研究者業績
基本情報
研究分野
1経歴
3-
2016年4月 - 現在
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2015年4月
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2011年4月
学歴
2-
2011年4月 - 2015年3月
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2001年4月 - 2007年3月
受賞
5論文
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Molecular Psychiatry 28(7) 2848-2856 2023年2月21日 査読有りAbstract Large-scale genome-wide association studies (GWASs) on bipolar disorder (BD) have implicated the involvement of the fatty acid desaturase (FADS) locus. These enzymes (FADS1 and FADS2) are involved in the metabolism of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are thought to potentially benefit patients with mood disorders. To model reductions in the activity of FADS1/2 affected by the susceptibility alleles, we generated mutant mice heterozygously lacking both Fads1/2 genes. We measured wheel-running activity over six months and observed bipolar swings in activity, including hyperactivity and hypoactivity. The hyperactivity episodes, in which activity was far above the norm, usually lasted half a day; mice manifested significantly shorter immobility times on the behavioral despair test performed during these episodes. The hypoactivity episodes, which lasted for several weeks, were accompanied by abnormal circadian rhythms and a marked decrease in wheel running, a spontaneous behavior associated with motivation and reward systems. We comprehensively examined lipid composition in the brain and found that levels of certain lipids were significantly altered between wild-type and the heterozygous mutant mice, but no changes were consistent with both sexes and either DHA or EPA was not altered. However, supplementation with DHA or a mixture of DHA and EPA prevented these episodic behavioral changes. Here we propose that heterozygous Fads1/2 knockout mice are a model of BD with robust constitutive, face, and predictive validity, as administration of the mood stabilizer lithium was also effective. This GWAS-based model helps to clarify how lipids and their metabolisms are involved in the pathogenesis and treatment of BD.
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PloS one 18(6) e0287122 2023年Among antipsychotics, clozapine is associated with a high risk of seizures. This study aimed to generate novel hypotheses regarding trends in the onset of clozapine-induced seizures using the JADER (Japanese Adverse Drug Event Report) database. Seizures were defined according to the Standardized MedDRA Queries (SMQ) for convulsions (SMQ20000079). Trends in the onset of clozapine-induced seizures were assessed using multivariate logistic regression analysis with covariates of sex, age, clozapine dose, antipsychotic polypharmacy, concomitant medications, and history of convulsive disorder. In addition, we assessed the time-to-onset of clozapine-induced seizures using the median time, interquartile range, and Weibull shape parameter. The JADER database registered 2,745 cases of adverse events with clozapine, and 1,784 cases were included in the analysis after excluding cases for which clinical information was not available. Medium (200-400 mg) and high (> 400 mg) doses of clozapine had a significantly higher reporting rate of seizures than low doses (< 200 mg) (adjusted reporting odds ratio [aROR] = 3.05, 95% confidence interval [CI]: 1.86-4.99 and aROR = 9.81, 95% CI: 6.06-15.89, respectively). Younger age, antipsychotic polypharmacy, and concomitant use of lithium were also significantly associated with reports of seizures. The time-to-onset analysis of 222 cases of clozapine-induced seizures showed that the median time was 134 (interquartile range, 72-295) days. The 95% CI of the WSP β-value for clozapine-induced seizures included 1 and was classified as a random failure type. In conclusion, the results suggest that clozapine-induced seizures are dose-dependent adverse events that should be monitored with consideration of the effects of age and concomitant medications. Further epidemiological research is needed to strengthen and validate our hypotheses.
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Neuropsychiatric disease and treatment 19 615-622 2023年PURPOSE: Clozapine is more effective than other antipsychotics and is the only antipsychotic approved for treatment-resistant schizophrenia. The objective of this study is to reveal the effect of clozapine on employment using a bidirectional mirror-image model. PATIENTS AND METHODS: This design was a retrospective observational study that investigated the employment status of patients with treatment-resistant schizophrenia based on medical records. The bidirectional mirror-image model consisted of 1) switching from other antipsychotics to clozapine and 2) switching from clozapine to other antipsychotics. The observation period was 1 year for each pre- and post-clozapine initiation and discontinuation. RESULTS: We included 36 patients in the bidirectional mirror-image model. The regular employment plus employment support rate was significantly higher in the clozapine phase than in the other antipsychotic phase in the bidirectional mirror-image model (30.6% vs 11.1%, P = 0.039). The days of regular employment plus employment support were also significantly longer in the clozapine phase (61.3 ± 106.2 vs 24.7 ± 82.7 days, P = 0.032). As per the unidirectional mirror-image model, switching to clozapine resulted in significantly higher regular employment plus employment support rates in the clozapine phase than those in the other antipsychotic phase (33.3% vs 10.0%, P = 0.039). Switching from clozapine to other antipsychotics did not exhibit significant differences in any outcomes. CONCLUSION: The results suggest that clozapine is superior to other antipsychotics with respect to achieving employment in patients with treatment-resistant schizophrenia. However, biases specific to the mirror-image model need to be considered.
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Psychiatry and clinical neurosciences 76(11) 596-598 2022年11月
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Psychiatry and clinical neurosciences 77(2) 118-119 2022年10月25日
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Biological psychiatry 92(5) 362-374 2022年9月1日BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25-0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.
