gp protein in the cell by the binding of oxytocin. In humans, it exists on the third chromosome and consists of the amino acid sequence shown in SEQ ID NO: 12. Examples of the base sequence of the OXTR gene include the sequence shown in SEQ ID NO: 11.
  • the OXTR gene has 10 SNPs (single nucleotide polymorphism: single nucleotide polymorphism) showing strong correlation with the sensitivity of oxytocin and the improvement of ASD in its base sequence, that is, rs53576, rs11706648, rs17049528, rs4686300, rs237900, Includes rs2254298, rs11131149, rs2268495, rs237887, and rs237878.
  • rs53576, rs2254298, rs11706648, and rs2268495 are particularly strongly correlated with oxytocin sensitivity, and rs53576 and rs2254298 are even stronger.
  • these SNPs in the OXTR gene can be biomarkers that predict oxytocin sensitivity.
  • each of the SNPs is a major allele present in a large proportion in the population or a minor allele present in a small proportion as an index, is the subject having high sensitivity to oxytocin in the OXTR gene? Or low.
  • the major allele of each SNP is a base shown in Table 1.
  • the major allele of rs53576 is GG (referred to as “rs53576GG” in this specification. The same applies to other alleles).
  • the OXTR gene serves as an oxytocin hyposensitivity predictive marker and can predict that a subject is less sensitive to oxytocin. Therefore, if the test subject is an ASD patient, it can be estimated that the therapeutic effect by oxytocin administration cannot be expected.
  • the OXTR gene serves as an oxytocin-sensitive predictive marker and can predict that the subject is highly sensitive to oxytocin. Therefore, if the subject is an ASD patient, it can be estimated that the therapeutic effect by oxytocin administration can be expected.
  • the 2nd aspect of this invention is the oxytocin sensitivity prediction method in a test subject.
  • the oxytocin sensitivity prediction method of the present invention is a method that can predict the sensitivity of a subject to oxytocin using the oxytocin sensitivity prediction marker according to the first aspect as an index without requiring the intervention of a doctor. It is a method to assist the act.
  • Method The oxytocin sensitivity prediction method of the present invention can be divided into the following three methods according to the oxytocin sensitivity prediction marker group used, that is, the methylation index gene and the SNP index gene.
  • 2-2-1. Method Using Methylation Index Gene This method is a method for predicting the oxytocin sensitivity of a subject by measuring the methylation frequency of a methylation index gene on genomic DNA.
  • Genomic DNA extraction process refers to a process of extracting genomic DNA from a subject-derived sample.
  • sample refers to a biological sample that may contain genomic DNA.
  • cells including tissues and organs
  • body fluids that can contain cells are applicable.
  • body fluid refers to a fluid sample collected directly from an individual.
  • blood including whole blood, serum, plasma and interstitial fluid
  • lymph fluid cerebrospinal fluid
  • perineural fluid perineural fluid
  • synovial fluid synovial fluid
  • tear fluid nasal discharge, saliva, urine, sweat, milk, sputum, vaginal fluid, This includes semen, pleural effusion, and ascites.
  • the sample of the present invention may be any cell or body fluid, but is preferably a cell or body fluid that is less invasive when collected from an individual.
  • epithelial cells, hair matrix cells, and corneocytes that constitute the oral mucosa, nasal mucosa, vaginal mucosa and intestinal mucosa can be mentioned.
  • body fluids include blood, saliva, nasal discharge, sputum, vaginal fluid, and semen.
  • a particularly preferred sample is blood because it can easily and sufficiently extract a sufficient amount of genomic DNA required for the method of the present invention.
  • the blood may be peripheral blood.
  • sample derived from a subject refers to a sample collected from a subject.
  • the collecting method is not particularly limited as long as it is a known method.
  • the collection may be performed based on a known method in the field.
  • a known blood collection method may be followed.
  • peripheral blood it is collected by injecting into a peripheral vein or the like.
  • the sample can be used in the oxytocin sensitivity prediction method of the present invention immediately after collection, but it may be immediately cooled after collection and stored in a cryogenic bath or the like after thawing and used.
  • the sample can also be diluted or concentrated as necessary.
  • a blood coagulation inhibitor such as heparin may be added.
  • the amount of the sample used in the method of the present invention may be appropriately determined according to the type of sample. For example, about 200 ⁇ L is usually sufficient for peripheral blood.
  • genomic DNA extraction kit As a method for extracting genomic DNA from a sample, a conventional method known in the art may be used. See, for example, Green, MR and Sambrook, J., 2012, Molecular Cloning: A Laboratory Manual Fourth Ed. , Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York. Moreover, you may prepare using a commercially available genomic DNA extraction kit.
