Acute-Stage Mental Health Symptoms by Natural Disaster Type: Consultations of Disaster Psychiatric Assistance Teams (DPATs) in Japan.

This study analyzed the support activities that the Disaster Psychiatric Assistance Team (DPAT) in Japan provided following four previous disasters (a volcanic eruption, a mudslide, a flood, and an earthquake) to identify links between the disaster type and the characteristics of acute stage mental disorders observed. Using Disaster Mental Health Information Support System database records of consultations with patients supported by the DPAT during the survey period from 2013 (when DPAT was launched) to 2016, we performed cross-tabulations and investigated significant differences using chi-squared tests. For expected values less than 5, Fisher's exact test was performed. Frequently occurring acute-stage symptoms after a disaster include anxiety, sleep problems, mood and affect, and physical symptoms. The affected population characteristics, victim attributes, severity of damage sustained, and evacuation status were the chief factors that influenced acute-stage mental health symptoms. The psychiatric symptoms detected in our study together with the results of diagnoses are important for determining the types of early interventions needed during the acute stage of a disaster. By sharing baseline mental health information, together with disaster-related characteristics highlighted in this study, mental health providers are better able to predict future possible mental disorders and symptoms.

Acute Mental Health Needs Duration during Major Disasters: A Phenomenological Experience of Disaster Psychiatric Assistance Teams (DPATs) in Japan.

BACKGROUND: How long acute mental health needs continue after the disaster are problems which must be addressed in the treatment of victims. The aim of this study is to determine victims' needs by examining activity data from Disaster Psychiatric Assistance Teams (DPATs) in Japan. METHODS: Data from four disasters were extracted from the disaster mental health information support system (DMHISS) database, and the transition of the number of consultations and the activity period were examined. RESULTS: Common to all four disasters, the number of consultations increased rapidly from 0-2 days, reaching a peak within about a week. The partial correlation coefficient between the number of days of activity and the maximum number of victims showed significance. The number of victims and days of activity can be used to obtain a regression curve. CONCLUSIONS: This is the first report to reveal that mental health needs are the greatest in the hyper-acute stage, and the need for consultation and the duration of needs depends on the number of victims.

[The revised system of hospitalization for medical care and protection].

The Act to Partially Amend the Act on Mental Health and Welfare for the Mentally Disabled was passed on June 13, 2013. Major amendments regarding hospitalization for medical care and protection include the points listed below. The guardianship system will be abolished. Consent by a guardian will no longer be required in the case of hospitalization for medical care and protection. In the case of hospitalization for medical care and protection, the administrators of the psychiatric hospital are required to obtain the consent of one of the following persons: spouse, person with parental authority, person responsible for support, legal custodian, or curator. If no qualified person is available, consent must be obtained from the mayor, etc. of the municipality. The following three obligations are imposed on psychiatric hospital administrators. (1) Assignment of a person, such as a psychiatric social worker, to provide guidance and counseling to patients hospitalized for medical care and protection regarding their postdischarge living environment. (2) Collaboration with community support entities that consult with and provide information as necessary to the person hospitalized, their spouse, a person with parental authority, a person responsible for support, or their legal custodian or curator. (3) Organizational improvements to promote hospital discharge. With regard to requests for discharge, the revised law stipulates that, in addition to the person hospitalized with a mental disorder, others who may file a request for discharge with the psychiatric review board include: the person's spouse, a person with parental authority, a person responsible for support, or their legal custodian or curator. If none of the above persons are available, or if none of them are able to express their wishes, the mayor, etc. of the municipality having jurisdiction over the place of residence of the person hospitalized may request a discharge. In order to promote transition to life in the community by persons with mental disorders, efforts will be made to enhance psychiatric care for them, with guidelines to be developed to ensure the provision of medical care to persons with mental disorders. The revised law clarifies that members of psychiatric review boards shall be "persons with expert knowledge and experience pertaining to the health and/or welfare of persons with mental disorders." Provision is made for a review of conditions related to implementation of the revised law approximately three years after it takes effect, with measures to be taken as necessary based on results of the review. The main focus of this presentation will be the revisions to the system of hospitalization for medical care and protection, and the deletion of provisions relating to the system of guardianship.