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Journal of psychopharmacology (Oxford, England) 36(9) 2698811221112937-2698811221112937 2022年7月21日BACKGROUND: Although clozapine-induced granulocytopenia (CIG) is less severe than clozapine-induced agranulocytosis (CIA), and some patients with CIG may not go on to develop serious complications, clozapine is discontinued in cases of both CIA and CIG. Understanding the pathogenic mechanisms of CIA/CIG could provide better management of clozapine therapy. Recently, as a mechanistic insight into adaptive immune systems, European groups reported clozapine-specific proliferative responses and clozapine-specific T cells using blood taken from patients with CIA and/or CIG. AIMS: The aims of our study are to support this mechanistic evidence and to investigate the difference in the lymphocyte response to clozapine between patients with CIG and those with CIA. METHODS: Lymphocyte stimulation tests (LSTs) were conducted using CD25-positive cell-depleted peripheral blood-derived mononuclear cells (PBMCs) isolated from blood of four Japanese patients with CIA, four patients with CIG, and nine clozapine-tolerant subjects. RESULTS: Three of four patients with CIA and one of four patients with CIG showed proliferative responses to clozapine with a stimulation index of greater than 2. In contrast, none of the nine clozapine-tolerant subjects showed any response to clozapine. Olanzapine did not stimulate PBMCs of patients with CIA, patients with CIG, or clozapine-tolerant subjects. CONCLUSIONS: Clozapine- and CIA-specific lymphocyte reactions in a Japanese population provided supportive evidence that the pathogenesis of CIA is based on adaptive immune reactions. In addition, patients with CIG who show a positive response to an LST may at the very least not be chosen for clozapine-rechallenge and further prospective studies are desirable to verify this hypothesis.
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Psychiatry and clinical neurosciences 76(8) 361-366 2022年5月10日AIM: The genetic relationship between schizophrenia (SCZ) and other nonpsychiatric disorders remains largely unknown. We examined the shared genetic components between these disorders based on multipopulation data sets. METHODS: We used two data sets for East Asian (EAS) and European (EUR) samples. SCZ data was based on the Psychiatric Genomics Consortium Asia with our own genome-wide association study for EAS and Psychiatric Genomics Consortium for EUR. Nonpsychiatric data (20 binary traits [mainly nonpsychiatric complex disorders] and 34 quantitative traits [mainly laboratory examinations and physical characteristics]) were obtained from Biobank Japan and UK Biobank for EAS and EUR samples, respectively. To evaluate genetic correlation, linkage disequilibrium score regression analysis was utilized with further meta-analysis for each result from EAS and EUR samples to obtain robust evidence. Subsequent mendelian randomization analysis was also included to examine the causal effect. RESULTS: A significant genetic correlation between SCZ and several metabolic syndrome (MetS) traits was detected in the combined samples (meta-analysis between EAS and EUR data) (body mass index [rg = -0.10, q-value = 1.0 × 10-9 ], high-density-lipoprotein cholesterol [rg = 0.072, q-value = 2.9 × 10-3 ], blood sugar [rg = -0.068, q-value = 1.4 × 10-2 ], triglycerides [rg = -0.052, q-value = 2.4 × 10-2 ], systolic blood pressure [rg = -0.054, q-value = 3.5 × 10-2 ], and C-reactive protein [rg = -0.076, q-value = 7.8 × 10-5 ]. However, no causal relationship on SCZ susceptibility was detected for these traits based on the mendelian randomization analysis. CONCLUSION: Our results indicate shared genetic components between SCZ and MetS traits and C-reactive protein. Specifically, we found it interesting that the correlation between MetS traits and SCZ was the opposite of that expected from clinical studies: this genetic study suggests that SCZ susceptibility was associated with reduced MetS. This implied that MetS in patients with SCZ was not associated with genetic components but with environmental factors, including antipsychotics, lifestyle changes, poor diet, lack of exercise, and living conditions.
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Psychiatry research 310 114481-114481 2022年4月SETD1A has been identified as a substantial risk gene for schizophrenia. To further investigate the role of SETD1A in the genetic etiology of schizophrenia in the Japanese population, we performed resequencing and association analyses. First, we resequenced the SETD1A coding regions of 974 patients with schizophrenia. Then, we genotyped variants, prioritized via resequencing, in 2,027 patients with schizophrenia and 2,664 controls. Next, we examined the association between SETD1A and schizophrenia in 3,001 patients with schizophrenia and 2,664 controls. Finally, we performed a retrospective chart review of patients with prioritized SETD1A variants. We identified two novel missense variants (p.Ser575Pro and p.Glu857Gln) via resequencing. We did not detect these variants in 4,691 individuals via genotyping. These variants were not significantly associated with schizophrenia in the association analysis. Additionally, we found that a schizophrenia patient with the p.Glu857Gln variant had developmental delays. In conclusion, novel SETD1A missense variants were exclusively identified in Japanese patients with schizophrenia. However, our study does not provide evidence for the contribution of these variants to the genetic etiology of schizophrenia in the Japanese population.
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Frontiers in pharmacology 13 1016669-1016669 2022年The identification of pharmacogenetic factors that increase the susceptibility to clozapine-induced agranulocytosis or granulocytopenia (CIAG) has received increasing interest. The SLCO1B3-SCLO1B7 variant (rs149104283) and single amino acid changes in human leukocyte antigen (HLA) HLA-DQB1 (126Q) and HLA-B (158T) were associated with an increased risk of CIAG. In this study, we evaluated the effectiveness and cost-effectiveness of adding the SLCO1B3-SCLO1B7 to HLA variants as a new pharmacogenomic (PGx) approach and explored the evolution of a cohort of schizophrenic patients taking long-term clozapine as a third-line antipsychotic medication. The decision model included probabilistic and deterministic sensitivity analyses to assess the expected costs and quality-adjusted life-years (QALYs). The current monitoring scheme was compared with the PGx-guided strategy, where all patients underwent pre-emptively a genetic test before taking clozapine, over 10 years. By adding the SLCO1B3-SCLO1B7 variant into HLA variants, CIAG sensitivity increased from 36.0% to 43.0%, the specificity decreased from 89.0% to 86.9%, and the probability of cost-effectiveness improved from 74.1% to 87.8%. The incremental cost-effectiveness ratio was £16,215 per QALY and remained below the conventional decision threshold (£30,000 or US$50,000 per QALY). Therefore, the SLCO1B3-SCLO1B7 variant, as an additional risk allele to HLA variants, increases preemptive test sensitivity and improves the effectiveness and cost-effectiveness of PGx-guided clozapine administration.