  • Methylation detection step refers to a methylation indicator gene that is an oxytocin sensitivity prediction marker according to the first aspect, that is, the C3orf59 gene in the genomic DNA obtained in the genomic DNA extraction step, It is a step of detecting the presence or absence of cytosine methylation at a specific methylation target site as described in the first aspect for any one or more of the UQCRC1 gene, VARS2 gene, ZNF92 gene, and ZSCAN26 gene. It is preferable to examine methylation of a specific methylation target site for 2 or more, 3 or more, 4 or more, or all methylation indicator genes. This is because the more methylation index genes in which a specific methylation target site is methylated, in other words, the higher the methylation index gene methylation frequency, the higher the accuracy of predicting oxytocin sensitivity to the subject.
  • This step makes it possible to detect whether cytosine at the target methylation target site in the methylation indicator gene is methylated.
  • a method for detecting methylation of a specific methylation target site in a methylation indicator gene on genomic DNA a method known in the art may be used. Examples include the bisulfite sequence method, COBRA (Combined Bisulfite Restriction Analysis) method, qAMP (quantitative analysis of DNA DNA methylation using real-time PCR) method, and the like. Usually, the bisulfite sequence method is suitable.
  • unmethylated cytosine in genomic DNA is converted to uracil by bisulfite treatment. Thereafter, amplification is performed by a nucleic acid amplification reaction such as PCR using a primer set that specifically amplifies the analysis target region including a specific methylation target site of the methylation indicator gene.
  • a nucleic acid amplification reaction such as PCR using a primer set that specifically amplifies the analysis target region including a specific methylation target site of the methylation indicator gene.
  • the design of a primer for amplifying a region containing a specific methylation target site in the methylation index gene may be appropriately determined for each methylation index gene.
  • the position and sequence of the methylation target site can be examined using UCSC Genome Browser (http://genome.ucsc.edu/cgi-bin/hgGateway).
  • the bisulfite sequence method may be performed using a commercially available kit. For example, MethylEasy TM Xceed Rapid DNA Bisulphite Modification Kit (TAKARA Bio) can be used for bisulfite treatment, and TaKaRa Taq TM Hot Start Version (TAKARA Bio) can be used for subsequent PCR.
  • TAKARA Bio MethylEasy TM Xceed Rapid DNA Bisulphite Modification Kit
  • TaKaRa Taq TM Hot Start Version TAKARA Bio
  • the “sensitivity prediction step” is a step of predicting the sensitivity of the subject to oxyto
  • the subject predicts that the sensitivity to oxytocin is significantly high. It can be determined that the higher the number of methylated index genes that are methylated, the higher the prediction accuracy. On the other hand, if the methylation target site in the methylation indicator gene is not methylated, the subject predicts that the oxytocin sensitivity is low.
  • “significant” means statistically significant, and this includes a case where the obtained risk value (significance level) is small. Usually, it can be judged significant if p ⁇ 0.05 (less than 5%), p ⁇ 0.01 (less than 1%) or p ⁇ 0.001 (less than 0.1%).
  • “p (value)” indicates the probability that the assumption is accidentally correct in the distribution assumed by the statistic in the statistical test. Therefore, the smaller the p value, the closer the assumption is.
  • the test method for statistical processing is not particularly limited as long as a known test method capable of determining the presence or absence of significance is appropriately used. For example, Student's t test or multiple comparison test can be used. 2-2-2. Method using SNP indicator gene This method is a method for predicting the sensitivity of a subject to oxytocin by analyzing SNP information of the OXTR gene.
  • This method includes a nucleic acid extraction step, an SNP identification step, and a sensitivity prediction step as essential steps.
  • each step will be specifically described.
  • the “genomic DNA extraction step” refers to a step of extracting nucleic acid from a subject-derived sample.
  • the nucleic acid in this step includes not only genomic DNA but also RNA.
  • the RNA to be extracted is not limited to total RNA and mRNA (including pre-mRNA and mature mRNA) as long as it includes OXTR mRNA.
  • SNP identification step is a step of identifying a specific SNP on the OXTR gene that is the oxytocin sensitivity prediction marker according to the first aspect in the nucleic acid obtained in the nucleic acid extraction step. .
  • the SNP to be identified is one or more SNP sets selected from the group consisting of rs53576, rs2254298, rs11706648, rs2268495, rs11131149, rs17049528, rs4686300, rs237878, rs237887, and rs237900. This is because by combining and identifying a plurality of SNP sets, the accuracy of predicting oxytocin sensitivity is improved, and the relevance to the therapeutic effect of ASD by oxytocin administration is significantly increased.