Relationship between nicotine dependence and the endophenotype-related trait of cognitive function but not acoustic startle reponses in Japanese patients with schizophrenia.

OBJECTIVES: We investigated whether nicotine dependence affects these endophenotypes in Japanese schizophrenia patients and whether alpha4 and beta2 subunits of neuronal nicotinic acetylcholine receptor genes (alpha4 subunit of the nAChR gene (CHRNA4)/beta2 subunit of the nAChR gene (CHRNB2)) were associated with nicotine dependence in patients (n = 100) and healthy controls (n = 107). METHODS: First, in patients, we evaluated cognitive function, using the Brief Assessment of Cognition in Schizophrenia, and acoustic startle responses. Second, we evaluated the severity of nicotine dependence, using the Tobacco Dependence Screener, the Fagerström Test for Nicotine Dependence, and the Brinkman index in current smokers in both groups. Third, we evaluated the relationship between acoustic startle responses, cognitive function, and severity of nicotine dependence. Finally, using 12 tagging single-nucleotide polymorphisms in each the CHRNA4/CHRNB2, we used multiple linear regression analysis to examine the association between nicotine dependence measures and each selected single-nucleotide polymorphism. RESULTS: The presence and severity of nicotine dependence were associated with verbal memory and executive function in schizophrenia patients. However, nicotine dependence was not correlated with any acoustic startle response. In addition, rs755203 and rs1044397 in CHRNA4 were associated with nicotine dependence in healthy controls. CONCLUSIONS: Nicotine dependence might influence the level of verbal memory and executive function in schizophrenia patients. In addition, rs755203 and rs1044397 in CHRNA4 might play a role in the pathophysiology of nicotine dependence in healthy controls in the Japanese population.

Analysis of the VAV3 as candidate gene for schizophrenia: evidences from voxel-based morphometry and mutation screening.

In recently completed Japanese genome-wide association studies (GWAS) of schizophrenia (JPN_GWAS) one of the top association signals was detected in the region of VAV3, a gene that maps to the chromosome 1p13.3. In order to complement JPN_GWAS findings, we tested the association of rs1410403 with brain structure in healthy individuals and schizophrenic patients and performed exon resequencing of VAV3. We performed voxel-based morphometry (VBM) and mutation screening of VAV3. Four independent samples were used in the present study: (1) for VBM analysis, we used case-control sample comprising 100 patients with schizophrenia and 264 healthy controls, (2) mutation analysis was performed on a total of 321 patients suffering from schizophrenia, and 2 case-control samples (3) 729 unrelated patients with schizophrenia and 564 healthy comparison subjects, and (4) sample comprising 1511 cases and 1517 healthy comparison subjects and were used for genetic association analysis of novel coding variants with schizophrenia. The VBM analysis suggests that rs1410403 might affect the volume of the left superior and middle temporal gyri (P=.011 and P=.013, respectively), which were reduced in patients with schizophrenia compared with healthy subjects. Moreover, 4 rare novel missense variants were detected. The mutations were followed-up in large independent sample, and one of the novel variants (Glu741Gly) was associated with schizophrenia (P=.02). These findings demonstrate that VAV3 can be seen as novel candidate gene for schizophrenia in which both rare and common variants may be related to increased genetic risk for schizophrenia in Japanese population.

The serotonin 1A receptor gene confer susceptibility to mood disorders: results from an extended meta-analysis of patients with major depression and bipolar disorder.