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Translational psychiatry 11(1) 362-362 2021年7月7日Pharmacogenetics/pharmacogenomics have enabled the detection of risk of human leukocyte antigen (HLA) variants for clozapine-induced agranulocytosis/granulocytopenia (CIAG). To apply this evidence to the clinical setting, we compared the cost-effectiveness of the proposed "HLA-guided treatment schedule" and the "current schedule" being used in Japan and the United Kingdom (UK) (absolute neutrophil count (ANC) cutoff at 1500/mm3); in the "HLA-guided treatment schedules," we considered a situation wherein the HLA test performed before clozapine initiation could provide "a priori information" by detecting patients harboring risk of HLA variants (HLA-B*59:01 and "HLA-B 158T/HLA-DQB1 126Q" for Japanese and Caucasian populations, respectively), a part of whom can then avoid CIAG onset (assumed 30% "prevention rate"). For the primary analysis, we estimated the incremental cost-effectiveness ratio (ICER) of "HLA-guided treatment schedule" and "current schedule" used in Japan and the UK, using a Markov model to calculate the cost and quality-adjusted life years (QALYs) over a 10-year time period. Furthermore, as an explorative analysis, we simulated several situations with various ANC cutoffs (1000/mm3 and 500/mm3) and plotted the cost/QALYs for each option to identify the best, or estimate the next best candidate option applicable in actual clinical settings. The primary probabilistic analysis showed that the "HLA-guided treatment schedule" was more cost effective than the "current schedule"; the ICER was £20,995 and £21,373 for the Japanese and the UK populations, respectively. Additional simulation revealed that the treatment option of ANC cutoff at 500/mm3 without HLA screening was the most cost-effective option; however, several options may be candidates to break away from the "current schedule" of ANC cutoff at 1500/mm3. Owing to its cost-effectiveness, we propose such pharmacogenetic-guided/pharmacogenomic-guided clozapine treatment for use in the real-world setting, which provides key information for optimization of clinical guidelines for high-risk patients for gradual change of clozapine treatment schedule under the safety consideration.
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Nature genetics 53(6) 817-829 2021年6月Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
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Translational Psychiatry 11(1) 2021年6月<title>Abstract</title><italic>SLC6A4</italic>, which encodes the serotonin transporter, has a functional polymorphism called the serotonin transporter-linked polymorphic region (5-HTTLPR). The 5-HTTLPR consists of short (S) and long (L) alleles, each of which has 14 or 16 tandem repeats. In addition, the extralong (XL) and other rare alleles have been reported in 5-HTTLPR. Although they are more frequent in Asian and African than in other populations, the extent of variations and allele frequencies (AFs) were not addressed in a large population. Here, we report the AFs of the rare alleles in a large number of Japanese subjects (<italic>N</italic> = 2894) consisting of two cohorts. The first cohort (case-control study set, CCSS) consisted of 1366 subjects, including 485 controls and 881 patients with psychosis (bipolar disorder or schizophrenia). The second cohort (the Arao cohort study set, ACSS) consisted of 1528 elderly subjects. During genotyping, we identified 11 novel 5-HTTLPR alleles, including 3 XL alleles. One novel allele had the longest subunit ever reported, consisting of 28 tandem repeats. We named this XL28-A. An in vitro luciferase assay revealed that XL28-A has no transcriptional activity. XL28-A was found in two unrelated patients with bipolar disorder in the CCSS and one healthy subject in the ACSS who did not show depressive symptoms or a decline in cognitive function. Therefore, it is unlikely that XL28-A is associated with psychiatric disorders, despite its apparent functional deficit. Our results suggest that unraveling the complex genetic variations of 5-HTTLPR will be important for further understanding its role in psychiatric disorders.
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Brain, behavior, and immunity 94 471-471 2021年5月
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精神医学の基盤 5(1) 137-144 2021年4月統合失調症は有病率が約1%のありふれた疾患(コモンディジーズ)であり、遺伝的要因の関与が大きいこと(遺伝率約80%)が以前から指摘されている。ただし、1990年代に普及した連鎖解析や候補遺伝子の関連解析では、目立だった結果は得られなかった。しかし、2000年代後半に普及した全ゲノム関連解析(GWAS:Genome Wide Association Study)という方法論は革命的な結果をもたらし、統合失調症を含めた精神疾患でも多くの疾患感受性遺伝子が同定されるようになった。GWASでは数10万から100万以上という膨大な一塩基多型(SNP:Single Nucleotide Polymorphism)を網羅的に解析することが可能となり、100を超える遺伝領域が有意と報告されている。しかし、その一つ一つに焦点を当てるとその効果量は小さく、それら「小さい効果量の感受性SNP」の集合体が相加的に作用し、発症に寄与するPolygenic modelという仮説が一定の支持を集めている。本稿では統合失調症のゲノム研究、特にSNPやコピー数変異(CNV:Copy Number Variant)についての説明や現時点での研究成果を概説する。さらに多遺伝子リスクスコア(PRS:polygenic risk score)などのゲノム研究の臨床応用や今後の展望についても紹介する。(著者抄録)
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Frontiers in Genetics 12 2021年3月18日Variability in the enzymatic activity of <italic>N</italic>-acetyltransferase 2 (NAT2) is an important contributor to interindividual differences in drug responses. However, there is little information on functional differences in <italic>N</italic>-acetylation activities according to NAT2 phenotypes, i.e., rapid, intermediate, slow, and ultra-slow acetylators, between different substrate drugs. Here, we estimated <italic>NAT2</italic> genotypes in 990 Japanese individuals and compared the frequencies of different genotypes with those of different populations. We then calculated <italic>in vitro</italic> kinetic parameters of four NAT2 alleles (NAT2∗4, ∗5, ∗6, and ∗7) for <italic>N</italic>-acetylation of aminoglutethimide, diaminodiphenyl sulfone, hydralazine, isoniazid, phenelzine, procaineamide, sulfamethazine (SMZ), and sulfapyrizine. NAT2∗5, ∗6, and ∗7 exhibited significantly reduced <italic>N</italic>-acetylation activities with lower Vmax and CLint values of all drugs when compared with NAT2∗4. Hierarchical clustering analysis revealed that 10 <italic>NAT2</italic> genotypes were categorized into three or four clusters. According to the results of <italic>in vitro</italic> metabolic experiments using SMZ as a substrate, the frequencies of ultra-slow acetylators were calculated to be 29.05–54.27% in Europeans, Africans, and South East Asians, whereas Japanese and East Asian populations showed lower frequencies (4.75 and 11.11%, respectively). Our findings will be helpful for prediction of responses to drugs primarily metabolized by NAT2.