  • SNP combinations include, for example, rs53576 and rs2254298, rs53576 and rs11706648, rs53576 and rs2268495, rs11706648 and rs2254298, rs11706648 and rs2268495, rs2254298 and rs2268495, rs53576, rs11706648 and rs2254298 Rs53576, rs11706648 and rs2268495, rs11706648, rs2268495 and rs2254298, and rs53576, rs11706648, rs2268495 and rs2254298. It may be a combination of all the above SNP sets.
  • Identification of SNP on the OXTR gene may be performed according to a method known in the art. Usually, this can be achieved by determining the base sequence of the entire region or a partial region of the OXTR gene containing the target SNP.
  • the base sequence may be determined by a conventional method described in Green, M.R. and Sambrook, J., 2012 (described above).
  • the nucleic acid obtained in the nucleic acid extraction step is genomic DNA
  • a 50 to 3000 nt DNA region containing the target SNP is amplified by a nucleic acid amplification method such as PCR.
  • the nucleic acid amplification method may be performed according to a conventional method as described above.
  • the base sequence of the amplified fragment is determined.
  • the nucleic acid obtained in the nucleic acid extraction step is RNA
  • a 50 to 3000 nt DNA region containing the target SNP is amplified by a nucleic acid amplification method such as PCR.
  • PCR nucleic acid amplification method
  • the base sequence of the amplified fragment may be determined.
  • the nucleic acid obtained in the nucleic acid extraction step is RNA
  • the RNA is converted into cDNA by, for example, RT-PCR. Subsequent operations may be performed in the same manner as described in the previous paragraph.
  • Sensitivity prediction step In the method using the SNP indicator gene, the “sensitivity prediction step” is different from the “sensitivity prediction step” in the method using the methylation indicator gene. It is the process of predicting the sensitivity to oxytocin.
  • the sensitivity of the subject to oxytocin is predicted depending on whether the specific SNP identified in the SNP identification step is a major allele or a minor allele. Whether the sensitivity is high or low is determined by each SNP.
  • rs53576, rs11706648, rs17049528, rs4686300, and rs237900 is a major allele shown in Table 1
  • the subject is predicted to be significantly more sensitive to oxytocin.
  • the minor allele shown in Table 1 that is, an allele other than the major allele, the subject is predicted to be significantly less sensitive to oxytocin.
  • the order in which the method using the methylation indicator gene and the method using the SNP are performed is not limited.
  • the method using the methylation indicator gene may be performed before or after the method using SNP, or both methods may be performed simultaneously.
  • 3. Method for estimating therapeutic effect of oxytocin administration in patients with autism spectrum disease The third aspect of the present invention is a method subordinate to the oxytocin sensitivity prediction method of the second aspect, and the oxytocin is transferred to an ASD patient from the prediction result of the second aspect. Estimate the therapeutic effect when
  • This method includes a therapeutic effect estimation step as an essential step.
  • the essential step in the method of the second aspect is necessarily an essential step in the method of the present aspect. Since the essential steps in the method of the second aspect are as described above, the treatment effect estimation step specific to this aspect will be specifically described below.
  • the “therapeutic effect estimation step” means whether the therapeutic effect of oxytocin administration on ASD patients can be expected or not from the prediction result of the sensitivity prediction step in the oxytocin sensitivity prediction method of the second aspect. This is a guessing step.
  • the subject subject is an ASD patient.
  • Example 1 Search for methylation index gene as a marker for predicting oxytocin sensitivity> (the purpose) To search for methylation index genes that correlate with the therapeutic effects of oxytocin administration in ASD patients. (Method) For all methylated sites on the genomic DNA (methylated target sites), we comprehensively searched for methylated target sites that correlate with the therapeutic effects of ASD patients treated with oxytocin, and found genes that have significant methyl sites located Isolated as a marker for predicting oxytocin sensitivity.
  • a doctor-led clinical trial (randomized, double-blind, placebo active drug crossover) was conducted.
  • 20 adult male patients suffering from ASD were divided into two groups of 10 people, one group receiving oxytocin (referred to as “the first group that received oxytocin”) and the other group receiving placebo.
  • the group that first received placebo 24 units per dose, twice daily (total 48 units), administered nasally for 6 consecutive weeks.