The serotonin 1A receptor gene (HTR1A) has been associated with mood disorders (MDs), including major depressive disorder (MDD) and bipolar disorder (BP). Therefore, we conducted a systematic review and meta-analysis between rs6295 (C-1019G) as well as rs878567 in HTR1A and MDs. Searching PubMed through May 2012, 15 studies, including our own, previously unpublished association study (135 MDD patients and 107 healthy controls), met inclusion criteria for the meta-analysis of rs6295 (4,297 MDs patients and 5,435 controls). Five association studies met criteria for the meta-analysis of rs878567 (2041MDs patients and 2,734 controls). rs6295 was associated with combined MDs (P allele model = 0.007 and P recessive model = 0.01). When divided by diagnostic subgroup (MDD = 3,119 patients and 4,380 controls or BP = 1,170 patients and 2,252 controls), rs6295 was associated with each MDs separately (MDD: P allele model = 0.006, P recessive model = 0.01; BP: P dominant model = 0.003). Likewise, rs878567 was associated with combined MDs (2,041 patients and 2,734 controls (P allele model = 0.0002, P dominant model = 0.0008, and P recessive model = 0.01). When divided by diagnostic subgroup (MDD = 1,013 patients and 1,728 controls or BP = 1,051 patients and 2,099 controls), rs878567 was associated with MDD (P allele model = 0.0007 and P dominant model = 0.01), while only one BP study had such data, precluding a meta-analysis. All of these significances survived correction for multiple comparisons. Results from this expanded meta-analysis, which included our own new study, suggest that rs6295 (C-1019G) and rs878567 in HTR1A are related to the pathophysiology of MDs, with overlap between MDD and BP. Findings provide additional clues to the underlying biology and treatment targets in MDs.

A population-specific uncommon variant in GRIN3A associated with schizophrenia.

BACKGROUND: Genome-wide association studies have successfully identified several common variants showing robust association with schizophrenia. However, individually, these variants only produce a weak effect. To identify genetic variants with larger effect sizes, increasing attention is now being paid to uncommon and rare variants. METHODS: From the 1000 Genomes Project data, we selected 47 candidate single nucleotide variants (SNVs), which were: 1) uncommon (minor allele frequency < 5%); 2) Asian-specific; 3) missense, nonsense, or splice site variants predicted to be damaging; and 4) located in candidate genes for schizophrenia and bipolar disorder. We examined their association with schizophrenia, using a Japanese case-control cohort (2012 cases and 2781 control subjects). Additional meta-analysis was performed using genotyping data from independent Han-Chinese case-control (333 cases and 369 control subjects) and family samples (9 trios and 284 quads). RESULTS: We identified disease association of a missense variant in GRIN3A (p.R480G, rs149729514, p = .00042, odds ratio [OR] = 1.58), encoding a subunit of the N-methyl-D-aspartate type glutamate receptor, with study-wide significance (threshold p = .0012). This association was supported by meta-analysis (combined p = 3.3 × 10(-5), OR = 1.61). Nominally significant association was observed in missense variants from FAAH, DNMT1, MYO18B, and CFB, with ORs of risk alleles ranging from 1.41 to 2.35. CONCLUSIONS: The identified SNVs, particularly the GRIN3A R480G variant, are good candidates for further replication studies and functional evaluation. The results of this study indicate that association analyses focusing on uncommon and rare SNVs are a promising way to discover risk variants with larger effects.

An evaluation of polymorphisms in casein kinase 1 delta and epsilon genes in major psychiatric disorders.

Disturbances of the circadian rhythm are involved in the pathophysiology of bipolar disorder (BD), schizophrenia (SCZ) and major depressive disorder (MDD). Specifically, because clock gene dysfunction is good candidate for enhancing the susceptibility to these psychiatric disorders, we selected two circadian rhythm-related genes (CSNK1D and CSNK1E) and investigated genetic associations of the genes with these three disorders. None of the SNPs showed a significant association with MDD, but a SNP (rs2075984) in CSNK1E and SNP (rs6502097) in CSNK1D were associated with SCZ (P=0.0091, uncorrected) and BD (P=0.030, uncorrected), respectively. To confirm these findings, we analyzed an independent dataset (maximum N=3815) but found a lack of association (P=0.63 for rs2075984 and P=0.61 for rs6502097). The final meta-analysis showed no association between these SNPs with SCZ (P=0.21) and BD (P=0.53). These results do not support that genetic variation in CSNK1D and CSNK1E is a susceptibility factor for major psychiatric disorders in the Japanese population.

GTP cyclohydrolase 1 gene haplotypes as predictors of SSRI response in Japanese patients with major depressive disorder.