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臨床精神薬理 24(2) 145-149 2021年2月Clozapineは治療抵抗性統合失調症に対して適応がある唯一の薬剤である。しかし、clozapine誘発性無顆粒球症が1%程度の頻度で認められるために、使用頻度は低い。より安全に使用できるように副作用に対する薬理遺伝学・ゲノム学的研究はなされ、遺伝的リスクの同定は進んでいるが、感度が低いために、ゲノムバイオマーカーとして無顆粒球症の発症リスクを事前に推定し、完全に防ぐことが難しいこともわかっている。しかし費用対効果分析の視点を用いることで、これらの遺伝的リスクを用いた遺伝子検査が、患者のリスクを事前に見積もり、そして患者を層別化することで、臨床に役立つ可能性も十分有り得ることがわかった。遺伝子検査を用いることで、clozapineの安全性が向上し、患者と精神科医が安心してclozapineを使用できるようになり、治療抵抗性統合失調症患者の症状改善に繋がる。(著者抄録)
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臨床精神薬理 24(1) 13-20 2021年1月近年、全ゲノム関連解析(GWAS)では数千〜数十万人という大規模なサンプルと数十万のsingle nucleotide polymorphisms(SNP)データを用いることにより、多くの疾患の疾患感受性遺伝子の同定に成功している。精神疾患においてもGWASにより疾患感受性遺伝子の同定がなされており、特に統合失調症、双極性障害、うつ病において大きな成功を収めている。さらに、GAWSから得られたデータに基づいて算出されるpolygenic risk score(PRS)が、疾患の発症予測や薬剤の選択に役立つ可能性が示されている。本稿ではPRSが精神疾患の診断や薬物療法などの治療の選択に寄与するのかについて検討し、その課題と展望について述べる。(著者抄録)
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Journal of human genetics 66(1) 53-60 2021年1月Genome-wide association studies (GWASs) have detected many susceptible variants for common diseases, including psychiatric disorders. However, because of the small effect size of each variant, clinical utility that aims for risk prediction and/or diagnostic assistance based on the individual "variants" is difficult to use. Therefore, to improve the statistical power, polygenic risk score (PRS) has been established and applied in the GWAS as a robust analytic tool. Although PRS has potential predictive ability, because of its current "insufficient" discriminative power at the individual level for clinical use, it remains limited solely in the research area, specifically in the psychiatric field. For a better understanding of the PRS, in this review, we (1) introduce the clinical features of psychiatric disorders, (2) summarize the recent GWAS/PRS findings in the psychiatric disorders, (3) evaluate the problems of PRS, and (4) propose its possible utility to apply PRS into the psychiatric clinical setting.
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Schizophrenia Bulletin 2020年6月19日 査読有り<title>Abstract</title> Associations between altered DNA methylation of the serotonin transporter (5-HTT)-encoding gene SLC6A4 and early life adversity, mood and anxiety disorders, and amygdala reactivity have been reported. However, few studies have examined epigenetic alterations of SLC6A4 in schizophrenia (SZ). We examined CpG sites of SLC6A4, whose DNA methylation levels have been reported to be altered in bipolar disorder, using 3 independent cohorts of patients with SZ and age-matched controls. We found significant hypermethylation of a CpG site in SLC6A4 in male patients with SZ in all 3 cohorts. We showed that chronic administration of risperidone did not affect the DNA methylation status at this CpG site using common marmosets, and that in vitro DNA methylation at this CpG site diminished the promoter activity of SLC6A4. We then genotyped the 5-HTT-linked polymorphic region (5-HTTLPR) and investigated the relationship among 5-HTTLPR, DNA methylation, and amygdala volume using brain imaging data. We found that patients harboring low-activity 5-HTTLPR alleles showed hypermethylation and they showed a negative correlation between DNA methylation levels and left amygdala volumes. These results suggest that hypermethylation of the CpG site in SLC6A4 is involved in the pathophysiology of SZ, especially in male patients harboring low-activity 5-HTTLPR alleles.
