Research activity information

• Dec. 2021 日本神経精神薬理学会, JSNP Excellent Presentation Award for AsCNP, Epigenetic clock analysis of blood samples from Japanese schizophrenia patients


• Feb. 2021 日本神経精神薬理学会, JSNP Excellent Presentation Award for CINP, Accelerated extrinsic epigenetic aging and increased natural killer cells in blood of suicide completers

• Epigenetic Clock Analysis for National Institutes of Health Stroke Scale in Patients With Ischemic Stroke.

  Wenshan Jiang, Toshiyuki Shirai, Ikuo Otsuka, Satoshi Okazaki, Takaki Tanifuji, Tadasu Horai, Haruka Minami, Masao Miyachi, Shohei Okada, Akitoyo Hishimoto

  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.

  Mar. 2025, Neuropsychopharmacology reports, 45(1) (1), e70009, English, International magazine

  Scientific journal


• Relationship of Major Depressive Disorder and Schizophrenia Polygenic Risk Scores to Suicide: A Comparison Between European and Asian Ancestry Populations.

  Ikuo Otsuka, Hanga Galfalvy, Jia Guo, Masato Akiyama, Satoshi Okazaki, Chikashi Terao, Dan Rujescu, Gustavo Turecki, Akitoyo Hishimoto, J John Mann

  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, Archives of suicide research : official journal of the International Academy for Suicide Research, 29(1) (1), 309 - 316, English, International magazine

  Scientific journal


• Biological aging analysis based on DNA methylation status for social anxiety disorder.

  Nobuhiko Noguchi, Toshiyuki Shirai, Akira Suda, Saki Hattori, Masatoshi Miyauchi, Satoshi Okazaki, Junichi Fujita, Takeshi Asami, Ikuo Otsuka, Akitoyo Hishimoto

  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.

  Dec. 2024, Neuropsychopharmacology reports, 44(4) (4), 774 - 783, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Meta-analyses of epigenetic age acceleration and GrimAge components of schizophrenia or first-episode psychosis.

  Toshiyuki Shirai, Satoshi Okazaki, Takaki Tanifuji, Shusuke Numata, Tomohiko Nakayama, Tomohiro Yoshida, Kentaro Mouri, Ikuo Otsuka, Noboru Hiroi, Akitoyo Hishimoto

  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.

  Nov. 2024, Schizophrenia (Heidelberg, Germany), 10(1) (1), 108 - 108, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Preliminary development of a risk predictor for severe complication in patients with anorexia nervosa.

  Toshiyuki Shirai, Takaki Tanifuji, Ikuo Otsuka, Satoshi Okazaki, Tadasu Horai, Naruhisa Yamaki, Haruka Minami, Masao Miyachi, Shohei Okada, Akitoyo Hishimoto

  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).

  Sep. 2024, Psychiatry research, 342, 116151 - 116151, English, International magazine

  Scientific journal


• Comprehensive analysis including in-game spending and violent game playing in patients with internet gaming disorder.

  Haruka Minami, Toshiyuki Shirai, Shohei Okada, Masao Miyachi, Takaki Tanifuji, Satoshi Okazaki, Tadasu Horai, Kentaro Mouri, Ikuo Otsuka, Akitoyo Hishimoto

  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.

  Jul. 2024, Neuropsychopharmacology reports, 44(3) (3), 631 - 638, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• 精神疾患のエピジェネティクス研究 自殺のエピジェネティクス

  岡崎 賢志, 大塚 郁夫, 谷藤 貴紀, 白井 寿行, 毛利 健太朗, 菱本 明豊

  日本臨床精神神経薬理学会・日本神経精神薬理学会, May 2024, 日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集, 34回・54回, JSY1 - 3, Japanese


• Accelerated epigenetic aging in alcohol dependence.

  Toshiyuki Shirai, Satoshi Okazaki, Ikuo Otsuka, Masao Miyachi, Takaki Tanifuji, Ryota Shindo, Shohei Okada, Haruka Minami, Tadasu Horai, Kentaro Mouri, Akitoyo Hishimoto

  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.

  May 2024, Journal of psychiatric research, 173, 175 - 182, English, International magazine

  Scientific journal


• Association study of a single nucleotide polymorphism in the hypoxia response element of the macrophage migration inhibitory factor gene promoter with suicide completers in the Japanese population.

  Toshiyuki Shirai, Satoshi Okazaki, Takaki Tanifuji, Ikuo Otsuka, Masao Miyachi, Shohei Okada, Ryota Shindo, Tadasu Horai, Kentaro Mouri, Motonori Takahashi, Takeshi Kondo, Yasuhiro Ueno, Akitoyo Hishimoto

  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.

  Mar. 2024, Neuropsychopharmacology reports, 44(1) (1), 262 - 266, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Epigenome-wide association study on methamphetamine dependence.

  Toshiyuki Shirai, Satoshi Okazaki, Takaki Tanifuji, Ikuo Otsuka, Tadasu Horai, Kentaro Mouri, Yukihiro Takemura, Katsuro Aso, Noriya Yamamoto, Akitoyo Hishimoto

  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.

  Mar. 2024, Addiction biology, 29(3) (3), e13383, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.