BACKGROUND: Tetrahydrobiopterin (BH4) plays an important role in the biosynthesis of serotonin, melatonin and catecholamines, all of which are implicated in the pathophysiology of mood disorders (MDs), including major depressive disorder (MDD) and bipolar disorder (BP). Production of BH4 is regulated by GTP cyclohydrolase transcription and activity. Thus, we considered the GTP cyclohydrolase gene (GCH1) to be a good candidate gene in the pathophysiology of MDs and of the serotonin selective reuptake inhibitors (SSRIs) response in MDD, and conducted a case-control study utilizing three SNPs (rs8007267, rs3783641 and rs841) and moderate sample sizes (405 MDD patients, including 262 patients treated by SSRIs, 1022 BP patients and 1805 controls). METHOD: A multiple logistic regression analysis was carried out to compare the frequencies of each SNP genotype for the target phenotype across patients and controls in several genetic models, while adjusting for possible confounding factors. A clinical response was defined as a decrease of more than 50% from the baseline score on the Structured Interview Guide for Hamilton Rating Scale for Depression (SIGH-D) within 8 weeks, and clinical remission as a SIGH-D score of less than 7 at 8 weeks. RESULT: No associations between three SNPs in GCH1 and MDD or BP were observed; however, GCH1 was associated with SSRI therapeutic response in MDD in all the marker's haplotype analysis (Global P value=0.0379). CONCLUSIONS: Results suggest that GCH1 may predict response to SSRI in MDD in the Japanese population. Nevertheless, a replication study using larger samples may be required for conclusive results, since our sample size was small.

Serotonin 6 receptor gene and schizophrenia: case-control study and meta-analysis.

OBJECTIVES: Several lines of evidence suggest that genetic alterations in serotonin 6 (5-HT6) receptors might be associated with the pathophysiology of schizophrenia. We sought to assess the relationship between genotype alterations in 5-HT6 receptors and schizophrenia both in a case-control study and a meta-analysis. METHODS: We conducted an association study of the 5-HT6 receptor gene (HTR6) in Japanese patients with schizophrenia (n = 836) and controls (n = 857). Five tagging single-nucleotide polymorphisms (SNPs), including rs1805054 (C267T) in HTR6, were selected. In addition, we carried out a meta-analysis between rs1805054, which has been examined in other studies, and schizophrenia, searching PubMed through August 2011. RESULTS: There were no significant associations between the tagging SNPs in HTR6 and schizophrenia in any of the genotype models in both the simple and the multiple logistic regression analyses correcting for potential confounds. Similarly, no significant association was found in the all-marker haplotype multiple logistic regression analysis (p = 0.491). Moreover, in the meta-analysis of rs1805054, drawing data from five studies, including our own (schizophrenia patients = 1366, controls = 1376), rs1805054 was also not associated with schizophrenia. CONCLUSIONS: Our results indicate that tagging SNPs in HTR6 may not play a role in the pathophysiology of schizophrenia.

The relationship between acoustic startle response measures and cognitive functions in Japanese patients with schizophrenia.

Recently, schizophrenia endophenotypes have been actively investigated to better understand the pathophysiology of schizophrenia. Past studies have shown that cognitive functions, including working memory and executive function, correlate with acoustic startle responses, such as prepulse inhibition (PPI), in patients with schizophrenia. The aim of this study was to investigate the relationship between cognitive functions and acoustic startle response in Japanese patients with schizophrenia. In 100 patients with schizophrenia, we evaluated cognitive function, using the Brief Assessment of Cognition in Schizophrenia, Japanese-language version (BACS-J), and acoustic startle responses, including acoustic startle reflex, habituation, and PPI (three different intensities: 82, 86, and 90 dB SPL, equivalent to signal-to-noise ratios of +12, +16, and +20 dB, respectively). Using multiple regression analysis, we examined the relationship between acoustic startle responses and BACS-J primary measures or composite score. Level of attention was associated with magnitude of habituation in schizophrenia (P = 0.0009, ß = -0.357). None of the other domains of cognitive function were significantly associated with any measure of acoustic startle response. This included attention regarding ASR (P = 0.513), PPI (P = 0.521-0.842), verbal memory (P = 0.423-0.981), working memory (P = 0.312-0.966), motor speed (P = 0.323-0.955), verbal fluency (P = 0.125-0.920), executive function (P = 0.118-0.470), and the BACS-J composite score (P = 0.230-0.912). In this first investigation of the relationship between cognitive functions and acoustic startle responses in Japanese patients with schizophrenia, attentional deficits correlated highly with the level of habituation. However, a replication study using other population samples is required to further investigate this relationship.