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Aust N Z J Psychiatry 54(5) 545-546 2020年5月 査読有り
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実験医学 38(4) 556-559 2020年3月代表的な精神疾患である双極性障害は遺伝要因が強く寄与する疾患であり、ゲノムワイド関連研究が導入されて以降、現在までに数十個の有意な関連領域が報告されている。そのなかでも、脂質代謝に重要な役割を示すfatty acid desaturase(FADS)遺伝子関連は、機能がきわめて明確な感受性遺伝子であり、この結果は双極性障害の脂質代謝異常仮説を支持するものである。事実、双極性障害患者でみられる脂質代謝異常(メタボリック症候群を含む)は、複数報告されており、その基盤となりうる結果とも言える。本稿では、双極性障害のゲノム研究を概説するとともに、この「双極性障害の脂質異常仮説」にも焦点を当て概説する。(著者抄録)
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PloS one 15(10) e0240466 2020年Depressive symptoms are a serious problem in workplaces. Hospital staff members, such as newly licensed registered nurses (NLRNs), are at particularly increased risk of these symptoms owing to their limited experience. Previous studies have shown that a brief program-based cognitive behavioral therapy program (CBP) can offer effective treatment. Here, we conducted a longitudinal observational study of 683 NLRNs (CBP group, n = 522; no-CBP group, n = 181) over a period of 1 year (six times surveys were done during this period). Outcomes were assessed on the basis of surveys that covered the Beck Depression Inventory-I (BDI). The independent variables were CBP attendance (CBP was conducted 3 months after starting work), personality traits, personal stressful life events, workplace adversity, and pre-CBP change in BDI in the 3 months before CBP (ΔBDIpre-CBP). All factors were included in Cox proportional hazards models with time-dependent covariates for depressive symptoms (BDI ≥10), and we reported hazard ratios (HRs). Based on this analysis, we detected that CBP was significantly associated with benefit for depressive symptoms in all NLRNs (Puncorrected = 0.0137, HR = 0.902). To identify who benefitted most from CBP, we conducted a subgroup analysis based on the change in BDI before CBP (ΔBDIpre-CBP). The strongest association was when BDI scores were low after starting work and increased before CBP (Puncorrected = 0.00627, HR = 0.616). These results are consistent with previous findings, and indicate that CBP may benefit the mental health of NLRNs. Furthermore, selective prevention based on the pattern of BDI change over time may be important in identifying who should be offered CBP first. Although CBP is generally effective for all nurses, such a selective approach may be most appropriate where cost-effectiveness is a prominent concern.
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Prog Neuropsychopharmacol Biol Psychiatry 99 109855-109855 2020年1月 査読有りAccumulating evidence suggests that aberrant epigenetic regulation is involved in the pathophysiology of major psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BD). We previously showed that the plasma level of betaine (N,N,N-trimethylglycine), a methyl-group donor, was significantly decreased in patients with first episode schizophrenia (FESZ). In this study, we identified decrease of global DNA methylation level in FESZ (N = 24 patients vs N = 42 controls), and found that global DNA methylation level was inversely correlated with scores on the global assessment of functioning (GAF) scale, and positively correlated with plasma betaine level. Notably, correlations between levels of betaine and its metabolites (N,N-dimethylglycine and sarcosine, N-methylglycine) were lower or lost in FESZ plasma, but remained high in controls. We further examined global DNA methylation levels in patients with chronic SZ (N = 388) and BD (N = 414) as well as controls (N = 430), and confirmed significant hypomethylation and decreased betaine level in SZ. We also found that patients with BD type I, but not those with BD type II, showed significant global hypomethylation. These results suggest that global hypomethylation associated with decreased betaine level in blood cells is common to SZ and BD, and may reflect common pathophysiology such as psychotic symptoms.
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Psychiatry and clinical neurosciences 74(1) 35-39 2019年8月 査読有り
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Schizophrenia bulletin 45(4) 824-834 2019年6月18日 査読有りGenome-wide association studies (GWASs) have identified >100 susceptibility loci for schizophrenia (SCZ) and demonstrated that SCZ is a polygenic disorder determined by numerous genetic variants but with small effect size. We conducted a GWAS in the Japanese (JPN) population (a) to detect novel SCZ-susceptibility genes and (b) to examine the shared genetic risk of SCZ across (East Asian [EAS] and European [EUR]) populations and/or that of trans-diseases (SCZ, bipolar disorder [BD], and major depressive disorder [MDD]) within EAS and between EAS and EUR (trans-diseases/populations). Among the discovery GWAS subjects (JPN-SCZ GWAS: 1940 SCZ cases and 7408 controls) and replication dataset (4071 SCZ cases and 54479 controls), both comprising JPN populations, 3 novel susceptibility loci for SCZ were identified: SPHKAP (Pbest = 4.1 × 10-10), SLC38A3 (Pbest = 5.7 × 10-10), and CABP1-ACADS (Pbest = 9.8 × 10-9). Subsequent meta-analysis between our samples and those of the Psychiatric GWAS Consortium (PGC; EUR samples) and another study detected 12 additional susceptibility loci. Polygenic risk score (PRS) prediction revealed a shared genetic risk of SCZ across populations (Pbest = 4.0 × 10-11) and between SCZ and BD in the JPN population (P ~ 10-40); however, a lower variance-explained was noted between JPN-SCZ GWAS and PGC-BD or MDD within/across populations. Genetic correlation analysis supported the PRS results; the genetic correlation between JPN-SCZ and PGC-SCZ was ρ = 0.58, whereas a similar/lower correlation was observed between the trans-diseases (JPN-SCZ vs JPN-BD/EAS-MDD, rg = 0.56/0.29) or trans-diseases/populations (JPN-SCZ vs PGC-BD/MDD, ρ = 0.38/0.12). In conclusion, (a) Fifteen novel loci are possible susceptibility genes for SCZ and (b) SCZ "risk" effect is shared with other psychiatric disorders even across populations.
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Psychological Medicine 48(10) 1745-1748 2018年7月1日 査読有り
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Psychiatry and clinical neurosciences 72(4) 245-254 2018年4月 査読有りAIM: Schizophrenia (SZ) and bipolar disorder (BD) have been known to share genetic and environmental risk factors, and complex gene-environmental interactions may contribute to their pathophysiology. In contrast to high genetic overlap between SZ and BD, as revealed by genome-wide association studies, the extent of epigenetic overlap remains largely unknown. In the present study, we explored whether SZ and BD share epigenetic risk factors in the same manner as they share genetic components. METHODS: We performed DNA methylation analyses of the CpG sites in the top five candidate regions (FAM63B, ARHGAP26, CTAGE11P, TBC1D22A, and intergenic region [IR] on chromosome 16) reported in a previous methylome-wide association study (MWAS) of SZ, using whole blood samples from subjects with BD and controls. RESULTS: Among the five candidate regions, the CpG sites in FAM63B and IR on chromosome 16 were significantly hypomethylated in the samples from subjects with BD as well as those from subjects with SZ. On the other hand, the CpG sites in TBC1D22A were hypermethylated in the samples from subjects with BD, in contrast to hypomethylation in the samples from subjects with SZ. CONCLUSION: Hypomethylation of FAM63B and IR on chromosome 16 could be common epigenetic risk factors for SZ and BD. Further comprehensive epigenetic studies for BD, such as MWAS, will uncover the extent of similarity and uniqueness of epigenetic alterations.