  Anna R Docherty, Niamh Mullins, Allison E Ashley-Koch, Xuejun Qin, Jonathan R I Coleman, Andrey Shabalin, JooEun Kang, Balasz Murnyak, Frank Wendt, Mark Adams, Adrian I Campos, Emily DiBlasi, Janice M Fullerton, Henry R Kranzler, Amanda V Bakian, Eric T Monson, Miguel E Rentería, Consuelo Walss-Bass, Ole A Andreassen, Chittaranjan Behera, Cynthia M Bulik, Howard J Edenberg, Ronald C Kessler, J John Mann, John I Nurnberger Jr, Giorgio Pistis, Fabian Streit, Robert J Ursano, Renato Polimanti, Michelle Dennis, Melanie Garrett, Lauren Hair, Philip Harvey, Elizabeth R Hauser, Michael A Hauser, Jennifer Huffman, Daniel Jacobson, Ravi Madduri, Benjamin McMahon, David W Oslin, Jodie Trafton, Swapnil Awasthi, Wade H Berrettini, Martin Bohus, Xiao Chang, Hsi-Chung Chen, Wei J Chen, Erik D Christensen, Scott Crow, Philibert Duriez, Alexis C Edwards, Fernando Fernández-Aranda, Hanga Galfalvy, Michael Gandal, Philip Gorwood, Yiran Guo, Jonathan D Hafferty, Hakon Hakonarson, Katherine A Halmi, Akitoyo Hishimoto, Sonia Jain, Stéphane Jamain, Susana Jiménez-Murcia, Craig Johnson, Allan S Kaplan, Walter H Kaye, Pamela K Keel, James L Kennedy, Minsoo Kim, Kelly L Klump, Daniel F Levey, Dong Li, Shih-Cheng Liao, Klaus Lieb, Lisa Lilenfeld, Christian R Marshall, James E Mitchell, Satoshi Okazaki, Ikuo Otsuka, Dalila Pinto, Abigail Powers, Nicolas Ramoz, Stephan Ripke, Stefan Roepke, Vsevolod Rozanov, Stephen W Scherer, Christian Schmahl, Marcus Sokolowski, Anna Starnawska, Michael Strober, Mei-Hsin Su, Laura M Thornton, Janet Treasure, Erin B Ware, Hunna J Watson, Stephanie H Witt, D Blake Woodside, Zeynep Yilmaz, Lea Zillich, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Lars Alfredsson, Vivek Appadurai, María Soler Artigas, Sandra Van der Auwera, M Helena Azevedo, Nicholas Bass, Claiton H D Bau, Bernhard T Baune, Frank Bellivier, Klaus Berger, Joanna M Biernacka, Tim B Bigdeli, Elisabeth B Binder, Michael Boehnke, Marco P Boks, David L Braff, Richard Bryant, Monika Budde, Enda M Byrne, Wiepke Cahn, Enrique Castelao, Jorge A Cervilla, Boris Chaumette, Aiden Corvin, Nicholas Craddock, Srdjan Djurovic, Jerome C Foo, Andreas J Forstner, Mark Frye, Justine M Gatt, Ina Giegling, Hans J Grabe, Melissa J Green, Eugenio H Grevet, Maria Grigoroiu-Serbanescu, Blanca Gutierrez, Jose Guzman-Parra, Marian L Hamshere, Annette M Hartmann, Joanna Hauser, Stefanie Heilmann-Heimbach, Per Hoffmann, Marcus Ising, Ian Jones, Lisa A Jones, Lina Jonsson, René S Kahn, John R Kelsoe, Kenneth S Kendler, Stefan Kloiber, Karestan C Koenen, Manolis Kogevinas, Marie-Odile Krebs, Mikael Landén, Marion Leboyer, Phil H Lee, Douglas F Levinson, Calwing Liao, Jolanta Lissowska, Fermin Mayoral, Susan L McElroy, Patrick McGrath, Peter McGuffin, Andrew McQuillin, Divya Mehta, Ingrid Melle, Philip B Mitchell, Esther Molina, Gunnar Morken, Caroline Nievergelt, Markus M Nöthen, Michael C O'Donovan, Roel A Ophoff, Michael J Owen, Carlos Pato, Michele T Pato, Brenda W J H Penninx, James B Potash, Robert A Power, Martin Preisig, Digby Quested, Josep Antoni Ramos-Quiroga, Andreas Reif, Marta Ribasés, Vanesa Richarte, Marcella Rietschel, Margarita Rivera, Andrea Roberts, Gloria Roberts, Guy A Rouleau, Diego L Rovaris, Alan R Sanders, Peter R Schofield, Thomas G Schulze, Laura J Scott, Alessandro Serretti, Jianxin Shi, Lea Sirignano, Pamela Sklar, Olav B Smeland, Jordan W Smoller, Edmund J S Sonuga-Barke, Maciej Trzaskowski, Ming T Tsuang, Gustavo Turecki, Laura Vilar-Ribó, John B Vincent, Henry Völzke, James T R Walters, Cynthia Shannon Weickert, Thomas W Weickert, Myrna M Weissman, Leanne M Williams, Naomi R Wray, Clement C Zai, Esben Agerbo, Anders D Børglum, Gerome Breen, Ditte Demontis, Annette Erlangsen, Joel Gelernter, Stephen J Glatt, David M Hougaard, Hai-Gwo Hwu, Po-Hsiu Kuo, Cathryn M Lewis, Qingqin S Li, Chih-Min Liu, Nicholas G Martin, Andrew M McIntosh, Sarah E Medland, Ole Mors, Merete Nordentoft, Catherine M Olsen, David Porteous, Daniel J Smith, Eli A Stahl, Murray B Stein, Danuta Wasserman, Thomas Werge, David C Whiteman, Virginia Willour, Hilary Coon, Jean C Beckham, Nathan A Kimbrel, Douglas M Ruderfer

  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.

  Oct. 2023, The American journal of psychiatry, 180(10) (10), 723 - 738, English, International magazine

  Scientific journal


• Accelerated epigenetic aging and decreased natural killer cells based on DNA methylation in patients with untreated major depressive disorder.

  Ryota Shindo, Takaki Tanifuji, Satoshi Okazaki, Ikuo Otsuka, Toshiyuki Shirai, Kentaro Mouri, Tadasu Horai, Akitoyo Hishimoto

  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.