Resequencing and association analysis of the KALRN and EPHB1 genes and their contribution to schizophrenia susceptibility.

BACKGROUND: Our genome-wide association study of schizophrenia found association signals at the Kalirin gene (KALRN) and EPH receptor B1 gene (EPHB1) in a Japanese population. The importance of these synaptogenic pathway genes in schizophrenia is gaining independent supports. Although there has been growing interest in rare (<1%) missense mutations as potential contributors to the unexplained heritability of schizophrenia, there are no population-based studies targeting rare (<1%) coding mutations with a larger effect size (eg, OR >1.5) in KALRN or EPHB1. METHODS AND RESULTS: The present study design consisted of 3 phases. At the discovery phase, we conducted resequencing analyses for all exon regions of KALRN and EPHB1 using a DNA microarray-based method. Seventeen rare (<1%) missense mutations were discovered in the first sample set (320 schizophrenic patients). After the prioritization phase based on frequencies in the second sample set (729 cases and 562 controls), we performed association analyses for each selected mutation using the third sample set (1511 cases and 1517 controls), along with a combined association analysis across all selected mutations. In KALRN, we detected a significant association between schizophrenia and P2255T (OR = 2.09, corrected P = .048, 1 tailed); this was supported in the combined association analysis (OR = 2.07, corrected P = .006, 1 tailed). We found no evidence of association of EPHB1 with schizophrenia. In silico analysis indicated the functional relevance of these rare missense mutations. CONCLUSION: We provide evidence that multiple rare (<1%) missense mutations in KALRN may be genetic risk factors for schizophrenia.

The CLOCK gene and mood disorders: a case-control study and meta-analysis.

The clock gene (CLOCK) is considered to be a good candidate gene for the pathophysiology of mood disorders, including bipolar disorder (BP) and major depressive disorder (MDD). rs1801260 (T3111C) has been detected at position 3111 in the CLOCK mRNA 3' untranslated region, and was reported to be associated with a substantial delay in preferred timing for activity and sleep in a human study. As for function, rs1801260 has been speculated to affect mRNA. Therefore, the authors investigated the association between the three tagging single-nucleotide polymorphisms (SNPs) (rs3736544, rs1801260, and rs3749474) in CLOCK and risk of BP (n=867) and MDD (n=139) compared to controls (n=889) in the Japanese population. In addition, we also performed an updated meta-analysis of nine published, genetic association studies investigating the relationship between rs1801260 and mood disorder risk, comprising 3321 mood disorders cases and 3574 controls. We did not detect any associations between tagging SNPs in CLOCK and BP or MDD in the allele, genotype, or haplotype analysis (global p(BP)=.605 and global p(MDD)=.211). Moreover, rs1801260 was also not associated with BP, MDD, or any mood disorders in the meta-analysis. In conclusion, these data suggest that CLOCK does not play a major role in the pathophysiology of mood disorders.

Genetic Association Analysis of NOS1 and Methamphetamine-Induced Psychosis Among Japanese.