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Psychiatry and Clinical Neurosciences 72(2) 52-63 2018年2月1日 査読有りRecent advances in molecular genetics have enabled assessments of the associations among genetic variants (e.g., single-nucleotide polymorphisms) and susceptibility for complex diseases, including psychiatric disorders. Specifically, genome-wide association studies (GWAS), meta-analyses of the GWAS summary statistics, and mega-analyses (which use raw data, not summary statistics) of GWAS have provided revolutionary results and have identified numerous susceptibility genes or single-nucleotide polymorphisms. By using several tens of thousands of subjects, > 40 genes have been identified as being associated with susceptibility for bipolar disorder so far. The purpose of this systematic review was to summarize the recent findings of bipolar disorder GWAS and discuss their clinical implications.
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Biological psychiatry 82(1) e9-e10-e10 2017年7月1日 査読有り
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PSYCHIATRY AND CLINICAL NEUROSCIENCES 71(4) 289-290 2017年4月 査読有り
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PSYCHIATRY AND CLINICAL NEUROSCIENCES 70(11) 489-497 2016年11月 査読有りAim: Pegylated interferon (PegIFN) therapies for hepatitis C virus (HCV) infection often induce a depressive state. This study aimed to identify the risk factors for and clinical characteristics of PegIFN-induced depressive state. Methods: Sixty-nine subjects with HCV who received PegIFN therapy were enrolled. Before beginning therapy, all subjects were evaluated using the Neuroticism-Extraversion-Openness Five-Factor Inventory and the List of Threatening Events Questionnaire. Beck Depression Inventory (BDI) scores were also evaluated at baseline, 2-4 weeks after initiating therapy, and every 4 weeks thereafter. Results: During the study, 18 subjects (24.3%) developed a depressive state (BDI >= 10). A bimodal peak of onset was observed during the early (28 weeks) and late (after 20 weeks) therapy phases. Moreover, we observed that baseline BDI scores (odds ratio [OR] = 1.40, P = 0.0104) and neuroticism (OR = 1.14, P = 0.0275) were significant risk factors for developing a depressive state. To determine the specific characteristics of this condition, we compared the BDI subscales between the 'PegIFN-induced' and 'general' depressive state reported previously. We found that the score at 'somatic symptoms' was higher in the 'PegIFN-induced' group. Conclusion: Our results indicate the following: (i) PegIFN-induced depressive state most frequently develops during the first 8 weeks of therapy; (ii) baseline BDI and neuroticism scores are risk factors for PegIFN-induced depressive state; and (iii) the core symptoms of PegIFN-induced depressive state are different from those of 'general' depression.
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Pharmacogenomic Study of Clozapine-Induced Agranulocytosis/Granulocytopenia in a Japanese PopulationBIOLOGICAL PSYCHIATRY 80(8) 636-642 2016年10月 査読有りBACKGROUND: Clozapine-induced agranulocytosis (CIA)/clozapine-induced granulocytopenia (CIG) (CIAG) is a life-threatening event for schizophrenic subjects treated with clozapine. METHODS: To examine the genetic factor for CIAG, a genome-wide pharmacogenomic analysis was conducted using 50 subjects with CIAG and 2905 control subjects. RESULTS: We identified a significant association in the human leukocyte antigen (HLA) region (rs1800625, p = 3.46 x 10(-9), odds ratio [OR] = 3.8); therefore, subsequent HLA typing was performed. We detected a significant association of HLA-B*59:01 with CIAG (p = 3.81 x 10(-8), OR = 10.7) and confirmed this association by comparing with an independent clozapine-tolerant control group (n = 380, p = 2.97 x 10(-5), OR = 6.3). As we observed that the OR of CIA (OR: 9.3 similar to 15.8) was approximately double that in CIG (OR: 4.4 similar to 7.4), we hypothesized that the CIG subjects were a mixed population of those who potentially would develop CIA and those who would not develop CIA (non-CIA). This hypothesis allowed the proportion of the CIG who were non-CIA to be calculated, enabling us to estimate the positive predictive value of the nonrisk allele on non-CIA in CIG subjects. Assuming this model, we estimated that 1) similar to 50% of CIG subjects would be non-CIA; and 2) similar to 60% of the CIG subjects without the risk allele would be non-CIA and therefore not expected to develop CIA. CONCLUSIONS: Our results suggest that HLA-B*59:01 is a risk factor for CIAG in the Japanese population. Furthermore, if our model is true, the results suggest that rechallenging certain CIG subjects with clozapine may not be always contraindicated.
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AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS 171(6) 797-805 2016年9月 査読有りRare genomic variations inherited in multiplex schizophrenia families are suggested to play a role in the genetic etiology of the disease. To identify rare variations with large effects on the risk of developing schizophrenia, we performed whole-exome sequencing (WES) in two affected and one unaffected individual of a multiplex family with 10 affected individuals. We also performed follow-up resequencing of the unc-13 homolog B (Caenorhabditis elegans) (UNC13B) gene, a potential risk gene identified by WES, in the multiplex family and undertook a case-control study to investigate association between UNC13B and schizophrenia. UNC13B coding regions (39 exons) from 15 individuals of the multiplex family and 111 affected offspring for whom parental DNA samples were available were resequenced. Rare missense UNC13B variations identified by resequencing were further tested for association with schizophrenia in two independent case-control populations comprising a total of 1,753 patients and 1,602 controls. A rare missense variation (V1525M) in UNC13B was identified by WES in the multiplex family; this variation was present in five of six affected individuals, but not in eight unaffected individuals or one individual of unknown disease status. Resequencing UNC13B coding regions identified five rare missense variations (T103M, M813T, P1349T, I1362T, and V1525M). In the case-control study, there was no significant association between rare missense UNC13B variations and schizophrenia, although single-variant meta-analysis indicated that M813T was nominally associated with schizophrenia. These results do not support a contribution of rare missense UNC13B variations to the genetic etiology of schizophrenia in the Japanese population. (c) 2016 Wiley Periodicals, Inc.
