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大塚 郁夫大学院医学研究科 医科学専攻准教授
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■ 論文- BackgroundMild cognitive impairment (MCI) is an intermediate stage between normal aging and dementia. Not a small number of patients with MCI progress to Alzheimer's disease within 1 year. Epigenetic changes in DNA methylation, such as those observed in the epigenetic clock, are receiving increasing attention in the field of aging research. It is crucial to demonstrate the effectiveness of interventions for patients with MCI from a biological perspective to promote the prevention of dementia.ObjectiveWe conducted epigenetic clock analysis, mainly longitudinal evaluation, on patients with MCI who received intervention with vitamin D and/or marine omega-3 fatty acid supplements.MethodsWe conducted epigenetic clock analyses with public DNA methylation datasets from the Gene Expression Omnibus database. This dataset contains two timepoints' longitudinal DNA methylation data of 25 patients with MCI and 20 controls. They received two-year intervention with vitamin D and/or marine omega-3 fatty acid supplements. We conducted comparative analyses with Wilcoxon signed-rank test, and regression analyses of three models.ResultsIn patients with MCI, PhenoAge and GrimAge significantly decelerated after the intervention in comparative analyses. These clocks nominally significantly decelerated also in most of regression analyses. Moreover, natural killer cells showed significant differences before and after the intervention.ConclusionsWe found deceleration of some epigenetic clocks in patients with MCI with interventions. We believe that it is crucial to conduct additional epigenetic clock analyses in cohorts with larger sample sizes or in cohorts with interventions such as occupational therapy and pharmacotherapy are actively conducted.2025年07月, Journal of Alzheimer's disease : JAD, 13872877251360230 - 13872877251360230, 英語, 国際誌研究論文（学術雑誌）
- While numerous studies have examined the subjective response to alcohol as an intermediate phenotype to understand its variability, heritability, and predictive capacity for alcohol-related disorders, in-depth analyses linking alcohol reactivity indicators to genetic factors within a large cohort have been absent. Our study aimed to quantify the exact contribution of each genetic variant relevant to the alcohol metabolism to the variability in alcohol response. Specifically, we focused on two primary genes involved in alcohol metabolism (ALDH2 and ADH1B) and three additional loci (ALDH1B1, ALDH1A1, and GCKR) that have been shown to have significant associations with drinking behaviors in Japanese individuals. We conducted the first study to assess the relationship between subjective response to alcohol (SR), evaluated by various assessment subscales, and genetic factors using an intravenous clamp technique in 429 healthy Japanese young adults. By reducing the dimensionality of the data to assess similarity structures, we identified three distinct clusters of SRs and participants. Each participant cluster exhibited a distinct alcohol response profile shaped by specific genetic contributions. Participant cluster 1 demonstrated the strongest response, followed by participant cluster 2, and then participant cluster 3. Participant cluster 1 may also be the most strongly influenced by the allelic status of ALDH2 and ADH1B. SR patterns varied accordingly, and the enrichment of the ALDH2*2 and ADH1B*2, differed across both participant and subscale clusters. Notably, the three participant clusters closely aligned with the three subscale clusters, highlighting a consistent genotype-phenotype relationship. Furthermore, the proportion of variance explained by these genes also varied across subscale clusters. Contrary to known functions, ADH1B showed associations at later timings when ALDH2 associations attenuate. Our three-cluster classification may improve prevention by enabling early identification of individuals at health risk.2025年06月, Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Mosaic chromosomal alterations (mCAs) are classified as mosaic deletions (loss), copy-neutral loss of heterozygosity (CN-LOH), and duplications (gain), attracting special attention as biological aging-related acquired genetic alterations. While these mCAs have been linked with aging and various diseases, no study has investigated their association with suicide risk which is associated with abnormal biological aging. Here, we examined the association between suicide deaths and mCAs, including mosaic loss of the X (mLOX) and Y chromosomes, by leveraging blood-derived single nucleotide polymorphism-array data. The first (410 suicide decedents and 88,870 controls) and the second (363 suicide decedents and 88,870 controls) cohorts were analyzed and integrated using meta-analyses (773 suicide decedents and 177,740 controls). Total mCAs in autosomal chromosomes were significantly increased in suicide (p = 1.28 × 10-6, odds ratio [OR] = 1.78), mostly driven by loss (p = 4.05 × 10-9, OR = 2.70) and gain (p = 1.08 × 10-3, OR = 2.23). mLOX were significantly increased in female suicide (p = 2.66 × 10-21, OR = 4.00). The directions of effects of all mCAs in autosomal and sex chromosomes on suicide were the same in the first and second sets. Subgroup analyses suggest that our findings were mostly driven by suicide itself, and not confounded by comorbid psychiatric disorders or physical diseases, smoking status, sample location, or postmortem sample status. In conclusion, we provide the first evidence for aberrant mCAs in somatic autosomal and X chromosomes in suicide, which may contribute to an improved understanding of the genomic pathophysiology underlying suicide.2025年03月, Molecular Psychiatry, 30(3) (3), 881 - 888, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- AIM: Strokes are the second most common cause of mortality and disability worldwide. Ischemic strokes account for the main part of strokes. Recently, the epigenetic changes that occur during biological aging through DNA methylation have gained attention. The National Institutes of Health Stroke Scale (NIHSS) scores measure physical and cognitive function. We hypothesized that there are associations between acute changes in the NIHSS score and biological aging in patients with ischemic stroke. We conducted epigenetic clock analyses to investigate the association between the difference in NIHSS (dNIHSS) and epigenetic clock in patients with ischemic stroke. METHODS: We used two publicly available DNA methylation data sets from Caucasian patients with ischemic stroke in Spain. The discovery data set consists of 59 patients with ischemic stroke, and the replication dataset consists of 62. Acceleration of several epigenetic clocks (HorvathAge, HannumAge, SkinBloodAge, PhenoAge, GrimAge, GrimAge2, DNA methylation-based telomere length, and DunedinPACE), GrimAge components, and GrimAge2 components was analyzed with standard multiple regression analyses with dNIHSS. We obtained information on dNIHSS between discharge and baseline for each patient. We integrated these results from the two data sets using meta-analyses. RESULTS: There was no significant association in the epigenetic age acceleration. The predictive value of only Cystatin C showed a significant association with dNIHSS in the GrimAge components. CONCLUSIONS: We could not find a significant association between the severity during the acute phase of ischemic stroke and epigenetic clocks. We may be able to find different findings with a larger sample size and longitudinal data such as NIHSS scores at fixed intervals.2025年03月, Neuropsychopharmacology reports, 45(1) (1), e70009, 英語, 国際誌研究論文（学術雑誌）
- Psychiatric diagnosis rates in suicide decedents appear higher in European ancestry populations compared with East Asians. Shared genetic components exist between major depressive disorder (MDD)/schizophrenia (SCZ) and suicide, but no study has compared these shared polygenic architectures between Europeans and East Asians. We compared polygenic risk scores (PRSs) for MDD/SCZ determined from large data sets specific to each ancestry in European and East Asian suicide decedent samples. MDD/SCZ PRSs appeared more prominent in European suicides compared with Japanese suicides. A greater coexistence of psychiatric disorders in European suicide decedents than in East Asian suicide decedents may be partly explained by genetics. Our results are limited by the smaller sample size of our suicide decedents and sample size disparities between the European discovery data set and the East Asian data set for MDD/SCZ, resulting in less statistical power to detect robust difference between the two ancestries.2025年, Archives of Suicide Research : official journal of the International Academy for Suicide Research, 29(1) (1), 309 - 316, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Anorexia nervosa (AN) is life-threatening because of many physical complications, hence a quantitative indicator for early therapeutic intervention through hospitalization is needed. Here, we compared the demographics of 21 patients with AN who required intensive treatment in the internal medicine ward and those of 61 patients with AN who directly admitted to the psychiatric ward. We developed a risk score for severe physical complications in patients with AN, by using six items with significant differences between two groups; body mass index, blood urea nitrogen, corrected calcium, albumin, aspartate transaminase, and C-reactive protein (area under the curve = 0.824).2024年12月, Psychiatry research, 342, 116151 - 116151, 英語, 国際誌研究論文（学術雑誌）
- AIM: Social anxiety disorder (SAD) is a common disorder characterized by excessive fear of scrutiny and embarrassment, leading to severe distress and avoidance behaviors or dysfunctions. SAD and other relevant diseases have been reported to be associated with a higher risk of aging-related diseases, such as Alzheimer's disease, Parkinson's disease, and diabetes mellitus. Recently, epigenetic clock analysis, which measures biological aging based on comprehensive DNA methylation (DNAm) status, has been widely conducted. We conducted epigenetic clock analyses in patients with SAD and controls, examining various epigenetic age acceleration and DNAm-based predictive values of aging-related proteins (GrimAge components and GrimAge2 components), including leptin level. METHODS: We used the publicly available DNAm dataset, GSE164056, which consists of 66 patients with SAD and 77 controls of Caucasian descent aged between 18 and 50 years. We conducted regression analyses investigating the association between SAD and various indices of epigenetic aging, using age and sex as covariates. RESULTS: None of the epigenetic clocks showed significant differences in age acceleration. Of the DNAm-based predictive values of aging-related proteins, leptin level in GrimAge components (q = 0.0123) and GrimAge2 components (q = 0.0123) were significantly lower in patients with SAD than in controls. CONCLUSIONS: The results of this study suggested that leptin may be involved in SAD pathogenesis as an aging-related protein. Therefore, further studies with different designs are required.2024年12月, Neuropsychopharmacology reports, 44(4) (4), 774 - 783, 英語, 国際誌研究論文（学術雑誌）
- Schizophrenia is a common chronic psychiatric disorder that causes age-related dysfunction. The life expectancy in patients with schizophrenia is ≥10 years shorter than that in the general population because of the higher risk of other diseases, such as cardiovascular diseases. Aging studies based on DNA methylation status have received considerable attention. Several epigenetic age accelerations and predicted values of aging-related proteins (GrimAge and GrimAge2 components) have been analyzed in multiple diseases. However, no studies have investigated up to GrimAge and GrimAge2 components between patients with schizophrenia and controls. Therefore, we aimed to conduct multiple regression analyses to investigate the association between schizophrenia and epigenetic age accelerations and GrimAge and GrimAge2 components in seven cohorts. Furthermore, we included patients with first-episode psychosis whose illness duration was often shorter than schizophrenia in our analysis. We integrated these results with meta-analyses, noting the acceleration of GrimAge, GrimAge2, and DunedinPACE, and increase in adrenomedullin, beta-2 microglobulin, cystatin C, and plasminogen activation inhibitor-1 levels, in patients with schizophrenia or first-episode psychosis. These results corroborated the finding that patients with schizophrenia had an increased risk of diabetes, cardiovascular disease, and cognitive dysfunction from a biological perspective. Patients with schizophrenia and first-episode psychosis showed differences in the results when compared with controls. Such analyses may lead to the development of novel therapeutic targets to patients with schizophrenia or relevant diseases from the perspective of aging in the future.2024年11月, Schizophrenia (Heidelberg, Germany), 10(1) (1), 108 - 108, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Brexpiprazole is a second-generation antipsychotic approved in Japan in 2018; however, information on placental passage and breast milk transfer remains limited. In this report, the patient, a 30-year-old pregnant woman with schizophrenia, was medicated with brexpiprazole, risperidone, and quetiapine. METHODS: The study used high-performance liquid chromatography-tandem mass spectrometry to determine the concentrations of brexpiprazole, quetiapine, risperidone, and its active metabolite (paliperidone) in maternal and neonatal plasma, cord venous plasma, and breast milk. Maternal plasma samples were obtained approximately 2 and 8 hours after the last administration of antipsychotics on the day of delivery and at the estimated drugs' trough time on days 1, 3, and 5 after delivery. RESULTS: The maternal plasma concentrations of brexpiprazole, quetiapine, and paliperidone increased by approximately 3.5-fold on the fifth day compared with those on the day of delivery, whereas the risperidone concentration remained almost constant. Moreover, the neonatal plasma concentrations of the 4 drugs immediately after birth were indistinguishable from the umbilical cord concentrations and gradually decreased, except for risperidone. Relative infant doses of these compounds were below 1.1%. CONCLUSIONS: Pregnancy status notably alters the pharmacokinetic properties of antipsychotics. Therefore, close and careful monitoring of clinical symptoms should be considered during pregnancy and after delivery. Although brexpiprazole is transferred to neonates through the placenta, breastfeeding is still possible because the relative infant dose value of this drug was much less than 10%.2024年10月, Therapeutic drug monitoring, 46(5) (5), 687 - 691, 英語, 国際誌研究論文（学術雑誌）