  • each drug was replaced, placebo for the first group receiving oxytocin, and oxytocin for the first group receiving placebo, 24 units at a time, twice a day (total 48 units)
  • the nasal administration was continued for 6 weeks, and the evaluation was performed for a total of 12 weeks. No adverse side effects were observed with the administration of oxytocin and placebo.
  • each group continued verification with nine people.
  • ADOS Autism diagnostic observation schedule
  • CARS2 Childhood Autism Rating Scale 2
  • genomic DNA was extracted from peripheral leukocytes derived from peripheral blood collected from ASD patients immediately before the start of the clinical trial of oxytocin administration.
  • Genomic DNA was prepared using a standard phenol / chloroform method.
  • the methylation frequency of about 450,000 methylation target sites present on genomic DNA was measured using illumina Infinium HumanMethylation450 BeadChip Assay (illumina).
  • the correlation between this methylation frequency and the degree of improvement in ADOS social reciprocity by oxytocin administration was investigated using the Peason correlation coefficient. (result) Improvement of social reciprocity in ASD patients by repeated nasal administration of oxytocin is shown in FIG. 1 and Table 3, and methylation target sites significantly correlated with the degree of improvement of social reciprocity are shown in FIG.
  • CpG site 5 sites shown in Figure 2 i.e. cg04861640, cg12513795, cg16553574, cg19104656, and cg27278382 the social reciprocity improvement by oxytocin administration and significant (p ⁇ 1.0 ⁇ 10 - 5 ) It became clear that there is a correlation. These CpG sites are located in the ZSCAN26 gene, C3orf59 gene, ZNF92 gene, VARS2 gene, and UQCRC1 gene, respectively. From these results, it was suggested that the sensitivity of oxytocin in subjects can be predicted by measuring the methylation frequency of these genes.
  • Example 2 Search for SNP index gene as oxytocin sensitivity prediction marker> (the purpose) To explore SNPs in the OXTR gene that correlate with the therapeutic effects of oxytocin administration in ASD patients (Method) SNPs are included in the 600,000 SNP data banks that exist in the entire genome, and all SNPs that exist on the OXTR gene are not included in the SNP data bank but are often associated with ASD and social behavior. A total of 22 SNPs on the reported OXTR gene were included. Table 4 shows 22 SNPs targeted in this example.
  • oxytocin was administered to the above ASD patients as a single nasal administration in 24 units (randomized, double-blind, placebo active drug crossover), and psychological task results and brain activity showing the therapeutic effect, and on OXTR Correlation with SNP was verified using 6 oxytocin response indices, and SNP that could predict the oxytocin effect with the highest accuracy among all possible combinations of 16 SNPs and their combinations were identified.
  • the oxytocin response index increases the understanding of others based on facial expressions and voice color, shortens the reaction time required for understanding others, increases brain activity in the anterior cingulate cortex and dorsal medial prefrontal cortex when understanding others, Watanabe et al. (Watanabe, T.
  • Example 2 10 SNPs selected in Example 2 were combined to calculate the prediction effect of oxytocin for the six oxytocin response indicators by SVR (Support Vector Regression) (Bishop CM. Pattern Recognition and Machine Learning. Springer Verlag, 2006.) An attempt was made to distinguish parties with high oxytocin sensitivity from those with low sensitivity. (result) The results are shown in FIGS. 4, 5A and 5B.
  • regression analysis for 6 oxytocin response indices can predict experimentally observed effects with significant accuracy (P Bonferroni-corrected ⁇ 0.05 in F tests, adjusted R 2 > 0.27), a significantly high correlation was observed between the prediction effect and the actual measurement effect.
  • the prediction accuracy based on the machine learning method for classifying a party into an oxytocin response group and a group with a comparatively weak response was calculated.
  • the classification accuracy was significantly high in all response indices (PBonferroni-corrected P ⁇ 0.05).
  • Example 4 Functional separation between SNPs for oxytocin administration> (the purpose) In order to investigate the functional impact of 15 SNPs, it was verified whether the oxytocin effect was enhanced or decreased depending on whether the 10 SNPs in the regression analysis were major or minor alleles.
  • GG is a major allele of rs53576 and is represented by a larger dummy value than the GA / AA allele, so an individual with rs53576GG is It should show increased ACC activity after oxytocin administration.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Biotechnology (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Hematology (AREA)
  • Microbiology (AREA)
  • Wood Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Analytical Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Cell Biology (AREA)
  • Biophysics (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Plant Pathology (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