  Sep. 2023, npj aging, 9(1) (1), 19 - 19, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• 精神疾患とエピゲノム、そしてエピゲノム年齢

  白井 寿行, 岡崎 賢志, 谷藤 貴紀, 大塚 郁夫, 毛利 健太朗, 菱本 明豊

  (一財)仁明会, Sep. 2023, 仁明会精神医学研究, 21(1) (1), 51 - 71, Japanese


• Association of two variable number of tandem repeats in the monoamine oxidase A gene promoter with suicide completion: The present study and meta-analysis.

  Masashi Hasegawa, Takaki Tanifuji, Satoshi Okazaki, Ikuo Otsuka, Toshiyuki Shirai, Ryota Shindo, Tadasu Horai, Kentaro Mouri, Motonori Takahashi, Takeshi Kondo, Yasuhiro Ueno, Akitoyo Hishimoto

  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.

  May 2023, Neuropsychopharmacology reports, 43(3) (3), 338 - 345, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Epigenetic clock analysis reveals increased plasma cystatin C levels based on DNA methylation in major depressive disorder.

  Takaki Tanifuji, Satoshi Okazaki, Ikuo Otsuka, Kentaro Mouri, Tadasu Horai, Ryota Shindo, Toshiyuki Shirai, Akitoyo Hishimoto

  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.

  Apr. 2023, Psychiatry research, 322, 115103 - 115103, English, International magazine

  Scientific journal


• Telencephalon Organoids Derived from an Individual with ADHD Show Altered Neurodevelopment of Early Cortical Layer Structure.

  Danmeng Zhang, Noriomi Eguchi, Satoshi Okazaki, Ichiro Sora, Akitoyo Hishimoto

  Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that occurs in early childhood and can persist to adulthood. It can affect many aspects of a patient's daily life, so it is necessary to explore the mechanism and pathological alterations. For this purpose, we applied induced pluripotent stem cell (iPSC)-derived telencephalon organoids to recapitulate the alterations occurring in the early cerebral cortex of ADHD patients. We found that telencephalon organoids of ADHD showed less growth of layer structures than control-derived organoids. On day 35 of differentiation, the thinner cortex layer structures of ADHD-derived organoids contained more neurons than those of control-derived organoids. Furthermore, ADHD-derived organoids showed a decrease in cell proliferation during development from day 35 to 56. On day 56 of differentiation, there was a significant difference in the proportion of symmetric and asymmetric cell division between the ADHD and control groups. In addition, we observed increased cell apoptosis in ADHD during early development. These results show alterations in the characteristics of neural stem cells and the formation of layer structures, which might indicate key roles in the pathogenesis of ADHD. Our organoids exhibit the cortical developmental alterations observed in neuroimaging studies, providing an experimental foundation for understanding the pathological mechanisms of ADHD.

  Mar. 2023, Stem cell reviews and reports, 19(5) (5), 1482 - 1491, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Perceptual simultaneity range for two dichotically presented pure tones with frequency separation below 0.5 Bark.

  Satoshi Okazaki, Makoto Ichikawa, Minoru Tsuzaki

  The perceptual simultaneity range for two diotically presented tones increases with decreasing frequency separation of the two tones from approximately 0.5 Bark. As the present study of two frequency regions shows, this effect is not observed when the two tones are not presented to the same ear, i.e., presented dichotically. Since the increase in simultaneity is only observed when the tones are presented to the same ear, it is possible that it reflects the time-frequency uncertainty within a cochlear filter.

  Mar. 2023, JASA express letters, 3(3) (3), 034401 - 034401, English, International magazine

  Scientific journal


• Effective use of memantine for catatonia in major depressive disorder after failure of electroconvulsive therapy: A case report

  Takaki Tanifuji, Ikuo Otsuka, Toshio Atarashiya, Atsushi Kimura, Tadasu Horai, Satoshi Okazaki, Akitoyo Hishimoto

  Wiley, Mar. 2023, Psychiatry and Clinical Neurosciences Reports, 2(1) (1), e84, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Association of SLC6A3 variants with treatment-resistant schizophrenia: a genetic association study of dopamine-related genes in schizophrenia

  Masanobu Kogure, Nobuhisa Kanahara, Atsuhiro Miyazawa, Yuki Shiko, Ikuo Otsuka, Koichi Matsuyama, Masayuki Takase, Makoto Kimura, Hiroshi Kimura, Kiyomitsu Ota, Keita Idemoto, Masaki Tamura, Yasunori Oda, Taisuke Yoshida, Satoshi Okazaki, Fumiaki Yamasaki, Yusuke Nakata, Yoshinori Watanabe, Tomihisa Niitsu, Akitoyo Hishimoto, Masaomi Iyo

  2023, Frontiers in Psychiatry, 14, 1334335 - 1334335, English, International magazine

  Scientific journal


• Ribosomal DNA gene copies are increased in blood and brain of Japanese schizophrenia patients.

  Sen Li, Ikuo Otsuka, Takaki Tanifuji, Satoshi Okazaki, Tadasu Horai, Motonori Takahashi, Takeshi Kondo, Yasuhiro Ueno, Akitoyo Hishimoto

  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, PloS one, 18(1) (1), e0280694, English, International magazine

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Successful electroconvulsive therapy for 22q11.2 deletion syndrome with Schizophrenia and Parkinson's disease.

  Takaki Tanifuji, Ikuo Otsuka, Atsushi Kimura, Tadasu Horai, Satoshi Okazaki, Wataru Satake, Akitoyo Hishimoto

  Nov. 2022, Psychiatry and clinical neurosciences, 76(11) (11), 603 - 604, English, International magazine


• Epigenetic clock analysis in methamphetamine dependence.

  Yukihiro Takemura, Takaki Tanifuji, Satoshi Okazaki, Yutaka Shinko, Ikuo Otsuka, Tadasu Horai, Toshiyuki Shirai, Katsuro Aso, Noriya Yamamoto, Akitoyo Hishimoto

  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.

  Corresponding, Nov. 2022, Psychiatry research, 317, 114901 - 114901, English, International magazine

  [Refereed]

  Scientific journal


• Preventive effects of preoperative ramelteon on postoperative delirium in Asian elderly population: A randomized, double-blind, placebo-controlled trial, and a systematic review and meta-analysis.