- AIM: Internet gaming disorder (IGD) is receiving increasing attention. In particular, violent gameplay or in-game spending affects the psychiatric conditions and economic difficulties of patients. We conducted regression analysis and path analysis to investigate the associations between a comprehensive list of factors in patients with IGD, including the degree of internet or gaming dependence, developmental problems, family background, severity of depression, sleeping habits, in-game spending, and first-person shooter (FPS) and third-person shooter (TPS) game playing. METHODS: The participants were 47 Japanese individuals (39 males and 8 females) aged ≤20 years diagnosed with IGD with complete data from the internet addiction test, autism spectrum quotient, Quick Inventory of Depressive Symptomatology, and Pittsburgh Sleep Quality Index. All participants were asked whether their parents have divorce history, whether they have siblings, whether they play FPS or TPS games, and whether they engage in in-game spending. Firstly, we compared these factors between males and females; secondly, we conducted regression analysis and path analysis in male patients. RESULTS: As for simple comparison between sex, female patients showed greater severity of IGD and depressive score. In regression analysis of male patients, significant associations were found between FPS or TPS game playing and in-game spending. We also created path diagrams. CONCLUSION: The results of the comprehensive analyses suggest the possibility that bidirectional synergistic effects could be achieved by gradually reducing both violent game playing and in-game spending. The concept of internet dependence has a wide range of meanings, and for each subtype, it is important to consider the background that led to the dependence to make individualized environmental adjustments and provide psychotherapy.2024年09月, Neuropsychopharmacology reports, 44(3) (3), 631 - 638, 英語, 国際誌研究論文（学術雑誌）
- Alcohol dependence poses a global health threat associated with aging and reduced life expectancy. Recently, aging research through deoxyribonucleic acid (DNA) methylation has gained attention. New epigenetic clocks have been developed; however, no study has investigated GrimAge components, GrimAge2 components and DunedinPACE in patients with alcohol dependence. In this study, we aimed to perform epigenetic clock analysis to evaluate epigenetic age acceleration and DNA methylation-based age-predictive components in patients with alcohol dependence and controls. We utilized publicly available DNA methylation data (GSE98876) for our analysis. Additionally, we compared the values of the same items before and after the patients underwent a treatment program. The dataset comprised 23 controls and 24 patients. We observed that DunedinPACE accelerated more in patients with alcohol dependence. AgeAccelGrim and AgeAccelGrim2 decelerated more after the treatment program than before, and beta-2-microglobulin and Cystatin C decreased after the treatment program than before. These findings are crucial as they affect the cranial nerve area, potentially contributing to cognitive dysfunction and psychiatric symptoms in patients with alcohol dependence.2024年05月, Journal of psychiatric research, 173, 175 - 182, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: More than 800 000 people die by suicide annually. The heritability of suicide is 30%-50%. We focused on the hypoxia response element (HRE), which promotes the expression of macrophage migration inhibitory factor (MIF) via the hypoxia-inducible factor (HIF) pathway, important in neurogenesis and neuroprotection. We examined a genetic polymorphism of rs17004038, a single-nucleotide polymorphism (SNP), in suicide completers and controls. METHODS: The study population included 1336 suicide completers and 814 unrelated healthy controls. All participants were Japanese. We obtained peripheral blood, extracted DNA, and genotyped the patients for SNP rs17004038 (C > A). RESULTS: No significant differences were observed between the two groups in either the allele or genotype analyses. Subgroup analyses by sex, age (<40 or ≥40), and suicide method (violent or nonviolent suicide) were performed with similar results. CONCLUSION: No association was observed between SNP rs17004038 and suicide completion. Although it is challenging to collect a large number of samples from suicide completers, further MIF-related genetic studies, including those of rs17004038, are necessary with larger sample sizes.2024年03月, Neuropsychopharmacology reports, 44(1) (1), 262 - 266, 英語, 国際誌研究論文（学術雑誌）
- Repeated abuse of methamphetamine (METH) can cause dependence, repeated relapse of psychotic symptoms, compulsive drug-seeking behaviour, and various neurological symptoms. These long-term biological changes may be associated with epigenetic mechanisms; however, the association between METH use and epigenetic mechanisms has been poorly investigated. Thus, we performed an epigenome-wide association study of METH dependence using genomic DNA extracted from the blood samples of 24 patients with METH dependence and 24 normal controls. All participants were of Japanese descent. We tested the association between METH dependence and DNA methylation using linear regression analysis. We found epigenome-wide significant associations at four CpG sites, one of which occurred in the CNOT1 gene and another in the PUM1 gene. We especially noted the CNOT1 and PUM1 genes as well as several other genes that indicated some degree of association with METH dependence. Among the relatively enriched Gene Ontology terms, we were interested in terms of mRNA metabolism, respirasome, and excitatory extracellular ligand-gated ion channel activity. Among the relatively enriched Kyoto Encyclopedia of Genes and Genome pathways, we noted pathways of several neurological diseases. Our results indicate that genetic changes akin to those in other psychiatric or neurodegenerative disorders may also occur via epigenetic mechanisms in patients with METH dependence.2024年03月, Addiction biology, 29(3) (3), e13383, 英語, 国際誌研究論文（学術雑誌）
- OBJECTIVE: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. METHODS: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. RESULTS: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. CONCLUSIONS: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.2023年10月, American Journal of Psychiatry, 180(10) (10), 723 - 738, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Major depressive disorder (MDD) is known to cause significant disability. Genome-wide DNA methylation (DNAm) profiles can be used to estimate biological aging and as epigenetic clocks. However, information on epigenetic clocks reported in MDD patients is inconsistent. Since antidepressants are likely confounders, we evaluated biological aging using various DNAm-based predictors in patients with MDD who had never received depression medication. A publicly available dataset consisting of whole blood samples from untreated MDD patients (n = 40) and controls (n = 40) was used. We analyzed five epigenetic clocks (HorvathAge, HannumAge, SkinBloodAge, PhenoAge, and GrimAge), DNAm-based telomere length (DNAmTL), and DNAm-based age-related plasma proteins (GrimAge components), as well as DNAm-based white blood cell composition. The results indicate that patients with untreated MDD were significantly associated with epigenetic aging acceleration in HannumAge and GrimAge. Furthermore, a decrease in natural killer cells, based on DNAm, was observed in patients with untreated MDD.2023年09月, npj aging, 9(1) (1), 19 - 19, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: One potential cause of suicide is serotonergic dysfunction. Sex differences have been reported to modulate the effects of serotonergic polymorphisms. Monoamine oxidase A (MAOA) is an enzyme that degrades serotonin and is located on the X chromosome. A previous study indicated that the upstream (u) variable number of tandem repeat (VNTR) in the MAOA gene promoter may be associated with suicide. However, a meta-analysis showed that this polymorphism may not be related to suicide. According to a recent study, compared with the uVNTR, the distal (d)VNTR and the haplotypes of the two VNTRs modulate MAOA expression. METHODS: We examined the two VNTRs in the MAOA gene promoter in 1007 subjects who committed suicide and 844 healthy controls. We analyzed the two VNTRs using fluorescence-based polymerase chain reaction assays. We conducted a meta-analysis for the two VNTRs to update it. RESULTS: Our results demonstrated that neither the genotype-based associations nor allele/haplotype frequencies of the two VNTRs were significantly associated with suicide. In the meta-analysis, we did not indicate relationships between uVNTR and suicide nor did we identify articles analyzing dVNTR in suicide. CONCLUSION: Overall, we did not find a relationship between the two VNTRs in the MAOA promoter and suicide completion; thus, warranting further studies are required.2023年09月, Neuropsychopharmacology reports, 43(3) (3), 338 - 345, 英語, 国際誌研究論文（学術雑誌）
- Elsevier BV, 2023年05月, iScience, 26(5) (5), 106701 - 106701研究論文（学術雑誌）
- This study aimed to determine the effects of pregnancy and ontogeny on risperidone and paliperidone pharmacokinetics by assessing their serum concentrations in two subjects and constructing a customized physiologically-based pharmacokinetic (PBPK) model. Risperidone and paliperidone serum concentrations were determined in a pregnant woman and her newborn. PBPK models for risperidone and paliperidone in adults, pediatric, and pregnant populations were developed and verified using the Simcyp simulator. These models were then applied to our two subjects, generating their "virtual twins." Effects of pregnancy on both drugs were examined using models with fixed pharmacokinetic parameters. In the neonatal PBPK simulation, 10 different models for estimating the renal function of neonates were evaluated. Risperidone was not detected in the serum of both pregnant woman and her newborn. Maternal and neonatal serum paliperidone concentrations were between 2.05-3.80 and 0.82-1.03 ng/ml, respectively. Developed PBPK models accurately predicted paliperidone's pharmacokinetics, as shown by minimal bias and acceptable precision across populations. The individualized maternal model predicted all observed paliperidone concentrations within the 90% prediction interval. Fixed-parameter simulations showed that CYP2D6 activity largely affects risperidone and paliperidone pharmacokinetics during pregnancy. The Flanders metadata equation showed the lowest absolute bias (mean error: 22.3% ± 6.0%) and the greatest precision (root mean square error: 23.8%) in predicting paliperidone plasma concentration in the neonatal population. Our constructed PBPK model can predict risperidone and paliperidone pharmacokinetics in pregnant and neonatal populations, which could help with precision dosing using the PBPK model-informed approach in special populations.2023年04月, Clinical and translational science, 16(4) (4), 618 - 630, 英語, 国際誌研究論文（学術雑誌）