La présente invention aborde le problème de la mise au point d'un biomarqueur apte à prédire la sensibilité à l'ocytocine, et, par l'utilisation dudit biomarqueur, la fourniture d'un procédé permettant de prédire la sensibilité à l'ocytocine chez un sujet test, et un procédé servant à estimer l'effet thérapeutique de l'ocytocine chez un patient atteint d'un trouble du spectre de l'autisme (TSA) avant l'administration de l'ocytocine. L'invention concerne des biomarqueurs destinés à prédire la sensibilité à l'ocytocine : un gène indicatif d'une méthylation comportant un site cible de méthylation spécifique qui est en corrélation avec la sensibilité à l'ocytocine ; et un gène récepteur de l'ocytocine comprenant un SNP spécifique qui est en corrélation avec la sensibilité à l'ocytocine.
PCT/JP2016/074371 2015-08-24 2016-08-22 Marqueur de prédiction de la sensibilité à l'ocytocine WO2017033886A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2015165274A JP6757924B2 (ja) 2015-08-24 2015-08-24 オキシトシン感受性予測マーカー
JP2015-165274 2015-08-24

Publications (1)

Publication Number Publication Date
WO2017033886A1 true WO2017033886A1 (fr) 2017-03-02

Family

ID=58101261

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2016/074371 WO2017033886A1 (fr) 2015-08-24 2016-08-22 Marqueur de prédiction de la sensibilité à l'ocytocine

Country Status (2)

Country Link
JP (1) JP6757924B2 (fr)
WO (1) WO2017033886A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110982897A (zh) * 2020-01-03 2020-04-10 北京德能安康生物科技有限公司 用于检测催产素受体基因型的引物组及其应用