  Takaki Tanifuji, Ikuo Otsuka, Satoshi Okazaki, Tadasu Horai, Ryuhei So, Kyoichi Shiroiwa, Kentaro Mouri, Motofumi Tanaka, Nobuko Ohmoto, Ichiro Sora, Midori Hirai, Takumi Fukumoto, Yonson Ku, Akitoyo Hishimoto

  Oct. 2022, Asian journal of psychiatry, 78, 103282 - 103282, English, International magazine


• Epigenetic aging in Williams syndrome.

  Satoshi Okazaki, Ryo Kimura, Ikuo Otsuka, Kiyotaka Tomiwa, Yasuko Funabiki, Masatoshi Hagiwara, Toshiya Murai, Akitoyo Hishimoto

  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.

  Lead, Apr. 2022, Journal of child psychology and psychiatry, and allied disciplines, 63(12) (12), 1553 - 1562, English, International magazine

  [Refereed]

  Scientific journal


• Novel missense SETD1A variants in Japanese patients with schizophrenia: Resequencing and association analysis.

  Ryo Morikawa, Yuichiro Watanabe, Hirofumi Igeta, Reza K Arta, Masashi Ikeda, Satoshi Okazaki, Satoshi Hoya, Takeo Saito, Ikuo Otsuka, Jun Egawa, Takaki Tanifuji, Nakao Iwata, Toshiyuki Someya

  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.

  Apr. 2022, Psychiatry research, 310, 114481 - 114481, English, International magazine

  Scientific journal


• Accelerated epigenetic age and shortened telomere length based on DNA methylation in Nicolaides-Baraitser syndrome.

  Yutaka Shinko, Satoshi Okazaki, Ikuo Otsuka, Tadasu Horai, Saehyeon Kim, Takaki Tanifuji, Akitoyo Hishimoto

  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.

  Corresponding, Mar. 2022, Molecular genetics & genomic medicine, 10(3) (3), e1876, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors.

  Niamh Mullins, JooEun Kang, Adrian I Campos, Jonathan R I Coleman, Alexis C Edwards, Hanga Galfalvy, Daniel F Levey, Adriana Lori, Andrey Shabalin, Anna Starnawska, Mei-Hsin Su, Hunna J Watson, Mark Adams, Swapnil Awasthi, Michael Gandal, Jonathan D Hafferty, Akitoyo Hishimoto, Minsoo Kim, Satoshi Okazaki, Ikuo Otsuka, Stephan Ripke, Erin B Ware, Andrew W Bergen, Wade H Berrettini, Martin Bohus, Harry Brandt, Xiao Chang, Wei J Chen, Hsi-Chung Chen, Steven Crawford, Scott Crow, Emily DiBlasi, Philibert Duriez, Fernando Fernández-Aranda, Manfred M Fichter, Steven Gallinger, Stephen J Glatt, Philip Gorwood, Yiran Guo, Hakon Hakonarson, Katherine A Halmi, Hai-Gwo Hwu, Sonia Jain, Stéphane Jamain, Susana Jiménez-Murcia, Craig Johnson, Allan S Kaplan, Walter H Kaye, Pamela K Keel, James L Kennedy, Kelly L Klump, Dong Li, Shih-Cheng Liao, Klaus Lieb, Lisa Lilenfeld, Chih-Min Liu, Pierre J Magistretti, Christian R Marshall, James E Mitchell, Eric T Monson, Richard M Myers, Dalila Pinto, Abigail Powers, Nicolas Ramoz, Stefan Roepke, Vsevolod Rozanov, Stephen W Scherer, Christian Schmahl, Marcus Sokolowski, Michael Strober, Laura M Thornton, Janet Treasure, Ming T Tsuang, Stephanie H Witt, D Blake Woodside, Zeynep Yilmaz, Lea Zillich, Rolf Adolfsson, Ingrid Agartz, Tracy M Air, Martin Alda, Lars Alfredsson, Ole A Andreassen, Adebayo Anjorin, Vivek Appadurai, María Soler Artigas, Sandra Van der Auwera, M Helena Azevedo, Nicholas Bass, Claiton H D Bau, Bernhard T Baune, Frank Bellivier, Klaus Berger, Joanna M Biernacka, Tim B Bigdeli, Elisabeth B Binder, Michael Boehnke, Marco P Boks, Rosa Bosch, David L Braff, Richard Bryant, Monika Budde, Enda M Byrne, Wiepke Cahn, Miguel Casas, Enrique Castelao, Jorge A Cervilla, Boris Chaumette, Sven Cichon, Aiden Corvin, Nicholas Craddock, David Craig, Franziska Degenhardt, Srdjan Djurovic, Howard J Edenberg, Ayman H Fanous, Jerome C Foo, Andreas J Forstner, Mark Frye, Janice M Fullerton, Justine M Gatt, Pablo V Gejman, Ina Giegling, Hans J Grabe, Melissa J Green, Eugenio H Grevet, Maria Grigoroiu-Serbanescu, Blanca Gutierrez, Jose Guzman-Parra, Steven P Hamilton, Marian L Hamshere, Annette Hartmann, Joanna Hauser, Stefanie Heilmann-Heimbach, Per Hoffmann, Marcus Ising, Ian Jones, Lisa A Jones, Lina Jonsson, René S Kahn, John R Kelsoe, Kenneth S Kendler, Stefan Kloiber, Karestan C Koenen, Manolis Kogevinas, Bettina Konte, Marie-Odile Krebs, Mikael Landén, Jacob Lawrence, Marion Leboyer, Phil H Lee, Douglas F Levinson, Calwing Liao, Jolanta Lissowska, Susanne Lucae, Fermin Mayoral, Susan L McElroy, Patrick McGrath, Peter McGuffin, Andrew McQuillin, Sarah E Medland, Divya Mehta, Ingrid Melle, Yuri Milaneschi, Philip B Mitchell, Esther Molina, Gunnar Morken, Preben Bo Mortensen, Bertram Müller-Myhsok, Caroline Nievergelt, Vishwajit Nimgaonkar, Markus M Nöthen, Michael C O'Donovan, Roel A Ophoff, Michael J Owen, Carlos Pato, Michele T Pato, Brenda W J H Penninx, Jonathan Pimm, Giorgio Pistis, James B Potash, Robert A Power, Martin Preisig, Digby Quested, Josep Antoni Ramos-Quiroga, Andreas Reif, Marta Ribasés, Vanesa Richarte, Marcella Rietschel, Margarita Rivera, Andrea Roberts, Gloria Roberts, Guy A Rouleau, Diego L Rovaris, Dan Rujescu, Cristina Sánchez-Mora, Alan R Sanders, Peter R Schofield, Thomas G Schulze, Laura J Scott, Alessandro Serretti, Jianxin Shi, Stanley I Shyn, Lea Sirignano, Pamela Sklar, Olav B Smeland, Jordan W Smoller, Edmund J S Sonuga-Barke, Gianfranco Spalletta, John S Strauss, Beata Świątkowska, Maciej Trzaskowski, Gustavo Turecki, Laura Vilar-Ribó, John B Vincent, Henry Völzke, James T R Walters, Cynthia Shannon Weickert, Thomas W Weickert, Myrna M Weissman, Leanne M Williams, Naomi R Wray, Clement C Zai, Allison E Ashley-Koch, Jean C Beckham, Elizabeth R Hauser, Michael A Hauser, Nathan A Kimbrel, Jennifer H Lindquist, Benjamin McMahon, David W Oslin, Xuejun Qin, Esben Agerbo, Anders D Børglum, Gerome Breen, Annette Erlangsen, Tõnu Esko, Joel Gelernter, David M Hougaard, Ronald C Kessler, Henry R Kranzler, Qingqin S Li, Nicholas G Martin, Andrew M McIntosh, Ole Mors, Merete Nordentoft, Catherine M Olsen, David Porteous, Robert J Ursano, Danuta Wasserman, Thomas Werge, David C Whiteman, Cynthia M Bulik, Hilary Coon, Ditte Demontis, Anna R Docherty, Po-Hsiu Kuo, Cathryn M Lewis, J John Mann, Miguel E Rentería, Daniel J Smith, Eli A Stahl, Murray B Stein, Fabian Streit, Virginia Willour, Douglas M Ruderfer