- Major depressive disorder (MDD) is a common mental illness and a major public health concern worldwide. Depression is associated with epigenetic changes that regulate gene expression, and analyzing these changes may help elucidate the pathophysiology of MDD. Genome-wide DNA methylation (DNAm) profiles can function as 'epigenetic clocks' that can help estimate biological aging. Here, we assessed biological aging in patients with MDD using various DNAm-based indicators of epigenetic aging. We used a publicly available dataset containing data obtained from the whole blood samples of MDD patients (n = 489) and controls (n = 210). We analyzed five epigenetic clocks (HorvathAge, HannumAge, SkinBloodAge, PhenoAge, and GrimAge) and DNAm-based telomere length (DNAmTL). We also investigated seven DNAm-based age-predictive plasma proteins (including cystatin C) and smoking status, which are components of GrimAge. Following adjustment for confounding factors such as age and sex, patients with MDD showed no significant difference in epigenetic clocks and DNAmTL. However, DNAm-based plasma cystatin C levels were significantly higher in patients with MDD than controls. Our findings revealed specific DNAm changes predicting plasma cystatin C levels in MDD. These findings may help elucidate the pathophysiology of MDD, leading to the development of new biomarkers and medications.2023年04月, Psychiatry research, 322, 115103 - 115103, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Suicidal behavior is moderately heritable and a consequence of a combination of the diathesis traits for suicidal behavior and suicide-related major psychiatric disorders. Here, we sought to examine shared polygenic effects between various psychiatric disorders/traits and suicidal behavior and to compare the shared polygenic effects of various psychiatric disorders/traits on non-fatal suicide attempt and suicide death. METHODS: We used our genotyped European ancestry sample of 260 non-fatal suicide attempters, 317 suicide decedents and 874 non-psychiatric controls to test whether polygenic risk scores (PRSs) obtained from large GWASs for 22 suicide-related psychiatric disorders/traits were associated with suicidal behavior. Results were compared between non-fatal suicide attempt and suicide death in a sensitivity analysis. RESULTS: PRSs for major depressive disorder, bipolar disorder, schizophrenia, ADHD, alcohol dependence, sensitivity to environmental stress and adversity, educational attainment, cognitive performance, and IQ were associated with suicidal behavior (Bonferroni-corrected p < 2.5 × 10-4). The polygenic effects of all 22 psychiatric disorders/traits had the same direction (p for binomial tests = 4.8 × 10-7) and were correlated (Spearman's ρ = 0.85) between non-fatal suicide attempters and suicide decedents. CONCLUSIONS: We found that polygenic effects for major psychiatric disorders and diathesis-related traits including stress responsiveness and intellect/cognitive function contributed to suicidal behavior. While we found comparable polygenic architecture between non-fatal suicide attempters and suicide decedents based on correlations with PRSs of suicide-related psychiatric disorders/traits, our analyses are limited by small sample size resulting in low statistical power to detect difference between non-fatal suicide attempt and suicide death.2023年04月, Psychological Medicine, 53(6) (6), 2689 - 2697, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 2023年03月, PCN reports : psychiatry and clinical neurosciences, 2(1) (1), e84, 英語, 国際誌研究論文（学術雑誌）
- Importance Suicide is a leading cause of death; however, the molecular genetic basis of suicidal thoughts and behaviors (SITB) remains unknown. Objective To identify novel, replicable genomic risk loci for SITB. Design, Setting, and Participants This genome-wide association study included 633 778 US military veterans with and without SITB, as identified through electronic health records. GWAS was performed separately by ancestry, controlling for sex, age, and genetic substructure. Cross-ancestry risk loci were identified through meta-analysis. Study enrollment began in 2011 and is ongoing. Data were analyzed from November 2021 to August 2022. Main Outcome and Measures SITB. Results A total of 633 778 US military veterans were included in the analysis (57 152 [9%] female; 121 118 [19.1%] African ancestry, 8285 [1.3%] Asian ancestry, 452 767 [71.4%] European ancestry, and 51 608 [8.1%] Hispanic ancestry), including 121 211 individuals with SITB (19.1%). Meta-analysis identified more than 200 GWS (P &lt; 5 × 10−8) cross-ancestry risk single-nucleotide variants for SITB concentrated in 7 regions on chromosomes 2, 6, 9, 11, 14, 16, and 18. Top single-nucleotide variants were largely intronic in nature; 5 were independently replicated in ISGC, including rs6557168 in ESR1, rs12808482 in DRD2, rs77641763 in EXD3, rs10671545 in DCC, and rs36006172 in TRAF3. Associations for FBXL19 and AC018880.2 were not replicated. Gene-based analyses implicated 24 additional GWS cross-ancestry risk genes, including FURIN, TSNARE1, and the NCAM1-TTC12-ANKK1-DRD2 gene cluster. Cross-ancestry enrichment analyses revealed significant enrichment for expression in brain and pituitary tissue, synapse and ubiquitination processes, amphetamine addiction, parathyroid hormone synthesis, axon guidance, and dopaminergic pathways. Seven other unique European ancestry–specific GWS loci were identified, 2 of which (POM121L2 and METTL15/LINC02758) were replicated. Two additional GWS ancestry-specific loci were identified within the African ancestry (PET112/GATB) and Hispanic ancestry (intergenic locus on chromosome 4) subsets, both of which were replicated. No GWS loci were identified within the Asian ancestry subset; however, significant enrichment was observed for axon guidance, cyclic adenosine monophosphate signaling, focal adhesion, glutamatergic synapse, and oxytocin signaling pathways across all ancestries. Within the European ancestry subset, genetic correlations (r &gt; 0.75) were observed between the SITB phenotype and a suicide attempt-only phenotype, depression, and posttraumatic stress disorder. Additionally, polygenic risk score analyses revealed that the Million Veteran Program polygenic risk score had nominally significant main effects in 2 independent samples of veterans of European and African ancestry. Conclusions and Relevance The findings of this analysis may advance understanding of the molecular genetic basis of SITB and provide evidence for ESR1, DRD2, TRAF3, and DCC as cross-ancestry candidate risk genes. More work is needed to replicate these findings and to determine if and how these genes might impact clinical care.American Medical Association (AMA), 2023年02月, JAMA Psychiatry, 80(2) (2), 135 - 135研究論文（学術雑誌）
- Past evidence has indicated increased ribosomal DNA (rDNA) content in the blood of patients with schizophrenia (SCZ) among European populations. Here, for the first time, we investigated the rDNA copy number (rDNAcn) of SCZ in East Asian populations as well as in blood and brain tissues. In this study, we measured 18S/28S rDNAcn in the peripheral blood of live participants (81 patients with SCZ and 98 healthy controls) and the dorsolateral prefrontal cortices (DLPFCs) of postmortem individuals (10 patients with SCZ and 23 non-psychiatric controls) in the Japanese population. Patients with SCZ had significantly increased 18S/28S rDNAcn in the blood compared to controls (p < 0.05). 18S rDNAcn was significantly increased in the brain of patients with SCZ compared to controls (p < 0.05). In conclusion, regarding the increased rDNAcn in the blood of patients with SCZ that was previously reported in Europeans, we successfully replicated this by using a different, ethnically East Asian, cohort. Additionally, we provide the first evidence of increased rDNAcn in the brain of patients with SCZ. These findings may help to elucidate the molecular underpinnings of SCZ pathophysiology related to ribosomal DNA abnormalities.2023年, PloS one, 18(1) (1), e0280694, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Most genetic analyses that have attempted to identify a locus or loci that can distinguish patients with treatment-resistant schizophrenia (TRS) from those who respond to treatment (non-TRS) have failed. However, evidence from multiple studies suggests that patients with schizophrenia who respond well to antipsychotic medication have a higher dopamine (DA) state in brain synaptic clefts whereas patients with TRS do not show enhanced DA synthesis/release pathways. PATIENTS AND METHODS: To examine the contribution (if any) of genetics to TRS, we conducted a genetic association analysis of DA-related genes in schizophrenia patients (TRS, n = 435; non-TRS, n = 539) and healthy controls (HC: n = 489). RESULTS: The distributions of the genotypes of rs3756450 and the 40-bp variable number tandem repeat on SLC6A3 differed between the TRS and non-TRS groups. Regarding rs3756450, the TRS group showed a significantly higher ratio of the A allele, whereas the non-TRS group predominantly had the G allele. The analysis of the combination of COMT and SLC6A3 yielded a significantly higher ratio of the putative low-DA type (i.e., high COMT activity + high SLC6A3 activity) in the TRS group compared to the two other groups. Patients with the low-DA type accounted for the minority of the non-TRS group and exhibited milder psychopathology. CONCLUSION: The overall results suggest that (i) SLC6A3 could be involved in responsiveness to antipsychotic medication and (ii) genetic variants modulating brain DA levels may be related to the classification of TRS and non-TRS.2023年, Frontiers in psychiatry, 14, 1334335 - 1334335, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Williams syndrome (WS) is a rare genetic disorder caused by a microdeletion at the 7q11.23 region and is characterized by diverse symptoms encompassing physical and cognitive features. WS was reported to be associated to altered DNA methylation (DNAm) patterns. However, due to the limited information from long-term studies, it remains unclear whether WS accelerates aging. Genome-wide DNAm profiles can serve as "epigenetic clocks" to help estimate biological aging along with age-related markers, such as plasma proteins and telomere length. METHODS: We investigated GrimAge, DNAm-based telomere length (DNAmTL), and other epigenetic clocks in blood samples of 32 patients with WS and 32 healthy controls. RESULTS: We observed a significant acceleration in GrimAge, DNAmTL, and other epigenetic clocks in patients with WS as compared with those of controls. In addition, several GrimAge components, such as adrenomedullin, growth differentiation factor-15, leptin and plasminogen activator inhibitor-1, were altered in patients with WS. CONCLUSIONS: This study provides novel evidence supporting the hypothesis that WS may be associated to accelerated biological aging. A better understanding of the overall underlying biological effects of WS can provide new foundations for improved patient care; thus, long-term follow-up studies are still warranted.2022年12月, Journal of child psychology and psychiatry, and allied disciplines, 63(12) (12), 1553 - 1562, 英語, 国際誌研究論文（学術雑誌）
- 2022年12月, Asian journal of psychiatry, 78, 103282 - 103282, 英語, 国際誌
- 2022年11月, Psychiatry and clinical neurosciences, 76(11) (11), 603 - 604, 英語, 国際誌
- Methamphetamine (MA) is used worldwide and causes serious public health and social problems. MA affects the central nervous, cardiac, and immune systems, which causes neuropsychiatric and cardiovascular diseases and infection. Epigenetic changes, including DNA methylation (DNAm), are associated with various clinical phenotypes of MA abuse. DNAm is related to biological aging and health risks; hence, we aimed to assess the changes in biological aging in MA dependence using the DNAm age and DNA methylation-based telomere length (DNAmTL). We used five measures of DNAm age (HorvathAge, HannumAge, SkinBloodAge, PhenoAge, and GrimAge), DNAmTL, and DNAm-based age-predictive factors (plasma proteins and blood cell composition). We compared patients with MA dependence and healthy controls (n = 24 each) using the DNAm profiles obtained from whole-blood samples. Patients with MA dependence showed significant acceleration in PhenoAge and GrimAge, as well as a trend for significant acceleration in DNAmTL. Following adjustment for confounding factors, MA dependence was significantly associated with accelerations in PhenoAge, GrimAge, and DNAmTL, as well as alterations in DNAm-based age-predictive factors (beta-2-microglobulin, granulocytes, and naive cluster of differentiation 4+ T cells). Our results suggested an acceleration of biological aging and specific changes in the DNAm of age- predictive factors in MA dependence.2022年11月, Psychiatry research, 317, 114901 - 114901, 英語, 国際誌研究論文（学術雑誌）
- Springer Science and Business Media LLC, 2022年05月, Nature Genetics, 54(5) (5), 573 - 580研究論文（学術雑誌）
- 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.2022年04月, Psychiatry research, 310, 114481 - 114481, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: GABAergic system dysfunction has been implicated in the etiology of schizophrenia and of cognitive impairments in particular. Patients with treatment-resistant schizophrenia (TRS) generally suffer from profound cognitive impairments in addition to severe positive symptoms, suggesting that GABA system dysfunction could be involved more closely in patients with TRS. METHODS AND RESULTS: In the present study, exome sequencing was conducted on fourteen TRS patients, whereby four SNPs were identified on GAD1, GABBR1 and GABBR2 genes. An association study for five SNPs including these 4 SNPs and rs3749034 on GAD1 as then performed among 357 patients with TRS, 682 non-TRS patients and 508 healthy controls (HC). The results revealed no significant differences in allelic and/or genetic distributions for any of the five SNPs. However, several subanalyses in comparisons between schizophrenia and HC groups, as well as between the three groups, showed nominal-level significance for rs3749034 on GAD1 and rs10985765/rs3750344 on GABBR2. In particular, in comparisons of female subjects, rigorous analysis for rs3749034 showed a statistical difference between the schizophrenia and HC groups and between the TRS and HC groups. CONCLUSIONS: Several positive results in subanalyses suggested that genetic vulnerability in the GABA system to schizophrenia or TRS could be affected by sex or sampling area, and overall, that rs3749034 on GAD1 and rs10985765 on GABBR2 could be related to TRS. In the present study, only a few SNPs were examined; it is possible that other important genetic variants in other regions of GABA-related genes were not captured in this preliminary study.2022年03月, Molecular biology reports, 49(3) (3), 2015 - 2024, 英語, 国際誌研究論文（学術雑誌）