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102374865B1 (ko) * 2020-10-07 2022-03-18 서울대학교산학협력단 인체 모발 탄력 인장강도 관련 유전자 다형성 마커 및 이의 용도

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008148072A2 (fr) * 2007-05-24 2008-12-04 The Brigham And Women's Hospital, Inc. Variations genetiques liees a une maladies et methodes de detection et d'utilisation de ces variations
JP2010500568A (ja) * 2006-08-09 2010-01-07 ホームステッド クリニカル コーポレイション 器官特異的蛋白質およびその使用方法
WO2011144718A2 (fr) * 2010-05-19 2011-11-24 Signature Diagnostics Ag Méthodes et nécessaires de diagnostic du cancer colorectal
WO2013070984A1 (fr) * 2011-11-08 2013-05-16 Bayer Healthcare, Llc Systèmes et méthodes intégrées pour l'analyse de l'expression génétique dans le cadre de la sclérose en plaques
JP2014508525A (ja) * 2011-03-08 2014-04-10 アナリティック イエナ アーゲー ヒトゲノムに対応するポリヌクレオチドの初期セットから患者の宿主応答の重症度をインビトロ決定するためのポリヌクレオチドのサブセットを同定するための方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010500568A (ja) * 2006-08-09 2010-01-07 ホームステッド クリニカル コーポレイション 器官特異的蛋白質およびその使用方法
WO2008148072A2 (fr) * 2007-05-24 2008-12-04 The Brigham And Women's Hospital, Inc. Variations genetiques liees a une maladies et methodes de detection et d'utilisation de ces variations
WO2011144718A2 (fr) * 2010-05-19 2011-11-24 Signature Diagnostics Ag Méthodes et nécessaires de diagnostic du cancer colorectal
JP2014508525A (ja) * 2011-03-08 2014-04-10 アナリティック イエナ アーゲー ヒトゲノムに対応するポリヌクレオチドの初期セットから患者の宿主応答の重症度をインビトロ決定するためのポリヌクレオチドのサブセットを同定するための方法
WO2013070984A1 (fr) * 2011-11-08 2013-05-16 Bayer Healthcare, Llc Systèmes et méthodes intégrées pour l'analyse de l'expression génétique dans le cadre de la sclérose en plaques

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
CAMPBELL DB. ET AL.: "Association of oxytocin receptor (OXTR) gene variants with multiple phenotype domains of autism spectrum disorder.", J NEURODEV DISORD., vol. 3, no. 2, 2011, pages 101 - 112, XP055373535 *
CHEN FS. ET AL.: "Genetic modulation of oxytocin sensitivity: a pharmacogenetic approach.", TRANSL PSYCHIATRY., vol. 5, October 2015 (2015-10-01), pages e664, XP055373536, Retrieved from the Internet <URL:http://www.nature.com/tp/journal/v5/n10/pdf/tp2015163a.pdf> [retrieved on 20161028] *
HARAM M. ET AL.: "An attempt to identify single nucleotide polymorphisms contributing to possible relationships between personality traits and oxytocin-related genes.", NEUROPSYCHOBIOLOGY, vol. 69, no. 1, 2014, pages 25 - 30 *
KRIAUCIONIS S. ET AL.: "Gene expression analysis exposes mitochondrial abnormalities in a mouse model of Rett syndrome.", MOL CELL BIOL., vol. 26, no. 13, 2006, pages 5033 - 5042, XP002488309 *
PARKER KJ. ET AL.: "Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder.", PROC NATL ACAD SCI U S A., vol. 111, no. 33, 2014, pages 12258 - 12263, XP055373534 *
ROBERTS KE . ET AL.: "Genetic risk factors for hepatopulmonary syndrome in patients with advanced liver disease.", GASTROENTEROLOGY, vol. 139, no. 1, 2010, pages 130 - 139, XP027202920 *
SOUZA RP. ET AL.: "Schizophrenia severity and clozapine treatment outcome association with oxytocinergic genes.", INT J NEUROPSYCHOPHARMACOL., vol. 13, no. 6, 2010, pages 793 - 798, XP008159626 *
WARRIER V. ET AL.: "A comprehensive meta- analysis of common genetic variants in autism spectrum conditions.", MOL AUTISM., vol. 6, 28 August 2015 (2015-08-28), Retrieved from the Internet <URL:http://download.springer.com/static/pdf/454/art%253A10.1186%252Fs13229-015-0041-0.pdf?originUrl=http%3A%2F%2Fmolecularautism.biomedcentral.com%2Farticle%2F10.1186%2Fs13229-015-0041-0&token2=exp=1477623145~acl=%2Fstatic%2Fpdf%2F454%2Fart%25253A10.1186%25252Fs13229-015-0041-0.pdf*~hmac=645253e6> [retrieved on 20061028] *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110982897A (zh) * 2020-01-03 2020-04-10 北京德能安康生物科技有限公司 用于检测催产素受体基因型的引物组及其应用