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PSYCHIATRY RESEARCH 235 13-18 2016年1月 査読有りRare inherited variations in multiplex families with schizophrenia are suggested to play a role in the genetic etiology of schizophrenia. To further investigate the role of rare inherited variations, we performed whole-exome sequencing (WES) in three families, each with two affected siblings. We also performed a three-stage follow-up case-control study in a Japanese population with a total of 2617 patients and 2396 controls. WES identified 15 rare truncating variations that were variously present in the two affected siblings in each family. These variations did not necessarily segregate with schizophrenia within families, and they were different in each family. In the follow-up study, four variations (NWDI W169X, LCORL R7fsX53, CAMK2B L497fsX497, and C9orf89 Q102X) had a higher mutant allele frequency in patients compared with controls, although these associations were not significant in the combined population, which comprised the first-, second- and third-stage populations. These results do not support a contribution of the rare truncating variations identified in the three families to the genetic etiology of schizophrenia. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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JOURNAL OF CLINICAL PSYCHIATRY 77(1) E29-+ 2016年1月 査読有り
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JOURNAL OF HUMAN GENETICS 60(6) 343-344 2015年6月 査読有り
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JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY 35(1) 85-88 2015年2月 査読有り
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PLOS ONE 9(12) e115135 2014年12月 査読有りGenome-wide association studies (GWASs) have identified a number of susceptibility genes for schizophrenia (SCZ) and bipolar disorder (BD). However, the identification of risk genes for major depressive disorder (MDD) has been unsuccessful because the etiology of MDD is more influenced by environmental factors; thus, gene-environment (G x E) interactions are important, such as interplay with stressful life events (SLEs). We assessed the GxE interactions and main effects of genes targeting depressive symptoms. Using a case-control design, 922 hospital staff members were evaluated for depressive symptoms according to Beck Depressive Inventory (BDI; "depression" and "control" groups were classified by scores of 10 in the BDI test), SLEs, and personality. A total of sixty-three genetic variants were selected on the basis of previous GWASs of MDD, SCZ, and BD as well as candidate-gene (SLC6A4, BDNF, DBH, and FKBP5) studies. Logistic regression analysis revealed a marginally significant interaction (genetic variant x SLE) at rs4523957 (P-uncorrected = 0.0034) with depression and a significant association of single nucleotide polymorphism identified from evidence of BD GWAS (rs7296288, downstream of DHH at 12q13.1) with depression as the main effect (P-uncorrected = 9.4x10(-4), P-corrected = 0.0424). We also found that SLEs had a larger impact on depression (odds ratio similar to 3), as reported previously. These results suggest that DHH plays a possible role in depression etiology; however, variants from MDD or SCZ GWAS evidence or candidate genes showed no significant associations or minimal effects of interactions with SLEs on depression.
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AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS 165(5) 421-427 2014年7月 査読有りRecent genome-wide association studies (GWASs) of schizophrenia (SCZ) identified several susceptibility genes and suggested shared genetic components between SCZ and bipolar disorder (BD). We conducted a genetic association study of single nucleotide polymorphisms (SNPs) selected according to previous SCZGWA Stargeting psychotic disorders (SCZ and BD) in the Japanese population. Fifty-one SNPs were analyzed in a two-stage design using first-set screening samples (all SNPs: 1,032 SCZ, 1,012 BD, and 993 controls) and second-set replication samples ("significant" SNPs in the first-set screening analysis: 1,808 SCZ, 821 BD, and 2,321 controls). We assessed allelic associations between the selected SNPs and the three phenotypes (SCZ, BD, and "psychosis" [SCZ + BD]). Nine SNPs revealed nominal association signals for all comparisons (P-uncorrected < 0.05), of which two SNPs located in the major histocompatibility complex region (rs7759855 in zincfinger and SCAN domain containing 31 [ZSCAN31] and rs1736913 in HLA-F antisense RNA1 [HLA-F-AS1]) were further assessed in the second-set replication samples. The associations were confirmed for rs7759855 (P-corrected = 0.026 for psychosis; P-corrected = 0.032 for SCZ), although the direction of effect was opposite to that in the original GWAS of the Chinese population. Finally, a meta-analysis was conducted using our two samples and using our data and data from Psychiatric GWAS Consortium (PGC), which have shown the same direction of effect. SNP in ZSCAN31 (rs7759855) had the strongest association with the phenotypes (best P = 6.8 x 10(-5) for psychosis: present plus PGC results). These data support shared risk SNPs between SCZ and BD in the Japanese population and association between MHC and psychosis. (C) 2014 Wiley Periodicals, Inc.
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JOURNAL OF HUMAN GENETICS 59(1) 54-56 2014年1月 査読有りSeveral epidemiological and genetic studies have suggested that the risk of type II diabetes (T2D) is likely to overlap with the susceptibility to psychotic disorders such as schizophrenia (SCZ) and bipolar disorder (BD). In this study, we aimed to examine the association of single-nucleotide polymorphisms (SNPs) detected in previous T2D genome-wide association studies (GWAS) with SCZ, BD and psychosis (SCZ plus BD). A total of 37 SNPs were selected from the literature. A two-stage analysis was conducted using a first set of screening samples (total N = 3037) and a second set of replication samples (N = 4950). None of the SNPs showed a significant association to the screening samples after correction for multiple testing. To avoid type II error, we genotyped the top three SNPs in BCL11A, HMG20A and HNF4A showing associations with any of the phenotypes (P-uncorrected<0.01) using independent samples to replicate the nominal associations. However, we were unable to find any significant associations based on the screening results (P-uncorrected>0.05). Our findings did not support the shared genetic risk between T2D and psychotic disorders in the Japanese population. However, further replication using a larger sample size is required.