- Metabolomics has been attracting attention in recent years as an objective method for diagnosing schizophrenia. In this study, we analyzed 378 metabolites in the serum of schizophrenia patients using capillary electrophoresis- and liquid chromatography-time-of-flight mass spectrometry. Using multivariate analysis with the orthogonal partial least squares method, we observed significantly higher levels of alanine, glutamate, lactic acid, ornithine, and serine and significantly lower levels of urea, in patients with chronic schizophrenia compared to healthy controls. Additionally, levels of fatty acids (15:0), (17:0), and (19:1), cis-11-eicosenoic acid, and thyroxine were significantly higher in patients with acute psychosis than in those in remission. Moreover, we conducted a systematic review of comprehensive metabolomics studies on schizophrenia over the last 20 years and observed consistent trends of increase in some metabolites such as glutamate and glucose, and decrease in citrate in schizophrenia patients across several studies. Hence, we provide substantial evidence for metabolic biomarkers in schizophrenia patients through our metabolomics study.2022年03月, Neuropsychopharmacology reports, 42(1) (1), 42 - 51, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Nicolaides-Baraitser syndrome (NCBRS) is a rare disorder characterized by neurodevelopmental delays, seizures, and diverse physical characteristics. The DNA methylation (DNAm) profile in NCBRS is significantly different. DNAm is linked to the biological aging of cells and the health risks associated with biological aging. In this study, we examined changes in biological ages in NCBRS to provide insights into the prognosis and health risks of NCBRS. METHODS: We used a publicly available dataset to examine biological aging in NCBRS using DNAm-based epigenetic ages, such as PhenoAge and GrimAge, as well as DNAm-based estimator of telomere length (DNAmTL). We investigated 12 cases, clinically diagnosed as NCBRS, and 27 controls. RESULTS: Compared to controls, NCBRS cases exhibited significantly accelerated PhenoAge and GrimAge as well as significantly shortened DNAmTL. CONCLUSION: These results suggest an acceleration of biological aging in NCBRS and provide insights into the prognosis and health risks of NCBRS.2022年03月, Molecular genetics & genomic medicine, 10(3) (3), e1876, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.2022年02月, Biological Psychiatry, 91(3) (3), 313 - 327, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- BACKGROUND: Autism spectrum disorder (ASD) is characterized by impaired social communication and behavioral problems. An increased risk of premature mortality has been observed in individuals with ASD. Therefore, we hypothesized that biological aging is accelerated in individuals with ASD. Recently, several studies have established genome-wide DNA methylation (DNAm) profiles as 'epigenetic clocks' that can estimate biological aging. In addition, ASD has been associated with differential DNAm patterns. METHODS: We used two independent datasets from blood samples consisting of adult patients with high-functioning ASD and controls: the 1st cohort (38 ASD cases and 31 controls) and the 2nd cohort (6 ASD cases and 10 controls). We explored well-studied epigenetic clocks such as HorvathAge, HannumAge, SkinBloodAge, PhenoAge, GrimAge, and DNAm-based telomere length (DNAmTL). In addition, we investigated seven DNAm-based age-related plasma proteins, including plasminogen activator inhibitor-1 (PAI-1), and smoking status, which are the components of GrimAge. RESULTS: Compared to controls, individuals with ASD in the 1st cohort, but not in the 2nd cohort, exhibited a trend for increased GrimAge acceleration and a significant increase of PAI-1 levels. A meta-analysis showed significantly increased PAI-1 levels in individuals with ASD compared to controls. CONCLUSION: Our findings suggest there is no epigenetic age acceleration in the blood of individuals with ASD. However, this study provides novel evidence regarding increased plasma PAI-1 levels in individuals with high-functioning ASD. These findings suggest PAI-1 may be a biomarker for high-functioning ASD, however, larger studies based on epigenetic clocks and PAI-1 will be necessary to confirm these findings.2022年, PloS one, 17(2) (2), e0263478, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine that promotes neurogenesis and neuroprotection. MIF is predominantly expressed in astrocytes in the brain. The serum MIF level and microsatellites/single nucleotide polymorphisms (SNPs) in the MIF gene promoter region are known to be associated with schizophrenia (SCZ). Interestingly, previous studies reported that hypoxia, an environmental risk factor for SCZ, induced MIF expression through binding of the hypoxia inducible factor (HIF)-1 to the hypoxia response element (HRE) in the MIF promoter. METHODS: We investigated the involvement of MIF in SCZ while focusing on the HIF pathway. First, we conducted an association study of the SNP rs17004038 (C>A) in the HRE of the MIF promoter between 1758 patients with SCZ and 1507 controls. Next, we investigated the effect of hypoxia on MIF expression in primary cultured astrocytes derived from neonatal mice forebrain. RESULTS: SNP rs17004038 was significantly associated with SCZ (p = 0.0424, odds ratio = 1.445), indicating that this SNP in the HRE of the MIF promoter was a genetic risk factor for SCZ. Hypoxia induced MIF mRNA expression and MIF protein production and increased HIF-1 binding to the MIF promoter, while the activity of the MIF promoter was suppressed by mutations in the HRE and by deletion of the HRE in astrocytes. CONCLUSION: These results suggest that SNP rs17004038 in the HRE of the MIF promoter was significantly associated with SCZ and may be involved in the pathophysiology of SCZ via suppression of hypoxia and HIF pathway-induced MIF expression.2022年, PloS one, 17(3) (3), e0265738, 英語, 国際誌研究論文（学術雑誌）
- Glial cell line-derived neurotrophic factor (GDNF) plays an important role in the pathophysiology of neuropsychiatric disorders. We examined serum GDNF levels in bipolar disorder (BD) patients and major depressive disorder (MDD) patients and their association with response to lithium therapy. We used a multicenter (six sites), exploratory, cross-sectional case-control design and recruited 448 subjects: 143 BD patients, 116 MDD patients, and 158 healthy controls (HCs). We evaluated the patients' clinical severity using the Clinical Global Impression (CGI), and responses to lithium therapy using the Alda scale. The serum GDNF levels were significantly decreased in the BD and MDD groups compared to the HCs, with no significant difference between the BD and MDD groups. After adjustment, the serum GDNF levels in the BD and MDD patients in remission or depressive states were decreased compared to the HC values. Lower serum GDNF levels in BD patients were associated with higher CGI and Alda scores (i.e., severe illness and good response to lithium therapy, respectively). Our findings suggest that the serum GDNF level may be a biomarker for both BD and MDD in remission or depressive states. The serum GDNF level may be associated with the lithium response of BD patients.2021年07月, Psychiatry research, 301, 113967 - 113967, 英語, 国際誌研究論文（学術雑誌）
- Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine and promotes neurogenesis and neuroprotection in brains. In addition, MIF has been identified as a potential marker of schizophrenia (SCZ). Our recent study also showed that serum MIF level is higher in SCZ and positively correlated with antipsychotic doses, and that MIF promoter polymorphisms are associated with SCZ. Here, we investigated the effects of antipsychotics such as clozapine on MIF expression in primary cultured astrocytes derived from neonatal mouse forebrain. MIF mRNA expression was estimated with quantitative reverse-transcription polymerase chain reaction. MIF protein concentration was measured with enzyme-linked immunosorbent assay. The histone acetylation of MIF promoter was examined with chromatin immunoprecipitation assay. As a result, common antipsychotics, especially clozapine, increased MIF mRNA expression in a dose-dependent manner. Clozapine increased MIF mRNA expression and protein concentration in a time-dependent manner. Moreover, clozapine increased the acetylation of histone H3 at lysine 27 residues (H3K27) in MIF promoter. In conclusion, we provide novel evidence that antipsychotics such as clozapine increases MIF expression via the acetylation of H3K27 in astrocytes, and that MIF may have a potential role for astrocytes in the action mechanisms of antipsychotics.2021年03月, Journal of psychiatric research, 135, 237 - 242, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Fetal alcohol spectrum disorder (FASD) is characterized by severe clinical impairment, considerable social burden, and high mortality and morbidity, which are due to various malformations, sepsis, and cancer. As >50% of deaths from FASD occur during the first year of life, we hypothesized that there is the acceleration of biological aging in FASD. Several recent studies have established genome-wide DNA methylation (DNAm) profiles as "epigenetic clocks" that can estimate biological aging, and FASD has been associated with differential DNAm patterns. Therefore, we tested this hypothesis using epigenetic clocks. METHODS: We investigated 5 DNAm-based measures of epigenetic age (HorvathAge, HannumAge, SkinBloodAge, PhenoAge, and GrimAge) and telomere length (DNAmTL) using 4 independent publicly available DNAm datasets; 2 datasets were derived from buccal epithelium, and the other 2 datasets were derived from peripheral blood. RESULTS: Compared with controls, children with FASD exhibited an acceleration of GrimAge in 1 buccal and 2 blood datasets. No significant difference was found in other DNAm ages and DNAmTL. Meta-analyses showed a significant acceleration of GrimAge in the blood samples but not in the buccal samples. CONCLUSIONS: This study provides novel evidence regarding accelerated epigenetic aging in children with FASD.2021年02月, Alcoholism, clinical and experimental research, 45(2) (2), 329 - 337, 英語, 国際誌研究論文（学術雑誌）
- Bipolar disorder (BD) is frequently misdiagnosed as major depressive disorder (MDD) due to overlapping depressive symptoms. This study investigated whether serum platelet-derived growth factor BB (PDGF-BB) is a differential diagnostic biomarker for BD and MDD. An initial SOMAscan proteomics assay of 1311 proteins in small samples from patients with BD and MDD and healthy controls (HCs) suggested that serum levels of PDGF-BB differed between BD and MDD. We then conducted a two-step, exploratory, cross-sectional, case-control study at our institute and five sites that included a total of 549 participants (157 with BD, 144 with MDD, and 248 HCs). Clinical symptoms were assessed using the Hamilton Depression Rating Scale and the Young Mania Rating Scale. In the initial analysis at our institute, serum PDGF-BB levels in the MDD group (n = 36) were significantly lower than those in the BD (n = 39) and HC groups (n = 36). In the multicenter study, serum PDGF-BB levels in the MDD group were again significantly lower than those in the BD and HC groups, with no significant difference between the BD and HC groups. Treatment with sodium valproate was associated with significantly lower serum PDGF-BB levels in patients with BD. After controlling for confounding factors (sex, age, body mass index, clinical severity, and valproate medication), serum PDGF-BB levels were lower in the MDD group than in the BD group regardless of mood state. Our findings suggest that serum PDGF-BB may be a potential biomarker to differentiate BD and MDD.2021年02月, Journal of psychiatric research, 134, 48 - 56, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Monoamine oxidase-A (MAO-A) decomposes dopamine and serotonin, and decreased MAO-A expression increases monoamine levels and is related to the pathophysiology of schizophrenia. Previous studies have reported that variable number of tandem repeats (VNTR), namely, upstream (u)VNTR, and some single nucleotide polymorphisms (SNPs) in the MAOA gene are associated with schizophrenia. METHODS: We investigated the two VNTRs and their related SNPs (rs6323 and rs1137070) in the MAOA gene promoter in 859 patients with schizophrenia and 826 healthy controls. Distal (d)VNTR and uVNTR were genotyped with fluorescence-based fragment polymerase chain reaction assays, and rs6323 and rs1137070 with TaqMan SNP genotyping assays. RESULTS: Neither the genotype nor allelic frequency of the VNTRs or SNPs showed significant differences between the schizophrenia and control groups. On the other hand, analysis of the dVNTR-uVNTR-rs6323-rs1137070 haplotype showed significant association for nine repeats (9R)-3R-T-C in female patients (corrected p = 0.0006, odds ratio [confidence interval] = 2.17 [1.446-3.257]). CONCLUSION: Our findings provide novel evidence that MAOA gene polymorphisms are associated with an increased risk of developing schizophrenia in females.2021年, Neuropsychiatric disease and treatment, 17, 3315 - 3323, 英語, 国際誌研究論文（学術雑誌）
- MicroRNAs (miRNAs) have been investigated in neurodevelopmental and psychiatric disorders including schizophrenia (SZ). Previous studies showed miRNAs dysregulation in postmortem brain tissues and peripheral blood of SZ patients. These suggest that miRNAs may play a role in the pathophysiology of SZ and be a potential biomarker of SZ. Previous studies also showed that miRNAs regulated neurogenesis and that neurogenesis was involved in the pathophysiology of SZ. In addition, a recent study showed that miR-19a and 19b, enriched in neural progenitor cells (NPC) in adult hippocampus, were increased in human NPC derived from induced pluripotent stem cell derived from SZ patients. However, it remains unclear whether the levels of miR-19a and 19b are altered in peripheral blood of SZ patients and how miR-19a and 19b affects neurogenesis. To elucidate them, first we examined the levels of miR-19a and 19b in peripheral blood of SZ patients with quantitative RT-PCR and showed that the level of miR-19b, but not miR-19a, was significantly higher (miR-19a: p = 0.5733, miR-19b: p = 0.0038) in peripheral blood of SZ patients (N = 22) than that of healthy controls (N = 19). Next, we examined the involvement of miR-19b in proliferation and survival of mouse neonatal mice hippocampus-derived NPC with BrdU assay and TUNEL assay. The silencing of miR-19b significantly increased proliferation (N = 5, p = 0.0139), but not survival (N = 5, p = 0.9571), of neonatal mice hippocampus-derived NPC. These results suggest that the level of miR-19b in peripheral blood is a potential biomarker of schizophrenia and that the higher level of miR-19b may increase the vulnerability of SZ via attenuating proliferation of hippocampal NPC.2020年12月, Journal of psychiatric research, 131, 102 - 107, 英語, 国際誌研究論文（学術雑誌）