Also Published As

Publication number Publication date
JP2017042064A (ja) 2017-03-02
JP6757924B2 (ja) 2020-09-23

Similar Documents

Publication Publication Date Title
Moayyeri et al. The UK adult twin registry (TwinsUK resource)
Lam et al. MC3R links nutritional state to childhood growth and the timing of puberty
Konradi et al. Mitochondria, oligodendrocytes and inflammation in bipolar disorder: evidence from transcriptome studies points to intriguing parallels with multiple sclerosis
JP2021176328A (ja) エピジェネティックな染色体相互作用
JP4155561B2 (ja) アレルギー性疾患検査方法
Gallagher et al. Genetic association studies in uterine fibroids: risk alleles presage the path to personalized therapies
Vetro et al. Loss‐of‐function FANCL mutations associate with severe Fanconi anemia overlapping the VACTERL association
US20200165680A1 (en) Method for detection of traumatic brain injury
Al-Jawahiri et al. SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile
US20200102610A1 (en) Method for cerebral palsy prediction
US20200024663A1 (en) Method for detecting mood disorders
Epting et al. Loss of CBY1 results in a ciliopathy characterized by features of Joubert syndrome
WO2017033886A1 (fr) Marqueur de prédiction de la sensibilité à l&#39;ocytocine
Kos et al. Exome sequences of multiplex, multigenerational families reveal schizophrenia risk loci with potential implications for neurocognitive performance
Canton et al. Rare variants in the MECP2 gene in girls with central precocious puberty: a translational cohort study
KR20160111925A (ko) 자살 위험과 연관된 유전적 마커 및 그의 사용 방법
JP5828407B2 (ja) 精神疾患の検査方法および精神疾患用の検査キット
Haberstick et al. Between-and within-family association test of the dopamine receptor D2 TaqIA polymorphism and alcohol abuse and dependence in a general population sample of adults
KR20180029776A (ko) 유전자 염기서열분석을 통한 폐암의 한의 진단 도구
JP2022520427A (ja) 脳損傷の唾液バイオマーカー
JP6338872B2 (ja) 視神経障害発症リスクの判定方法
US20220291231A1 (en) Compositions and methods for predicting lung function decline in idiopathic pulmonary fibrosis
KR102489098B1 (ko) Slc25a40 유전자를 이용한 항우울제 조기 치료반응이 불량한 남성 환자의 최종 비관해 예측용 바이오마커, 상기 바이오마커를 이용한 항우울제 조기 치료반응이 불량한 남성 환자의 최종비관해 진단에 대한 정보제공방법 및 진단키트
Wang et al. Investigating molecular markers linked to acute myocardial infarction and cuproptosis: bioinformatics analysis and validation in the AMI mice model
WO2015083779A1 (fr) Méthode de détection du syndrome de coffin-siris

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16839233

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16839233

Country of ref document: EP

Kind code of ref document: A1