  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.

  Feb. 2022, Biological psychiatry, 91(3) (3), 313 - 327, English, International magazine

  [Refereed]

  Scientific journal


• Epigenetic clock analysis and increased plasminogen activator inhibitor-1 in high-functioning autism spectrum disorder.

  Satoshi Okazaki, Ryo Kimura, Ikuo Otsuka, Yasuko Funabiki, Toshiya Murai, Akitoyo Hishimoto

  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.

  Lead, 2022, PloS one, 17(2) (2), e0263478, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Polymorphisms in the hypoxia inducible factor binding site of the macrophage migration inhibitory factor gene promoter in schizophrenia.

  Satoshi Okazaki, Shuken Boku, Yuichiro Watanabe, Ikuo Otsuka, Tadasu Horai, Ryo Morikawa, Atsushi Kimura, Naofumi Shimmyo, Takaki Tanifuji, Toshiyuki Someya, Akitoyo Hishimoto

  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.

  Lead, 2022, PloS one, 17(3) (3), e0265738, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Searching for biomarkers in schizophrenia and psychosis: Case-control study using capillary electrophoresis and liquid chromatography time-of-flight mass spectrometry and systematic review for biofluid metabolites.

  Saehyeon Kim, Satoshi Okazaki, Ikuo Otsuka, Yutaka Shinko, Tadasu Horai, Naofumi Shimmyo, Takashi Hirata, Naruhisa Yamaki, Takaki Tanifuji, Shuken Boku, Ichiro Sora, Akitoyo Hishimoto

  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.

  Dec. 2021, Neuropsychopharmacology reports, 42(1) (1), 42 - 51, English, International magazine

  [Refereed]

  Scientific journal


• A preliminary genetic association study of GAD1 and GABAB receptor genes in patients with treatment-resistant schizophrenia.

  Atsuhiro Miyazawa, Nobuhisa Kanahara, Masanobu Kogure, Ikuo Otsuka, Satoshi Okazaki, Yoshinori Watanabe, Fumiaki Yamasaki, Yusuke Nakata, Yasunori Oda, Akitoyo Hishimoto, Masaomi Iyo

  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.

  Nov. 2021, Molecular biology reports, 49(3) (3), 2015 - 2024, English, International magazine

  [Refereed]

  Scientific journal


• Epigenetic Clock Analysis in Children With Fetal Alcohol Spectrum Disorder.

  Satoshi Okazaki, Ikuo Otsuka, Yutaka Shinko, Tadasu Horai, Takashi Hirata, Naruhisa Yamaki, Ichiro Sora, Akitoyo Hishimoto

  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.

  Feb. 2021, Alcoholism, clinical and experimental research, 45(2) (2), 329 - 337, English, International magazine

  [Refereed]

  Scientific journal


• Clozapine increases macrophage migration inhibitory factor (MIF) expression via increasing histone acetylation of MIF promoter in astrocytes.

  Satoshi Okazaki, Shuken Boku, Ikuo Otsuka, Tadasu Horai, Atsushi Kimura, Naofumi Shimmyo, Naruhisa Yamaki, Akitoyo Hishimoto

  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.

  Lead, Jan. 2021, Journal of psychiatric research, 135, 237 - 242, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Association of Two Variable Number of Tandem Repeats in the Monoamine Oxidase A Gene Promoter with Schizophrenia.