- There is high mortality among patients with bipolar disorder (BD). Studies have reported accelerated biological aging in patients with BD. Recently, Horvath and Hannum et al. independently developed DNA methylation (DNAm) profiles as "epigenetic clocks," which are the most accurate biological age estimate. This led to the development of two accomplished measures of epigenetic age acceleration (EAA) using blood samples, namely, intrinsic and extrinsic EAA (IEAA and EEAA, respectively). IEAA, which is based on Horvath's clock, is independent of blood cell counts and indicates cell-intrinsic aging. On the other hand, EEAA, which is based on Hannum's clock, is associated with age-dependent changes in blood cell counts and indicates immune system aging. Further, Lu et al. developed the "GrimAge" clock, which can strongly predict the mortality risk, and DNAm-based telomere length (DNAmTL). We used a DNAm dataset from whole blood samples obtained from 30 patients with BD and 30 healthy controls. We investigated Horvath EAA, IEAA, Hannum EAA, EEAA, Grim EAA, DNAmTL, and DNAm-based blood cell composition. Compared with controls, there was a decrease in Horvath EAA and IEAA in patients with BD. Further, there was a significant decrease in Horvath EAA and IEAA in patients with BD taking medication combinations of mood stabilizers (including lithium carbonate, sodium valproate, and carbamazepine) than in those taking no medication/monotherapy. This study provides novel evidence indicating decelerated epigenetic aging associated with mood stabilizers in patients with BD.2020年05月, Translational psychiatry, 10(1) (1), 129 - 129, 英語, 国際誌研究論文（学術雑誌）
- AIM: Electroconvulsive therapy (ECT) is effective for psychiatric disorders. However, its action mechanism remains unclear. We previously reported that transcription factor 7 (TCF7) was increased in patients successfully treated with ECT. TCF7 regulates Wnt pathway, which regulates adult hippocampal neurogenesis. Adult hippocampal neurogenesis is involved in the pathophysiology of psychiatric disorders. Astrocytes play a role in adult hippocampal neurogenesis via neurogenic factors. Of astrocyte-derived neurogenic factors, leukemia inhibitory factor (LIF) and fibroblast growth factor 2 (FGF2) activate Wnt pathway. In addition, adenosine triphosphate (ATP), released from excited neurons, activates astrocytes. Therefore, we hypothesized that ECT might increase LIF and/or FGF2 in astrocytes. To test this, we investigated the effects of ATP and electric stimulation (ES) on LIF and FGF2 expressions in astrocytes. METHODS: Astrocytes were derived from neonatal mouse forebrain and administered ATP and ES. The mRNA expression was estimated with quantitative reverse-transcription polymerase chain reaction. Protein concentration was measured with ELISA. RESULTS: ATP increased LIF, but not FGF2, expression. Multiple ES, but not single, increased LIF expression. Knockdown of P2X2 receptor (P2X2R) attenuated ATP-induced increase of LIF mRNA expression. In contrast, P2X3 and P2X4 receptors intensified it. CONCLUSION: P2X2R may mediate ATP-induced LIF expression in astrocytes and multiple ES directly increases LIF expression in astrocytes. Therefore, both ATP/P2X2R and multiple ES-induced increases of LIF expression in astrocytes might mediate the efficacy of ECT on psychiatric disorders. Elucidating detailed mechanisms of ATP/P2X2R and multiple ES-induced LIF expression is expected to result in the identification of new therapeutic targets for psychiatric disorders.2020年05月, Psychiatry and clinical neurosciences, 74(5) (5), 311 - 317, 英語, 国際誌研究論文（学術雑誌）
- Whole-exome sequencing (WES) studies have shown that de-novo variants contribute to the genetic etiology of schizophrenia. WES studies of families with a monozygotic twin pair concordant or discordant for a disease may be fruitful for identifying de-novo pathogenic variants. Here, we performed WES in six individuals from one family (affected monozygotic twins, their unaffected parents, and two siblings) and identified three de-novo missense variants (CPT2 Ala283Thr, CPSF3 Val584Ile, and RNF148 Val210Ile) in the monozygotic twin pair concordant for schizophrenia. These three missense variants were not found in 1760 patients with schizophrenia or schizoaffective disorder or 1508 healthy controls. Our data do not support the role of the three missense variants in conferring risk for schizophrenia.2020年04月, Psychiatric genetics, 30(2) (2), 60 - 63, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Studies suggest aberrant DNA methylation in victims of suicide. Recently, DNA methylation profiles have been developed for determining "epigenetic age," which is the most accurate estimate of biological age. Subsequently, two refined measures of epigenetic age acceleration have been expanded for blood samples as intrinsic and extrinsic epigenetic age acceleration (IEAA and EEAA, respectively). IEAA involves pure epigenetic aging independent of blood cell composition, whereas EEAA involves immunosenescence in association with blood cell composition. METHODS: We investigated epigenetic age acceleration using two independent DNA methylation datasets: a brain dataset from 16 suicide completers and 15 non-psychiatric controls and a blood dataset compiled using economical DNA pooling technique from 56 suicide completers and 60 living healthy controls. In the blood dataset, we considered IEAA and EEAA, as well as DNA methylation-based blood cell composition. RESULTS: There was no significant difference in universal epigenetic age acceleration between suicide completers and controls in both brain and blood datasets. Blood of suicide completers exhibited an increase in EEAA, but not in IEAA. We additionally found that suicide completers had more natural killer cells but fewer granulocytes compared to controls. CONCLUSION: This study provides novel evidence for accelerated extrinsic epigenetic aging in suicide completers and for the potential application of natural killer cells as a biomarker for suicidal behavior.2020年03月, Progress in Neuro-Psychopharmacology & Biological Psychiatry, 98, 109805 - 109805, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Suicide is a major health problem in the modern world. However, its physiological mechanisms have not been well elucidated yet. Immunological disturbances have been reported in psychiatric disorders such as major depressive disorder (MDD), bipolar disorder (BP), and schizophrenia. Some studies have also suggested an association between immunological alterations especially neuroinflammation, and suicide. Chemokines play important roles in inflammation, and studies investigating chemokines in psychiatric diseases such as schizophrenia, MDD, and BP have reported chemokine dysregulations. However, there have been very few studies on the association between chemokines and suicide. We studied chemokine alterations in the postmortem brains of suicide completers and compared them to those of controls. We obtained brain tissue samples of the dorsolateral prefrontal cortex from 16 suicide completers and 23 controls. We examined the concentrations of chemokines and related substances in the brain tissue from these two groups using the Bio-Plex Pro™ Human Chemokine Panel 40-Plex. We performed multiple regression analysis with covariates. The levels of CCL1, CCL8, CCL13, CCL15, CCL17, CCL19, CCL20, CXCL11, and IL-10 were significantly decreased, whereas the IL-16 levels were significantly increased in the suicide completers after adjustment with the Benjamini-Hochberg method to control for type Ⅰ errors (Q < 0.05). The observed chemokine alterations might suggest the presence of suicide-specific immunological mechanisms.2020年01月, Journal of psychiatric research, 120, 29 - 33, 英語, 国際誌研究論文（学術雑誌）
- Suicide is a significant public health problem worldwide, and several Asian countries including Japan have relatively high suicide rates on a world scale. Twin, family, and adoption studies have suggested high heritability for suicide, but genetics lags behind due to difficulty in obtaining samples from individuals who died by suicide, especially in non-European populations. In this study, we carried out genome-wide association studies combining two independent datasets totaling 746 suicides and 14,049 non-suicide controls in the Japanese population. Although we identified no genome-wide significant single-nucleotide polymorphisms (SNPs), we demonstrated significant SNP-based heritability (35-48%; P < 0.001) for completed suicide by genomic restricted maximum-likelihood analysis and a shared genetic risk between two datasets (Pbest = 2.7 × 10-13) by polygenic risk score analysis. This study is the first genome-wide association study for suicidal behavior in an East Asian population, and our results provided the evidence of polygenic architecture underlying completed suicide.2019年11月, Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 44(12) (12), 2119 - 2124, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- A recent genome-wide association study (GWAS) for major depressive disorder (MDD) in Chinese women identified a single-nucleotide polymorphism (SNP), rs12415800, near the Sirtuin1 (SIRT1) gene as one of the top candidate loci. However, no study has shown a genetic association between SIRT1 and completed suicide, which is one of the most serious outcomes of MDD. In this study, 778 suicide completers and 760 controls in a Japanese population were genotyped for two SNPs in strong linkage disequilibrium (rs12415800 and rs4746720 in 3'UTR). We found significant associations between both SNPs and completed suicide among women aged ≥50 years. Additional analysis using postmortem brain tissues (10 suicide brains and 13 non-suicide brains) revealed the following: while SIRT1 gene expression in the prefrontal cortex did not differ between suicide and non-suicide brains, DNAJC12 gene expression, potentially implicated by the SNPs genotyped here, was significantly decreased in suicide brains (p = 0.003). In conclusion, regarding the genetic association of SIRT1 with MDD that was previously identified in women by the Chinese GWAS, we successfully validated our results using a female suicidal cohort in the same Asian population with the same direction of allelic effect.2019年08月, Psychiatry research, 278, 141 - 145, 英語, 国際誌研究論文（学術雑誌）
- The accelerated aging hypothesis of schizophrenia (SCZ) has been proposed. DNA methylation profiles were developed for determining "epigenetic age." Here, we assessed intrinsic and extrinsic epigenetic age acceleration (IEAA and EEAA, respectively) in SCZ. We examined two independent cohorts of Japanese ancestry. The first cohort consisted of 80 patients with SCZ under long-term or repeated hospitalization and 40 controls, with the economical DNA pooling technique. The second cohort consisted of 24 medication-free patients with SCZ and 23 controls. Blood of SCZ subjects exhibited decreased EEAA in the first cohort (p = 0.0162), but not in the second cohort. IEAA did not differ in either cohort. We performed replication analyses using publicly available datasets from European ancestry (three blood and one brain datasets). One blood dataset showed increased EEAA in SCZ (p = 0.0228). Overall, our results provide evidence for decreased EEAA in SCZ associated with hospitalization in the Japanese population.2019年02月, NPJ schizophrenia, 5(1) (1), 4 - 4, 英語, 国際誌研究論文（学術雑誌）
- Background: Given a lack of markers, diagnoses of bipolar disorder (BD) and major depressive disorder (MDD) rely on clinical assessment of symptoms. However, the depressive mood states of BD and depressive symptoms of MDD are often difficult to distinguish, which leads to misdiagnoses, which in turn leads to inadequate treatment. Previous studies have shown that the hemodynamic responses of the left frontopolar cortex measured by near-infrared spectroscopy (NIRS) differ between BD and MDD; these hemodynamic responses are associated with altered mitochondrial metabolism; and mitochondrial DNA copy number (mtDNAcn), an index of mitochondrial dysfunction, tends to decrease in BD and increase in MDD patients. In this study, we confirmed that mtDNAcn trends in opposite directions in BD and MDD. We then determined whether mtDNAcn could enhance the utility of NIRS as a diagnostic marker to distinguish between BD and MDD. Methods: We determined mtDNAcn in peripheral blood samples from 58 healthy controls, 79 patients with BD, and 44 patients with MDD. Regional hemodynamic responses during a verbal fluency task (VFT) in 24 BD patients and 44 MDD patients, matched by age and depression severity, were monitored using NIRS. Results: Measurements of mtDNAcn were lower in BD patients and higher in MDD patients than in controls. The left frontopolar region exhibited the most significant differences in mean VFT-related oxy-Hb changes between the BD and MDD groups. Multivariate logistic regression analysis with variables including age, sex, hemodynamic response of the left frontopolar region, and mtDNAcn showed high accuracy for distinguishing BD from MDD (area under the curve = 0.917; 95% confidence interval = 0.849-0.985). For the BD group, we observed a positive correlation between hemodynamic responses in the left frontopolar region and mtDNAcn, while for the MDD group, we observed a negative correlation. Conclusions: Our findings suggest that the association between hemodynamic response and mitochondrial dysfunction in BD or MDD plays an important role in differentiating the pathophysiological mechanisms of BD from those of MDD.2019年, Frontiers in psychiatry, 10, 312 - 312, 英語, 国際誌研究論文（学術雑誌）