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JOURNAL OF HUMAN GENETICS 58(8) 568-569 2013年8月 査読有り
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PLOS ONE 8(8) 2013年8月 査読有りBackground: Recent genome-wide association studies (GWASs) investigating bipolar disorder (BD) have detected a number of susceptibility genes. These studies have also provided novel insight into shared genetic components between BD and schizophrenia (SCZ), two major psychotic disorders. To examine the replication of the risk variants for BD and the pleiotropic effect of the variants associated with BD, we conducted a genetic association study of single nucleotide polymorphisms (SNPs) that were selected based upon previous BD GWASs, which targeted psychotic disorders (BD and SCZ) in the Japanese population. Methods: Forty-eight SNPs were selected based upon previous GWASs. A two-stage analysis was conducted using first-set screening (for all SNPs: BD = 1,012, SCZ = 1,032 and control = 993) and second-set replication samples (for significant SNPs in the screening analysis: BD = 821, SCZ = 1,808 and control = 2,149). We assessed allelic association between BD, SCZ, psychosis (BD+SCZ) and the SNPs selected for the analysis. Results: Eight SNPs revealed nominal association signals for all comparisons (P-uncorrected<0.05). Among these SNPs, the top two SNPs (associated with psychosis: P-corrected = 0.048 and 0.037 for rs2251219 and rs2709722, respectively) were further assessed in the second-set samples, and we replicated the signals from the initial screening analysis (associated with psychosis: P-corrected = 0.0070 and 0.033 for rs2251219 and rs2709722, respectively). The meta-analysis between the current and previous GWAS results showed that rs2251219 in Polybromo1 (PBRM1) was significant on genome-wide association level (P = 5x10(-8)) only for BD (P = 9.4x10(-9)) and psychosis (P = 2.0x10(-10)). Although the association of rs2709722 in Sp8 transcription factor (SP8) was suggestive in the Asian population (P = 2.1x10(-7) for psychosis), this signal weakened when the samples size was increased by including data from a Caucasian population (P = 4.3x10(-3)). Conclusions: We found 3p21.1 (including PBRM1, strong linkage disequilibrium made it difficult to pinpoint the risk genes) and SP8 as risk loci for BD, SCZ and psychosis. Further replication studies will be required for conclusive results.
MISC
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精神科臨床Legato 7(3) 140-144 2021年12月統合失調症の病態は依然として不明のままであり、現在に至るまでさまざまな切り口から多くの研究がなされてきた。近年、全ゲノム関連研究(genome-wide association study;GWAS)は疾患感受性遺伝子同定に大きく寄与し、病態研究の新たなヒントを与えている。本稿では統合失調症GWASの成果について触れる。(著者抄録)
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日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集 29回・49回 124-124 2019年10月
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精神神経学雑誌 121(4) 251-258 2019年4月統合失調症(SZ)と双極性障害(BD)は遺伝要因と環境要因を共有することが知られており,複雑な遺伝環境相互作用が発症に関与すると考えられている.ゲノムワイド関連解析の結果,主要な精神疾患のなかでもSZとBDは遺伝要因の重なりが特に大きいことが知られているが,エピゲノム要因の重なりについては十分な検討がなされていない.本研究では,SZで行われた大規模なゲノムワイドメチル化関連解析(MWAS)で同定された上位5ヶ所の候補領域について,BD試料を用いた検討を行った.5ヶ所の候補領域のうち2ヶ所[FAM63B,染色体16番intergenic領域(IR in chr 16)]では,SZと同様に,BDにおいても有意な低メチル化状態が認められ,SZとBDに共通なエピゲノム要因である可能性が示唆された.また,1ヶ所(TBC1D22A)の領域では,SZとは異なり,BDでは健常者に比して有意な高メチル化状態が認められた.今後,BDを対象とした大規模なMWASによって,両疾患におけるエピゲノム要因の類似性や独自性の詳細がさらに明らかとなるであろう.(著者抄録)
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精神神経学雑誌 121(4) 251-258 2019年4月統合失調症(SZ)と双極性障害(BD)は遺伝要因と環境要因を共有することが知られており,複雑な遺伝環境相互作用が発症に関与すると考えられている.ゲノムワイド関連解析の結果,主要な精神疾患のなかでもSZとBDは遺伝要因の重なりが特に大きいことが知られているが,エピゲノム要因の重なりについては十分な検討がなされていない.本研究では,SZで行われた大規模なゲノムワイドメチル化関連解析(MWAS)で同定された上位5ヶ所の候補領域について,BD試料を用いた検討を行った.5ヶ所の候補領域のうち2ヶ所[FAM63B,染色体16番intergenic領域(IR in chr 16)]では,SZと同様に,BDにおいても有意な低メチル化状態が認められ,SZとBDに共通なエピゲノム要因である可能性が示唆された.また,1ヶ所(TBC1D22A)の領域では,SZとは異なり,BDでは健常者に比して有意な高メチル化状態が認められた.今後,BDを対象とした大規模なMWASによって,両疾患におけるエピゲノム要因の類似性や独自性の詳細がさらに明らかとなるであろう.(著者抄録)
共同研究・競争的資金等の研究課題
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日本学術振興会 科学研究費助成事業 2021年4月 - 2024年3月
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日本学術振興会 科学研究費助成事業 若手研究 2018年4月 - 2019年3月
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日本学術振興会 科学研究費助成事業 若手研究（Ｂ） 2016年4月 - 2018年3月