  Takaki Tanifuji, Satoshi Okazaki, Ikuo Otsuka, Tadasu Horai, Yutaka Shinko, Saehyeon Kim, Ichiro Sora, Akitoyo Hishimoto

  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, Neuropsychiatric disease and treatment, 17, 3315 - 3323, English, International magazine

  [Refereed]

  Scientific journal


• miR-19b is elevated in peripheral blood of schizophrenic patients and attenuates proliferation of hippocampal neural progenitor cells.

  Tadasu Horai, Shuken Boku, Satoshi Okazaki, Ikuo Otsuka, Woraphat Ratta-Apha, Kentaro Mouri, Naruhisa Yamaki, Takashi Hirata, Akitoyo Hishimoto

  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.

  Dec. 2020, Journal of psychiatric research, 131, 102 - 107, English, International magazine, Co-authored internationally

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Decelerated epigenetic aging associated with mood stabilizers in the blood of patients with bipolar disorder.

  Satoshi Okazaki, Shusuke Numata, Ikuo Otsuka, Tadasu Horai, Makoto Kinoshita, Ichiro Sora, Tetsuro Ohmori, Akitoyo Hishimoto

  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.

  Lead, May 2020, Translational psychiatry, 10(1) (1), 129 - 129, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• ATP and repetitive electric stimulation increases leukemia inhibitory factor expression in astrocytes: A potential role for astrocytes in the action mechanism of electroconvulsive therapy.

  Soichiro Maruyama, Shuken Boku, Satoshi Okazaki, Hiroki Kikuyama, Yoshito Mizoguchi, Akira Monji, Ikuo Otsuka, Ichiro Sora, Tetsufumi Kanazawa, Akitoyo Hishimoto, Hiroshi Yoneda

  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.

  May 2020, Psychiatry and clinical neurosciences, 74(5) (5), 311 - 317, English, International magazine, Co-authored internationally

  [Refereed]

  Scientific journal


• Accelerated extrinsic epigenetic aging and increased natural killer cells in blood of suicide completers.

  Satoshi Okazaki, Ikuo Otsuka, Tadasu Horai, Takashi Hirata, Motonori Takahashi, Yasuhiro Ueno, Shuken Boku, Ichiro Sora, Akitoyo Hishimoto

  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.

  Lead, Mar. 2020, Progress in neuro-psychopharmacology & biological psychiatry, 98, 109805 - 109805, English, International magazine

  [Refereed]

  Scientific journal


• Chemokine alterations in the postmortem brains of suicide completers.

  Yutaka Shinko, Ikuo Otsuka, Satoshi Okazaki, Tadasu Horai, Shuken Boku, Motonori Takahashi, Yasuhiro Ueno, Ichiro Sora, Akitoyo Hishimoto

  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.

  Jan. 2020, Journal of psychiatric research, 120, 29 - 33, English, International magazine

  [Refereed]

  Scientific journal


• Genome-wide association studies identify polygenic effects for completed suicide in the Japanese population.

  Ikuo Otsuka, Masato Akiyama, Osamu Shirakawa, Satoshi Okazaki, Yukihide Momozawa, Yoichiro Kamatani, Takeshi Izumi, Shusuke Numata, Motonori Takahashi, Shuken Boku, Ichiro Sora, Ken Yamamoto, Yasuhiro Ueno, Tatsushi Toda, Michiaki Kubo, Akitoyo Hishimoto

  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.

  Nov. 2019, Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 44(12) (12), 2119 - 2124, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Major depressive disorder-associated SIRT1 locus affects the risk for suicide in women after middle age.

  Takashi Hirata, Ikuo Otsuka, Satoshi Okazaki, Kentaro Mouri, Tadasu Horai, Shuken Boku, Motonori Takahashi, Yasuhiro Ueno, Ichiro Sora, Osamu Shirakawa, Akitoyo Hishimoto

  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.

  Aug. 2019, Psychiatry research, 278, 141 - 145, English, International magazine

  [Refereed]

  Scientific journal


• Mitochondrial DNA Copy Number Raises the Potential of Left Frontopolar Hemodynamic Response as a Diagnostic Marker for Distinguishing Bipolar Disorder From Major Depressive Disorder

  Noa Tsujii, Ikuo Otsuka, Satoshi Okazaki, Masaya Yanagi, Shusuke Numata, Naruhisa Yamaki, Yoshihiro Kawakubo, Osamu Shirakawa, Akitoyo Hishimoto

  May 2019, FRONTIERS IN PSYCHIATRY, 10, 312 - 312, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Epigenetic clock analysis of blood samples from Japanese schizophrenia patients.

  Satoshi Okazaki, Ikuo Otsuka, Shusuke Numata, Tadasu Horai, Kentaro Mouri, Shuken Boku, Tetsuro Ohmori, Ichiro Sora, Akitoyo Hishimoto

  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.

  Lead, Feb. 2019, NPJ schizophrenia, 5(1) (1), 4 - 4, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Mitochondrial DNA copy number of peripheral blood in bipolar disorder: The present study and a meta-analysis

  Naruhisa Yamaki, Ikuo Otsuka, Shusuke Numata, Masaya Yanagi, Kentaro Mouri, Satoshi Okazaki, Shuken Boku, Tadasu Horai, Tetsuro Ohmori, Osamu Shirakawa, Ichiro Sora, Akitoyo Hishimoto

  Nov. 2018, PSYCHIATRY RESEARCH, 269, 115 - 117, English, International magazine

  [Refereed]

  Scientific journal


• Increased serum levels and promoter polymorphisms of macrophage migration inhibitory factor in schizophrenia.

  Satoshi Okazaki, Akitoyo Hishimoto, Ikuo Otsuka, Yuichiro Watanabe, Shusuke Numata, Shuken Boku, Naofumi Shimmyo, Makoto Kinoshita, Emiko Inoue, Tetsuro Ohmori, Toshiyuki Someya, Ichiro Sora

  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.