- PURPOSE: Whole-exome sequencing (WES) of multiplex families is a promising strategy for identifying causative variations for common diseases. To identify rare recessive risk variations for schizophrenia, we performed a WES study in a consanguineous family with affected siblings. We then performed follow-up sequencing of SPATA7 in schizophrenia-affected families. In addition, we performed a case-control study to investigate association between SPATA7 variations and schizophrenia. PATIENTS AND METHODS: WES was performed on two affected siblings and their unaffected parents, who were second cousins, of a multiplex schizophrenia family. Subsequently, we sequenced the coding region of SPATA7, a potential risk gene identified by the WES analysis, in 142 affected offspring from 137 families for whom parental DNA samples were available. We further tested rare recessive SPATA7 variations, identified by WES and sequencing, for associations with schizophrenia in 2,756 patients and 2,646 controls. RESULTS: Our WES analysis identified rare compound heterozygous missense SPATA7 variations, p.Asp134Gly and p.Ile332Thr, in both affected siblings. Sequencing SPATA7 coding regions from 137 families identified no rare recessive variations in affected offspring. In the case-control study, we did not detect the rare compound heterozygous SPATA7 missense variations in patients or controls. CONCLUSION: Our data does not support the role of the rare compound heterozygous SPATA7 missense variations p.Asp134Gly and p.Ile332Thr in conferring a substantial risk of schizophrenia.2019年, Neuropsychiatric disease and treatment, 15, 2353 - 2363, 英語, 国際誌研究論文（学術雑誌）
- Numerous evidence indicated mitochondrial abnormalities in the pathophysiology of bipolar disorder (BD); however, it remains unclear whether aberrant mitochondrial DNA (mtDNA) copy number (cn) occur in BD due to the conflicting results in previous studies. Here, peripheral blood mtDNAcn in 69 BD patients and 54 controls were analysed via qPCR. BD patients had significantly lower mtDNAcn compared to controls (regardless of their BD type [BD I or II]). Meta-analysis for all previous BD-mtDNAcn studies combining our results with previously published studies failed to identify any significant association. Meanwhile, Asian-specific meta-analysis remarkably revealed lower mtDNAcn in BD patients.2018年11月, Psychiatry research, 269, 115 - 117, 英語, 国際誌研究論文（学術雑誌）
- Several previous studies have investigated an association between leukocyte telomere length (LTL) and schizophrenia (SCZ). However, results have been largely inconsistent, partially due to the relatively small sample sizes in each study and heterogeneity caused by various uncontrolled confounders (e.g., duration of illness or hospitalization, lifetime antipsychotic dose, and LTL assay methods). Here, we investigate the association of LTL with SCZ with the quantitative polymerase chain reaction method in independent cohorts consisting of 1241 patients with SCZ and 1042 controls (the largest independent sample in this field). Furthermore, we examined whether duration of hospitalization and lifetime antipsychotic dose had an effect on LTL in SCZ. In all samples, we observed significantly longer LTL in patients with SCZ relative to controls. In subgroup analyses, we observed that longer telomeres in SCZ were only visible in elderly patients and not in patients under 50 years old. Moreover, significantly longer LTL in elderly patients with SCZ was only specific to those with long-term hospitalization, but not outpatients or those with short-term hospitalization. This may be because the former received more appropriate lifestyle management. Meanwhile, lifetime antipsychotic dose had no effect on LTL. Our findings suggest that consideration of the effect of age and duration of hospitalization on LTL may improve our understanding of controversial results obtained in previous studies of telomeres in SCZ.2018年08月, Journal of psychiatric research, 103, 161 - 166, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Numerous studies have suggested that an immune system imbalance plays an important role in schizophrenia. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine. It plays multiple roles in various biological processes, including inflammation and neurogenesis. Furthermore, several exhaustive serum proteomic profiling studies have identified MIF as a potential biomarker of schizophrenia. Here, we investigate MIF protein levels in serum and postmortem prefrontal cortex in patients with schizophrenia and controls. Moreover, we investigate the association of two functional polymorphisms in the MIF gene promoter region (MIF-794CATT5-8 microsatellite and MIF-173G/C single-nucleotide polymorphism [SNP]) with schizophrenia. METHODS: We measured serum MIF levels with an enzyme-linked immunosorbent assay (ELISA) (51 patients vs. 86 controls) and postmortem brain MIF levels with a western blotting assay (18 patients vs. 22 controls). Subsequently, we genotyped the MIF-794CATT5-8 microsatellite with a fluorescence-based fragment assay and the MIF-173G/C SNP with a TaqMan SNP genotyping assay (1483 patients vs. 1454 controls). RESULTS: Serum MIF levels were significantly higher in patients with schizophrenia than in controls (p=0.00118), and were positively correlated with antipsychotic dose (Spearman's r=0.222, p=0.0402). In addition, an earlier age of onset was observed in patients with a high serum MIF level (≥40ng/mL) than those with a low serum MIF level (<40ng/mL) (p=0.0392). However, postmortem brain MIF levels did not differ between patients with schizophrenia and controls. The association study revealed that the CATT6-G haplotype was nominally significantly associated with schizophrenia (p=0.0338), and that the CATT6 allele and CATT6-G haplotype were significantly associated with female adolescent-onset schizophrenia (AsOS) (corrected p=0.0222 and p=0.0147, respectively). CONCLUSIONS: These results suggest that serum MIF level is a potential pharmacodynamic and/or monitoring marker of schizophrenia, and is related to a novel antipsychotic effect beyond dopamine antagonism. Furthermore, the MIF gene polymorphisms are associated with the risk for schizophrenia especially in adolescent females, and are potential stratification markers of schizophrenia. Further studies of MIF are warranted to elucidate the pathophysiology of schizophrenia and the effects of antipsychotics.2018年04月, Progress in neuro-psychopharmacology & biological psychiatry, 83, 33 - 41, 英語, 国際誌研究論文（学術雑誌）
- Men have a higher rate of completed suicide than women, which suggests that sex chromosome abnormalities may be related to the pathophysiology of suicide. Recent studies have found an aberrant loss of chromosome Y (LOY) in various diseases; however, no study has investigated whether there is an association between LOY and suicide. The purpose of this study was to determine whether LOY occurs in men who completed suicide. Our study consisted of 286 male Japanese subjects comprised of 140 suicide completers without severe physical illness (130 post-mortem samples of peripheral blood and 10 brains) and 146 age-matched control subjects (130 peripheral blood samples from healthy individuals and 16 post-mortem brains). LOY was measured as the chromosome Y/chromosome X ratio of the fluorescent signal of co-amplified short sequences from the Y-X homologous amelogenin genes (AMELY and AMELX). Regression analyses showed that LOY in the blood of suicide completers was significantly more frequent than that found in controls (odds ratio = 3.50, 95% confidence interval = 1.21-10.10), but not in the dorsolateral prefrontal cortex (DLPFC) region of brain. Normal age-dependent LOY in blood was found in healthy controls (r = -0.353, p < 0.001), which was not seen in suicide completers (r = -0.119, p = 0.177). DLPFC tissue had age-dependent LOY (B = -0.002, p = 0.015), which was independent of phenotype. To our knowledge, this is the first study demonstrating that LOY in blood is associated with suicide completion. In addition, our findings are the first to also indicate that age-dependent LOY may occur not only in blood, but also in specific brain regions.2018年, PloS one, 13(1) (1), e0190667, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Alcohol dependence induces low bone mineral density (BMD), predicting osteoporosis, while low and moderate alcohol consumption may even increase BMD. In recent years, undercarboxylated osteocalcin (ucOC) and tartrate-resistant acid phosphatase-5b (TRACP-5b), bone turnover markers, have gained special interest as useful indicators of low BMD. However, it remains unclear whether other alcohol-related variables (eg, duration of abstinence and continuous drinking) are linked to aberrant BMD. In addition, no previous study has investigated whether ucOC or TRACP-5b is clinically useful to predict low BMD not only in the general population, but also in alcohol-dependent subjects. PATIENTS AND METHODS: We recruited 275 male alcohol-dependent subjects and collected information about their drinking habits, comorbid diseases, smoking history and walking exercise behavior. BMD in each subject was determined by ultrasonography. Serum liver enzymes (AST, ALT, ALP, ChE, γ-GTP and LDH), ucOC and TRACP-5b were measured in all subjects. T-scores were calculated according to BMD for all subjects. RESULTS: The mean T-scores of our subjects were negatively shifted compared to the general population (-0.75±1.36 SD). We divided our subjects into a normal BMD group (n=137) and a low BMD group (n=138) according to their T-scores (T-score ≥-1 SD, normal BMD; T-score <-1 SD, low BMD). Multivariate logistic regression analysis showed that body mass index (BMI) was negatively associated with low BMD (95% CI: 0.75-0.90). By contrast, long abstinence period (95% CI: 1.40-4.21), smoking (95% CI: 1.30-5.56), hypertension (95% CI: 1.04-3.76), lactate dehydrogenase (LDH) (95% CI: 1.00-1.01) and ucOC (95% CI: 1.04-1.22) were positively associated with low BMD. CONCLUSION: In alcohol-dependent males, smoking habits and higher ucOC are associated with low BMD. Our study suggests that smoking cessation may prevent lower BMD, and ucOC may predict lower BMD in alcohol-dependent individuals.2018年, Neuropsychiatric disease and treatment, 14, 663 - 669, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Life expectancy is 10-20 years lower in patients with schizophrenia than in the general population. In addition, men with schizophrenia have an earlier age at onset, more pronounced deficit symptoms, poorer course, and poorer response to antipsychotic medications than women. Recent studies have indicated that loss of chromosome Y (LOY) in peripheral blood is associated with an increased risk of all-cause mortality. In order to elucidate the pathophysiology of male-specific features, we investigated the association between LOY and schizophrenia. MATERIALS AND METHODS: The present study included 360 Japanese men (146 patients with schizophrenia vs 214 controls). The relative amount of Y chromosome was defined as the ratio of chromosome Y to chromosome X (Y/X ratio) based on the fluorescent signal of co-amplified short sequences from the Y-X homologous amelogenin genes (AMELY and AMELX). RESULTS: There was no significant difference in the frequency of LOY between the schizophrenia and control groups. However, longer duration of illness was associated with LOY after controlling for age and smoking status in the schizophrenia group (P=0.007, OR =1.11 [95% CI =1.03-1.19]). CONCLUSION: According to our results, schizophrenia may not have a remarkable effect on blood LOY; however, LOY may be associated with disease course in patients with schizophrenia.2018年, Neuropsychiatric disease and treatment, 14, 2115 - 2122, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Risperidone is mainly metabolized by cytochrome P450 (CYP) 2D6 in the liver. The gene encoding CYP2D6 is highly polymorphic. The average steady-state plasma concentration of risperidone active moiety is higher in the CYP2D6 intermediate metabolizers (IMs) compared with that in the extensive metabolizers (EMs). An association between drug-induced extrapyramidal symptoms scale (DIEPSS) score and CYP2D6 polymorphisms has not been reported to date. This study investigates the association of CYP2D6 polymorphisms with the severity of extrapyramidal symptoms in schizophrenia patients receiving risperidone therapy. METHODS: Schizophrenia patients undergoing risperidone treatment were recruited for the study in the Kobe University Hospital. We evaluated extrapyramidal symptoms of schizophrenia using the DIEPSS. CYP2D6*10 and CYP2D6*14 were analyzed using TaqMan® assays, and CYP2D6*5 was analyzed using the long-PCR method. Patients with CYP2D6*1/*5, *1/*14, *5/*10, *10/*10, and *10/*14 were classified as IMs, and patients with CYP2D6*1/*1 and *1/*10 were classified as EMs. Patients with CYP2D6*5/*5, *5/*14, and *14/*14 were classified as poor metabolizers (PMs). RESULTS: A total of 22 patients were included in the study. No patients were classified as PMs. The dose of risperidone (mg/day) was not significantly different between EMs (n = 15) and IMs (n = 7) (median with the interquartile range: 4.0 (2.0-6.0) vs. 4.0 (2.0-7.0) mg, p = 0.31). The age and disease duration of schizophrenia were not significantly different between the EMs and IMs. The DIEPSS score in the IMs was significantly higher than that in the EMs (median with the interquartile range: 5.0 (3.5-6.5) vs. 0.0 (0.0-3.0), p < 0.001). The multiple regression analysis showed that CYP2D6 IMs is a significant risk factor for the DIEPSS (p < 0.05). CONCLUSION: Special attentions should be paid to the onset of extrapyramidal symptoms in schizophrenia patients identified as CYP2D6 IM undergoing risperidone therapy.2018年, Journal of pharmaceutical health care and sciences, 4, 28 - 28, 英語, 国際誌研究論文（学術雑誌）