The neuronal nitric oxide synthase gene (NOS1) is located at 12q24, a susceptibility region for schizophrenia, and produces nitric oxide (NO). NO has been reported to play important roles as a gaseous neurotransmitter in brain. NO is a second messenger for the N-methyl-D aspartate (NMDA) receptor and is related to the dopaminergic system. Because the symptomatology of methamphetamine (METH) use disorder patients with psychosis is similar to that of patients with schizophrenia, NOS1 is a good candidate gene for METH-induced psychosis. Therefore, we conducted a case-control association study between NOS1 and METH-induced psychosis with Japanese subjects (183 with METH-induced psychosis patients and 519 controls). We selected seven SNPs (rs41279104, rs3782221, rs3782219, rs561712, rs3782206, rs6490121, rs2682826) in NOS1 from previous reports. Written informed consent was obtained from each subject. This study was approved by the Ethics Committee at Fujita Health University School of Medicine and each participating institute of the Japanese Genetics Initiative for Drug Abuse (JGIDA). No significant association was found between NOS1 and METH-induced psychosis in the allele/genotype-wise or haplotype-wise analyses. In conclusion, we suggest that NOS1 might not contribute to the risk of METH-induced psychosis in the Japanese population.

No significant association between SIRT1 gene and methamphetamine-induced psychosis in the Japanese population.

OBJECTIVES: We previously showed that the sirtuin 1 gene (SIRT1 gene), one of the clock genes, was associated with schizophrenia in a Japanese patient population. Because the symptoms of methamphetamine (METH)-induced psychosis are similar to those of paranoid type schizophrenia and because not every METH user develops psychosis, it is conceivable that METH-induced psychosis and schizophrenia have common susceptibility genes. Therefore, we conducted an analysis of the association of SIRT1 gene with METH-induced psychosis, hypothesizing a significant relationship. METHODS: This paper presents a case-control study of the SIRT1 gene in 515 Japanese individuals (197 with METH-induced psychosis and 318 age-matched and sex-matched controls) with four tagging single nucleotide polymorphisms (rs12778366, rs2273773, rs4746720, and rs10997875), selected a priori using the HapMap database. RESULTS: rs10997875 (located in the 3' flanking region) was associated with METH-induced psychosis (unadjusted p(genotype) = 0.0203). However, these results became non-significant after Bonferroni correction (corrected p(genotype) = 0.0812). In the all-marker haplotype analysis, the SIRT1 gene was not associated with METH-induced psychosis (p = 0.146). CONCLUSION: Our findings suggest that SIRT1 gene does not contribute to the development of METH-induced psychosis in the Japanese population. However, a replication study using larger samples should be conducted to obtain conclusive results.

Possible association between ubiquitin-specific peptidase 46 gene and major depressive disorders in the Japanese population.

BACKGROUND: Several investigations have reported that abnormalities in circadian rhythms might be related to the pathophysiology of major depressive disorder (MDD) and the therapeutic response to selective serotonin reuptake inhibitors (SSRIs). Recently, ubiquitin-specific peptidase 46 (USP46), a new molecule related to the circadian clock system, has been described. We conducted a case control study between seven tagging SNPs (rs10517263, rs17675844, rs6554557, rs12646800, rs2244291, rs10034164, rs346005) in the USP46 gene, MDD, and the SSRI therapeutic response in MDD in the Japanese population. METHOD: We recruited 432 MDD patients (202 males and 230 females) and 792 healthy controls (319 males and 473 females). Two hundred sixty-one of 432 MDD patients were treated with SSRIs (fluvoxamine, sertraline or paroxetine). RESULT: We detected an association between the USP46 gene and MDD in a haplotype analysis (rs2244291-rs10034164-rs346005 and rs12646800-rs2244291-rs10034164-rs346005). However, we did not find any association between the USP46 gene and SSRI response or remission in MDD in the Japanese population. LIMITATIONS: A replication study using larger samples may be required for conclusive results, since our sample size was small. CONCLUSIONS: Our results suggest that the USP46 gene might play a role in the pathophysiology of MDD in the Japanese population.

Serotonin 6 receptor gene is associated with methamphetamine-induced psychosis in a Japanese population.