  Lead, Apr. 2018, Progress in neuro-psychopharmacology & biological psychiatry, 83, 33 - 41, English, International magazine

  [Refereed]

  Scientific journal


• Investigation of chromosome Y loss in men with schizophrenia.

  Takashi Hirata, Akitoyo Hishimoto, Ikuo Otsuka, Satoshi Okazaki, Shuken Boku, Atsushi Kimura, Tadasu Horai, Ichiro Sora

  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, Neuropsychiatric disease and treatment, 14, 2115 - 2122, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Loss of chromosome Y in blood, but not in brain, of suicide completers.

  Atsushi Kimura, Akitoyo Hishimoto, Ikuo Otsuka, Satoshi Okazaki, Shuken Boku, Tadasu Horai, Takeshi Izumi, Motonori Takahashi, Yasuhiro Ueno, Osamu Shirakawa, Ichiro Sora

  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, PloS one, 13(1) (1), e0190667, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• 自殺既遂者におけるテロメア異常短縮(Shorter telomere length in suicide completers)

  大塚 郁夫, 菱本 明豊, 泉 剛, 朴 秀賢, 木村 敦, 張 園, 毛利 健太朗, 岡崎 賢志, 高橋 玄倫, 上野 易弘, 白川 治, 曽良 一郎

  日本生物学的精神医学会・日本神経精神薬理学会, Sep. 2017, 日本生物学的精神医学会・日本神経精神薬理学会合同年会プログラム・抄録集, 39回・47回, 156 - 156, English


• Aberrant telomere length and mitochondrial DNA copy number in suicide completers

  Ikuo Otsuka, Takeshi Izumi, Shuken Boku, Atsushi Kimura, Yuan Zhang, Kentaro Mouri, Satoshi Okazaki, Kyoichi Shiroiwa, Motonori Takahashi, Yasuhiro Ueno, Osamu Shirakawa, Ichiro Sora, Akitoyo Hishimoto

  Jun. 2017, SCIENTIFIC REPORTS, 7, English

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• Association study of MIF promoter polymorphisms with suicide completers in the Japanese population.

  Naofumi Shimmyo, Akitoyo Hishimoto, Ikuo Otsuka, Satoshi Okazaki, Shuken Boku, Kentaro Mouri, Tadasu Horai, Motonori Takahashi, Yasuhiro Ueno, Osamu Shirakawa, Ichiro Sora

  2017, Neuropsychiatric disease and treatment, 13, 899 - 908, English, International magazine

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• A ssociation study of MIF promoter polymorphisms with suicide completers in the Japanese population

  Naofumi Shimmyo, Akitoyo Hishimoto, Ikuo Otsuka, Satoshi Okazaki, Shuken Boku, Kentaro Mouri, Tadasu Horai, Motonori Takahashi, Yasuhiro Ueno, Osamu Shirakawa, Ichiro Sora

  2017, NEUROPSYCHIATRIC DISEASE AND TREATMENT, 13, 899 - 908, English

  [Refereed]

  Scientific journal

  Link to Kobe Univ. Repository (Kernel)


• The cell cycle-related genes as biomarkers for schizophrenia

  Satoshi Okazaki, Shuken Boku, Ikuo Otsuka, Kentaro Mouri, Shinsuke Aoyama, Kyoichi Shiroiwa, Ichiro Sora, Aiko Fujita, Yutaka Shirai, Osamu Shirakawa, Masahiro Kokai, Akitoyo Hishimoto

  Oct. 2016, PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, 70, 85 - 91, English

  [Refereed]

  Scientific journal


• ニコチン依存におけるCDH13の役割 マウス神経前駆細胞と統合失調症臨床サンプルを用いた解析(Possible role of CDH13 in nicotine dependence: Investigations on mouse neural progenitors and schizophrenia patients)

  大塚 郁夫, 菱本 明豊, 朴 秀賢, 岡崎 賢志, 毛利 健太朗, 曽良 一郎

  (一社)日本神経精神薬理学会, Jul. 2016, 日本神経精神薬理学会年会プログラム・抄録集, 46回, 220 - 220, English


• Rare truncating variations and risk of schizophrenia: Whole-exome sequencing in three families with affected siblings and a three-stage follow-up study in a Japanese population

  Yuichiro Watanabe, Ayako Nunokawa, Masako Shibuya, Masashi Ikeda, Akitoyo Hishimoto, Kenji Kondo, Jun Egawa, Naoshi Kaneko, Tatsuyuki Muratake, Takeo Saito, Satoshi Okazaki, Ayu Shimasaki, Hirofumi Igeta, Emiko Inoue, Satoshi Hoya, Takuro Sugai, Ichiro Sora, Nakao Iwata, Toshiyuki Someya

  Jan. 2016, PSYCHIATRY RESEARCH, 235, 13 - 18, English

  [Refereed]

  Scientific journal


• A decrease in protein level and a missense polymorphism of KIF17 are associated with schizophrenia

  Woraphat Ratta-apha, Kentaro Mouri, Shuken Boku, Hiroki Ishiguro, Satoshi Okazaki, Ikuo Otsuka, Ichiro Sora, Tadao Arinami, Osamu Shirakawa, Akitoyo Hishimoto

  Dec. 2015, PSYCHIATRY RESEARCH, 230(2) (2), 424 - 429, English

  [Refereed]

  Scientific journal


• 統合失調症における細胞周期関連遺伝子に着目した3段階mRNA発現解析(A three-stage mRNA expression study to identify cell cycle-related genes associated with schizophrenia)

  岡崎 賢志, 菱本 明豊, 朴 秀賢, 毛利 健太朗, 白岩 恭一, 大塚 郁夫, 白井 豊, 藤田 愛子, 白川 治, 湖海 正尋, 曽良 一郎

  日本生物学的精神医学会・日本神経精神薬理学会, Sep. 2015, 日本生物学的精神医学会・日本神経精神薬理学会合同年会プログラム・抄録集, 37回・45回, 172 - 172, English