- AIM: Rare gene variations are thought to confer substantial risk for schizophrenia. We performed a three-stage study to identify rare variations that have a strong impact on the risk of developing schizophrenia. METHODS: In the first stage, we prioritized rare missense variations using whole-exome sequencing (WES) data from three families, consisting of a proband, an affected sibling, and parents. In the second stage, we performed targeted resequencing of the PDCD11 coding region in 96 patients. In the third stage, we conducted an association study of rare PDCD11 variations with schizophrenia in a total of 1357 patients and 1394 controls. RESULTS: Via WES, we identified two rare missense PDCD11 variations, p.(Asp961Asn) and p.(Val1240Leu), shared by two affected siblings within families. Targeted resequencing of the PDCD11 coding region identified three rare non-synonymous variations: p.(Asp961Asn), p.(Phe1835del), and p.(Arg1837His). The case-control study demonstrated no significant associations between schizophrenia and four rare PDCD11 variations: p.(Asp961Asn), p.(Val1240Leu), p.(Phe1835del), and p.(Arg1837His). CONCLUSION: Our data do not support the role of rare PDCD11 variations in conferring substantial risk for schizophrenia in the Japanese population.2017年11月, Psychiatry and clinical neurosciences, 71(11) (11), 780 - 788, 英語, 国際誌研究論文（学術雑誌）
- AIM: Rare variations are suggested to play a role in the genetic etiology of schizophrenia; to further investigate their role, we performed a three-stage study in a Japanese population. METHODS: In the first stage, we performed whole-exome sequencing (WES) of two parent-affected offspring trios. In the second stage, we resequenced the FBXO18 coding region in 96 patients. In the third stage, we tested rare non-synonymous FBXO18 variations for association with schizophrenia in two independent populations comprising a total of 1376 patients and 1496 controls. RESULTS: A rare frameshift variation (L116fsX) in the FBXO18 gene was recurrently identified by WES in both trios. Resequencing FBXO18 coding regions, we detected three rare non-synonymous variations (V15L, L116fsX, and V1006I). However, there were no significant associations between these rare FBXO18 variations and schizophrenia in the case-control study. CONCLUSION: Our present study does not provide evidence for the contribution of rare non-synonymous FBXO18 variations to the genetic etiology of schizophrenia in the Japanese population. However, to draw a definitive conclusion, further studies should be performed using sufficiently large sample sizes.2017年08月, Psychiatry and clinical neurosciences, 71(8) (8), 562 - 568, 英語, 国際誌研究論文（学術雑誌）
- Short telomere length (TL) occurs in individuals under psychological stress, and with various psychiatric diseases. Recent studies have also reported mitochondrial DNA copy number (mtDNAcn) alterations under several neuropsychiatric conditions. However, no study has examined whether aberrant TL or mtDNAcn occur in completed suicide, one of the most serious outcomes of mental illnesses. TL and mtDNAcn in post-mortem samples from 528 suicide completers without severe physical illness (508 peripheral bloods; 20 brains) and 560 samples from control subjects (peripheral bloods from 535 healthy individuals; 25 post-mortem brains) were analysed by quantitative polymerase chain reaction. Suicide completers had significantly shorter TL and higher mtDNAcn of peripheral bloods with sex/age-dependent differences (shorter TL was more remarkably in female/young suicides; higher mtDNAcn more so in male/elderly suicides). The normal age-related decline of TL and mtDNAcn were significantly altered in suicide completers. Furthermore, shorter TL and lower mtDNAcn of post-mortem prefrontal cortex were seen in suicide completers compared to controls. This study shows the first association of aberrant telomeres and mtDNA content with suicide completion. Our results indicate that further research on telomere shortening and mitochondrial dysfunction may help elucidate the molecular underpinnings of suicide-related pathophysiology.2017年06月, Scientific Reports, 7(1) (1), 3176 - 3176, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 2017年04月, Psychiatry and clinical neurosciences, 71(4) (4), 289 - 290, 英語, 国際誌
- BACKGROUND: Numerous studies suggest that inflammation plays a key role in suicidal behavior. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, has received increasing attention in depression research. However, no study has investigated whether MIF has genetic involvement in completed suicide. In this study, we sought to explore the relationship between two functional polymorphisms on the MIF gene promoter (MIF-794CATT5-8 microsatellite and MIF-173G/C single-nucleotide polymorphism [SNP]) and completed suicide by using one of the largest samples of suicide completers ever reported. METHODS: The subjects comprised 602 suicide completers and 728 healthy controls. We genotyped MIF-794CATT5-8 microsatellite by polymerase chain reaction-based size discrimination assay and MIF-173G/C SNP by TaqMan® SNP genotyping assay. The allele-, genotype-, or haplotype-based association analyses between the suicide completers and the controls were carried out with the χ2 test, the Cochran-Armitage trend test, or Fisher's exact test. RESULTS: Analyses of allele or genotype frequency distributions of the polymorphisms studied here did not reveal any significant differences between the suicide completers and the controls. Haplotype analysis also revealed no association with completed suicide. CONCLUSION: To our knowledge, this is the first study that has examined the genetic association between MIF and completed suicide. Our results suggest that the effects of MIF-794CATT5-8 microsatellite and MIF-173G/C SNP on the MIF gene promoter might not contribute to the genetic risk of completed suicide in the Japanese population.2017年, Neuropsychiatric disease and treatment, 13, 899 - 908, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Recent studies suggest that genomic abnormalities such as single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) may elevate the risk of schizophrenia. Such genomic abnormalities often occur during chromosomal DNA replication in the S phase of cell cycle. In addition, several studies showed that abnormal expressions of several cell cycle-related genes are associated with schizophrenia. Therefore, here we compared mRNA expression levels of cell cycle-related genes in peripheral blood cells between patients with schizophrenia and healthy controls. METHOD: mRNA expression levels of cell cycle-related genes in peripheral blood cells from patients with schizophrenia and healthy controls were measured with quantitative reverse transcription polymerase chain reaction (Q-RT-PCR). The discovery, replication and intervention studies with Q-RT-PCR were performed as follows: discovery (40 cases and 20 controls), replication (82 cases and 74 controls) and intervention (22 cases and 18 controls). RESULT: Nine genes were identified in the discovery and replication stages as schizophrenia-associated genes. Moreover, the combination of mRNA expression levels of CDK4, MCM7 and POLD4 was identified as a potential biomarker for schizophrenia with multivariate logistic regression analysis. The intervention stage revealed that the mRNA expression levels of these three genes were significantly decreased in the acute state of schizophrenia, and CDK4 was significantly recovered in the remission state of schizophrenia. CONCLUSION: The combination of mRNA expression levels of three cell cycle-related genes such as CDK4, MCM7 and POLD4 is expected to be a candidate for useful biomarkers for schizophrenia. Especially, the mRNA expression changes of CDK4 may be potential as both trait and state markers for schizophrenia.2016年10月, Progress in neuro-psychopharmacology & biological psychiatry, 70, 85 - 91, 英語, 国際誌研究論文（学術雑誌）
- It has been shown that the dysfunction of N-methyl-d-asparate (NMDA) receptors-mediated neurotransmission plays a role in the pathophysiology of schizophrenia. Especially, GluN2B, a subunit of NMDA receptors, associated trafficking complex is altered in the prefrontal cortex of schizophrenia. The kinesin superfamily motor protein 17 (KIF17) is known as a transporter of NR2B.Previous studies showed that a structural variant of KIF17 gene is associated with a schizophrenic phenotype. Therefore, here we investigated KIF17 levels in postmortem prefrontal cortex in schizophrenia and the association of a missense polymorphism (Ile341Val) in KIF17 with schizophrenia. The protein expression of KIF17 in schizophrenic postmortem brains was significantly lower than that in controls. Next, the association of missense polymorphisms (rs631375, rs13375609, rs522496 and rs2296225) of KIF17 gene in 567 schizophrenia and 710 healthy subjects was examined. Both genotypic distribution and allelic frequency of rs2296225 polymorphism were significantly different between the chronic schizophrenia subjects and controls. However, our findings described above were not replicated with the independent subjects (555 schizophrenia and 814 healthy controls). Furthermore, the two alleles of rs2296225 polymorphism did not affect the mRNA expression of KIF17. These results suggest that the dysfunction of KIF17 might be involved in the pathophysiology of schizophrenia.2015年12月, Psychiatry research, 230(2) (2), 424 - 9, 英語, 国際誌研究論文（学術雑誌）
- 2015年09月, Psychiatry research, 229(1-2) (1-2), 627 - 8, 英語, 国際誌
- BACKGROUND: Cadherin13 (CDH13) is a glycosylphosphatidylinositol-anchored cell adhesion molecule that plays a crucial role in morphogenesis and the maintenance of neuronal circuitry. CDH13 has been implicated in the susceptibility to a variety of psychiatric diseases. A recent genome-wide association study using Danish samples showed, for the first time, the involvement of a single nucleotide polymorphism (SNP) of CDH13 (intronic SNP rs8057927) in schizophrenia. Here, we investigated the association between other SNPs of CDH13 and schizophrenia and tried to replicate the association for the SNP of rs8057927, in the Japanese population. METHODS: Using TaqMan(®) SNP genotyping assays, five tag SNPs (rs12925602, rs7193788, rs736719, rs6565051, and rs7204454) in the promoter region of CDH13 were examined for their association with schizophrenia in two independent samples. The first sample comprised 665 patients and 760 controls, and the second sample comprised 677 patients and 667 controls. One tag SNP for rs8057927 was also examined for the association with schizophrenia in the first sample set. RESULTS: A GACAG haplotype of the five SNPs in the promoter region of CDH13 was significantly associated with schizophrenia in the first sample set (P=0.016 and corrected P=0.098). A combined analysis of the GACAG haplotype with the second sample set enhanced the significance (P=0.0026 and corrected P=0.021). We found no association between rs8057927 and schizophrenia in the first sample set. CONCLUSION: Our results suggest that CDH13 may contribute to the genetic risk of schizophrenia. Further replication on the association of CDH13 with schizophrenia and functional studies are required to confirm the current findings.2015年, Neuropsychiatric disease and treatment, 11, 1381 - 93, 英語, 国際誌研究論文（学術雑誌）
- BACKGROUND: Genome-wide association studies (GWAS) and gene expression analyses have revealed that single nucleotide polymorphisms (SNPs) associated with multifactorial diseases, such as schizophrenia, are significantly more likely to be associated with expression quantitative trait loci (eQTL). It was recently suggested that an immune system imbalance plays an important role in the pathogenesis of schizophrenia. Interleukin-19 is a novel cytokine that may play multiple roles in immune regulation and various diseases. METHOD: We selected eight tag SNPs in the eQTL of the IL-19 gene. Seven of the SNPs are putative cis-acting SNPs. Then, we conducted a case-control study using two independent samples. The first sample comprised 567 schizophrenia patients and 710 controls, and the second sample comprised 677 schizophrenia patients and 667 controls. RESULT: We identified the TGAA haplotype as being significantly associated with schizophrenia (p=0.0036 and corrected p=0.0264), although a combined analysis of the TGAA haplotype with the replication samples exhibited a nominally significant difference (p=0.022 and corrected p=0.235). CONCLUSIONS: These results suggest that the IL-19 gene might slightly contribute to the genetic risk of schizophrenia. Thus, further research on the association of eQTL SNPs with schizophrenia is warranted.2014年04月, Progress in neuro-psychopharmacology & biological psychiatry, 50, 151 - 6, 英語, 国際誌研究論文（学術雑誌）
- 2022年06月, 臨床精神医学, 51;9:p1057-1063, 日本語不安と自殺・自傷：特に遺伝学的知見の観点から.[招待有り]記事・総説・解説・論説等（学術雑誌）
- 2021年10月, 医学のあゆみ, 279;1:p29-34, 日本語臨床での活用が期待される自殺の生物学的知見.記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）
- 2021年06月, 臨床精神医学, 50;6:p577-583, 日本語自殺の神経生物学的異常.記事・総説・解説・論説等（学術雑誌）
- 2020年, 日本生物学的精神医学会誌 31;3:p134-140自殺の遺伝学的研究の現況.