BACKGROUND: Altered serotonergic neural transmission is hypothesized to be a susceptibility factor for psychotic disorders such as schizophrenia. The serotonin 6 (5-HT6) receptor is therapeutically targeted by several second generation antipsychotics, such as clozapine and olanzapine, and d-amphetamine-induced hyperactivity in rats is corrected with the use of a selective 5-HT6 receptor antagonist. In addition, the disrupted prepulse inhibition induced by d-amphetamine or phencyclidine was restored by 5-HT6 receptor antagonist in an animal study using rats. These animal models were considered to reflect the positive symptoms of schizophrenia, and the above evidence suggests that altered 5-HT6 receptors are involved in the pathophysiology of psychotic disorders. The symptoms of methamphetamine (METH)-induced psychosis are similar to those of paranoid type schizophrenia. Therefore, we conducted an analysis of the association of the 5-HT6 gene (HTR6) with METH-induced psychosis. METHOD: Using five tagging SNPs (rs6693503, rs1805054, rs4912138, rs3790757 and rs9659997), we conducted a genetic association analysis of case-control samples (197 METH-induced psychosis patients and 337 controls) in the Japanese population. The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients. RESULTS: rs6693503 was associated with METH-induced psychosis patients in the allele/genotype-wise analysis. Moreover, this association remained significant after Bonferroni correction. In the haplotype-wise analysis, we detected an association between two markers (rs6693503 and rs1805054) and three markers (rs6693503, rs1805054 and rs4912138) in HTR6 and METH-induced psychosis patients, respectively. CONCLUSION: HTR6 may play an important role in the pathophysiology of METH-induced psychosis in the Japanese population.

Genome-wide association study of schizophrenia in a Japanese population.

BACKGROUND: Genome-wide association studies have detected a small number of weak but strongly supported schizophrenia risk alleles. Moreover, a substantial polygenic component to the disorder consisting of a large number of such alleles has been reported by the International Schizophrenia Consortium. METHOD: We report a Japanese genome-wide association study of schizophrenia comprising 575 cases and 564 controls. We attempted to replicate 97 markers, representing a nonredundant panel of markers derived mainly from the top 150 findings, in up to three data sets totaling 1990 cases and 5389 controls. We then attempted to replicate the observation of a polygenic component to the disorder in the Japanese and to determine whether this overlaps that seen in UK populations. RESULTS: Single-locus analysis did not reveal genome-wide support for any locus in the genome-wide association study sample (best p = 6.2 × 10(-6)) or in the complete data set in which the best supported locus was SULT6B1 (rs11895771: p = 3.7 × 10(-5) in the meta-analysis). Of loci previously supported by genome-wide association studies, we obtained in the Japanese support for NOTCH4 (rs2071287: p(meta) = 5.1 × 10(-5)). Using the approach reported by the International Schizophrenia Consortium, we replicated the observation of a polygenic component to schizophrenia within the Japanese population (p = .005). Our trans Japan-UK analysis of schizophrenia also revealed a significant correlation (best p = 7.0 × 10(-5)) in the polygenic component across populations. CONCLUSIONS: These results indicate a shared polygenic risk of schizophrenia between Japanese and Caucasian samples, although we did not detect unequivocal evidence for a novel susceptibility gene for schizophrenia.

Pharmacogenetic study of serotonin 6 receptor gene with antidepressant response in major depressive disorder in the Japanese population.

OBJECTIVE: Several investigations have suggested that alterations in serotonin 6 (5-HT6) receptors might be associated with the pathophysiology of major depressive disorder (MDD), and that 5-HT6 receptors might be a therapeutic target for serotonin selective reuptake inhibitor (SSRI) in MDD. To evaluate the association between HTR6 and the efficacy of SSRI treatment in Japanese MDD patients, we conducted a case-control study in a Japanese population sample. METHODS: We selected five tagging SNPs (rs6693503, rs1805054, rs4912138, rs3790757 and rs9659997), and performed an association analysis of HTR6 and the efficacy of SSRI treatment in 260 MDD patients. RESULTS: We did not detect an association between tagging SNPs in HTR6 and the therapeutic response to SSRI in MDD in allele/genotype or haplotype analysis. CONCLUSIONS: HTR6 may not play an important role in the pathophysiology of SSRI response in the Japanese population. Because our sample was relatively small, statistical errors were possible in the results of our association analyses. To overcome these limitations, a replication study using a larger sample may be required for conclusive results.