- 2016年06月, 日本神経精神薬理学雑誌 36:p55-62自殺既遂の生物学的研究.
- 分担執筆, Resilience and Suicide., Nova Science Publishers, 2018年Facilitating Resilience after PTSD: A Translational Approach.
- 分担執筆, 自殺の遺伝子研究, 医薬ジャーナル社, 2017年Depression Frontier 2; うつ病臨床のこんな疑問に答える −脳科学からのアプローチ−
- 日本学術振興会, 科学研究費助成事業, 基盤研究(B), 神戸大学, 2024年04月01日 - 2027年03月31日若者を自殺に追い込む生物学的異常と可逆性：エピゲノム・シングルセルダイナミクス
- 日本学術振興会, 科学研究費助成事業, 基盤研究(C), 神戸大学, 2024年04月01日 - 2027年03月31日統合失調症の老化促進のエピジェネティクス的病態機序の解明
- 日本学術振興会, 科学研究費助成事業, 基盤研究(C), 神戸大学, 2024年04月01日 - 2027年03月31日自殺者GWASを用いた自殺のリスク遺伝子・体細胞モザイク異常の解明
- 国立研究開発法人科学技術振興機構（JST）, ムーンショット目標9, 2025年 - 2026年子ども・若者の虐待・抑うつ・自殺ゼロ化社会
- 日本学術振興会, 科学研究費助成事業, 基盤研究(B), 2021年04月01日 - 2024年03月31日ポリジェニックリスクスコアを用いた自殺リスクの予測と遺伝学的解明本研究では、自殺者試料の追加ジェノタイピングを実施し、アジア最大の自殺GWASデータを構築した。アジア人集団の自殺リスクに関連するSP4遺伝子プロモーター領域SNPを同定した。また自殺者GWASデータを用いた体細胞モザイク解析により、「自殺者における常染色体及びX染色体モザイクの異常増加」という先駆的な知見を見出した。さらに国際自殺ゲノムコンソーシアムにアジア最大の自殺者GWASデータを提供し、過去最大の人種横断的な自殺行動GWASを実施し、複数の関連遺伝子領域を同定した。Base dataとして用いる日本人自殺GWASをスケールアップするほど、自殺PRSの予測精度が向上することを見出した。
- 日本学術振興会, 科学研究費助成事業, 基盤研究(C), 神戸大学, 2021年04月01日 - 2024年03月31日大学生の末梢血テロメア長を用いた若年自殺リスクマーカーの確立若年者の高い自殺率が続いている深刻な社会状況の中、申請者らは「日本人若年自殺者において末梢血テロメア長・エピゲノム年齢といった生物学的年齢指標が老齢化している」現象を見出した。申請者はこの若年自殺者の生物学的異常老齢化の知見を、サンプルサイズをスケールアップして確実なものとした。その上で、自殺リスクを抱える若者の末梢血テロメア長・エ ピゲノム年齢を測定し、自殺念慮・行動の有無や心理学的スコアなどの推移との関連を調べることで、若年者の自殺リスクのバイオマーカーとして有用かどうかを検討した。特に衝動性の高い自殺ハイリスク者の末梢血で、エピゲノム年齢が有意に老齢化していた。
- 日本学術振興会, 科学研究費助成事業, 国際共同研究加速基金(国際共同研究強化(B)), 2020年10月27日 - 2024年03月31日自殺リスクの遺伝因子に関する国際共同研究本申請では、自殺研究の世界的中核機関であるコロンビア大学精神科等と連携し、世界で初めて立ち上げとなった「国際自殺遺伝学コンソーシアム（以下、ISGC）」の拡張を実施した。申請者らは、ISGCにアジア最大の自殺者GWASデータを提供し、過去最大の43,871例の人種横断的な自殺行動者GWASを実施し、複数の候補遺伝子領域を同定した。また自殺行動と様々な精神科領域関連のヒト表現型との遺伝的相関を示した。自殺GWASにおけるうつ病/統合失調症のポリジェニックリスクスコア解析を人種ごとに比較解析することで、白人に比してアジア人では、自殺とうつ病/統合失調症との遺伝的関連が弱い可能性を見出した。
- 先進医薬研究振興財団, 若手研究者助成（新規 及び 継続）, 2023年 - 2024年, 研究代表者網羅的ゲノム・エピゲノムデータを用いた若年自殺行動の機序解明とリスクマーカー開発
- 国立研究開発法人科学技術振興機構（JST）, ムーンショット目標9, 2023年 - 2024年子どもの虐待・自殺ゼロ化社会
- 国立研究開発法人日本医療研究開発機構（AMED）, ゲノム創薬基盤推進研究事業, 2022年 - 2024年, 研究分担者薬剤性パーキンソニズムのファーマコゲノミクスに関する医療実装開発
- 国立研究開発法人日本医療研究開発機構（AMED）, 障害者対策総合研究開発事業, 2022年 - 2024年, 研究分担者自殺ポリジェニックリスクスコアを用いた精神疾患患者の自殺リスク予測に関する 研究開発
- 日本学術振興会, 科学研究費助成事業, 若手研究, 神戸大学, 2021年04月01日 - 2023年03月31日ゲノム・エピゲノムデータを用いた若年自殺リスクのバイオマーカー開発本邦でも世界的にも自殺（特に若年者）が増加している。本研究では、未だそのバイオマーカーや生物学的機序が明らかとなっていない若年自殺について、申請者が既にプレリミナリーな知見として同定済みの新規的知見「若年自殺者におけるテロメア短縮・DNAメチル化年齢老齢化・GTF2IRD1遺伝子多型の関連」を独立した若年自殺コホートで追試できた他、若年自殺者のnatural killer細胞増加の知見や、非致死性自殺未遂と自殺完遂に区分しての自殺行動と他精神科関連表現型の遺伝的相関描出といった成果を得ることができた。
- 日本学術振興会, 科学研究費助成事業, 基盤研究(C), 神戸大学, 2018年04月01日 - 2021年03月31日テロメア長に着目した若年者の自殺リスクマーカーの開発自殺ハイリスク学生/健常学生に対し、末梢血テロメア長測定及び自殺企図の有無の確認、HAMD17・SRS18・C-SSRSといった心理学的検査を施行した。若年自殺行動者群において、Infinium Human Methylation 450K BeadChipの網羅的DNAメチル化解析(MWAS)データ由来のテロメア長が短縮している知見を見出した。またテロメア動態とも関連がある長寿遺伝子Sirtuin1の遺伝子多型が中高年女性の自殺リスクに寄与する可能性が示唆された。
- 日本学術振興会, 科学研究費助成事業, 若手研究(B), 神戸大学, 2016年04月01日 - 2019年03月31日男性統合失調症におけるX染色体上CpGアイランドの異常高メチル化の機能解析replicationセットの男性統合失調症/健常対照男性 各40名のDNAについて、MassARRAYを用いて対象となるCpGアイランドA内のCpGサイトのメチル化頻度を測定し、予備的研究のメチル化異常（統合失調症男性の一部において同領域が異常に高メチル化している現象）の追試に成功した。また各末梢血試料について関連遺伝子TAF1のmRNA発現量を測定し、対照群との比較やメチル化頻度との関連解析を行った。ヒト男性由来神経幹細胞やiPS細胞由来神経細胞の培養系を確立し、CRISPR/Cas9法にて異常高メチル化領域のDNA配列の機能欠失→細胞表現型にどのような影響があるかについても検討中である。
- 日本学術振興会, 科学研究費助成事業, 若手研究(B), 神戸大学, 2016年04月01日 - 2019年03月31日自殺者血液・死後脳におけるテロメア長およびミトコンドリアDNAコピー数の解析心理的ストレスへの曝露や、種々の精神疾患罹患により、テロメア長（TL）やミトコンドリアDNAコピー数（mtDNAcn）が異常を来すことが知られている。我々は自殺既遂者検体と対照者検体のTL・mtDNAcnを定量的PCR法にて測定した。自殺既遂者末梢血では有意にTLが短縮・mtDNAcnが増加しており、年代によって関連の強さに差異を認めた（TL短縮は若年自殺者でより顕著に、mtDNAcn増加は高齢自殺者でより顕著にみられた）。さらに自殺既遂者群の死後前頭前皮質では対照者群に比して顕著なTL短縮、mtDNAcn低下がみられた。
- 先進医薬研究振興財団, 海外留学助成, 2019年, 研究代表者大規模な自殺完遂者・未遂者試料を用いた自殺の遺伝因子の解明