• 統合失調症におけるCadherin13遺伝子多型解析(Association analysis of the Cadherin 13 gene with schizophrenia in the Japanese population)

  大塚 郁夫, 渡部 雄一郎, 菱本 明豊, 朴 秀賢, 毛利 健太朗, 白岩 恭一, 岡崎 賢志, 布川 綾子, 白川 治, 染矢 俊幸, 曽良 一郎

  Sep. 2015, 日本生物学的精神医学会・日本神経精神薬理学会合同年会プログラム・抄録集, 37回・45回, 201 - 201, English

  Link to Kobe Univ. Repository (Kernel)


• Association analysis of the HLA-DRB1*01 and HLA-DRB1*04 with schizophrenia by tag SNP genotyping in the Japanese population

  Woraphat Ratta-Apha, Shuken Boku, Kentaro Mouri, Satoshi Okazaki, Ikuo Otsuka, Ichiro Sora, Akitoyo Hishimoto, Yuichiro Watanabe, Ayako Nunokawa, Toshiyuki Someya, Osamu Shirakawa

  Sep. 2015, PSYCHIATRY RESEARCH, 229(1-2) (1-2), 627 - 628, English

  [Refereed]


• アルコール・薬物依存症の神経生物学・遺伝学的研究の動向 若手精神科医を中心に 細胞接着因子と精神疾患

  Hishimoto Akitoyo, 大塚郁夫, 岡崎賢志, 朴秀賢

  (一社)日本アルコール・アディクション医学会, Aug. 2015, 日本アルコール・薬物医学会雑誌, 50(4) (4), 186 - 186, Japanese


• 危険ドラッグの臨床症状への影響および遺伝子多型との関連の検討

  岡崎賢志, Hishimoto Akitoyo, 朴秀賢, 毛利健太朗, 竹村幸洋, 麻生克郎, 山本訓也, Ichiro Sora

  (一社)日本アルコール・アディクション医学会, Aug. 2015, 日本アルコール・薬物医学会雑誌, 50(4) (4), 230 - 230, Japanese


• 血清マイクロRNAの定性的解析による統合失調症の診断・病態マーカーの探索

  菱本 明豊, 毛利 健太朗, 朴 秀賢, 岡崎 賢志, 白岩 恭一, 曽良 一郎

  (公財)先進医薬研究振興財団, Mar. 2015, 先進医薬研究振興財団研究成果報告集, 2014年度, 24 - 25, Japanese


• Association analysis of the Cadherin13 gene with schizophrenia in the Japanese population.

  Otsuka I, Watanabe Y, Hishimoto A, Boku S, Mouri K, Shiroiwa K, Okazaki S, Nunokawa A, Shirakawa O, Someya T, Sora I

  2015, Neuropsychiatric disease and treatment, 11, 1381 - 1393

  [Refereed]

  Link to Kobe Univ. Repository (Kernel)


• Association analysis of putative cis-acting polymorphisms of interleukin-19 gene with schizophrenia

  Satoshi Okazaki, Yuichiro Watanabe, Akitoyo Hishimoto, Toru Sasada, Kentaro Mouri, Kyoichi Shiroiwa, Noriomi Eguchi, Woraphat Ratta-Apha, Ikuo Otsuka, Ayako Nunokawa, Naoshi Kaneko, Masako Shibuya, Toshiyuki Someya, Osamu Shirakawa, Ichiro Sora

  Apr. 2014, PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, 50, 151 - 156, English

  [Refereed]

  Scientific journal


• Haplotype analysis of the DISC1 Ser704Cys variant in Japanese suicide completers

  Woraphat Ratta-apha, Akitoyo Hishimoto, Kentaro Mouri, Kyoichi Shiroiwa, Toru Sasada, Masakuni Yoshida, Satoshi Okazaki, Irwan Supriyanto, Migiwa Asano, Yasuhiro Ueno, Osamu Shirakawa, Ichiro Sora

  Jan. 2014, PSYCHIATRY RESEARCH, 215(1) (1), 249 - 251, English

  [Refereed]

  Scientific journal


• 【物質使用障害とアディクション 臨床ハンドブック】(第I部)物質使用障害とアディクションの生物学 中毒性精神病の生物学

  曽良 一郎, 岡崎 賢志, 笹田 徹

  (株)星和書店, Oct. 2013, 精神科治療学, 28(増刊) (増刊), 31 - 34, Japanese


• A missense mutation in the ITGA8 gene, a cell adhesion molecule gene, is associated with schizophrenia in Japanese female patients

  Irwan Supriyanto, Yuichiro Watanabe, Kentaro Mouri, Kyoichi Shiroiwa, Woraphat Ratta-Apha, Masakuni Yoshida, Genki Tamiya, Toru Sasada, Noriomi Eguchi, Kenji Okazaki, Osamu Shirakawa, Toshiyuki Someya, Akitoyo Hishimoto

  Jan. 2013, PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, 40, 347 - 352, English

  [Refereed]

  Scientific journal


• Haplotypes in the expression quantitative trait locus of interleukin-1 beta gene are associated with schizophrenia

  Masakuni Yoshida, Kyoichi Shiroiwa, Kentaro Mouri, Hiroki Ishiguro, Irwan Supriyanto, Woraphat Ratta-Apha, Noriomi Eguchi, Satoshi Okazaki, Toru Sasada, Masaaki Fukutake, Takeshi Hashimoto, Toshiya Inada, Tadao Arinami, Osamu Shirakawa, Akitoyo Hishimoto

  Sep. 2012, SCHIZOPHRENIA RESEARCH, 140(1-3) (1-3), 185 - 191, English

  [Refereed]

  Scientific journal


• 体感異常を主訴とした青年期の統合失調症の1例

  岡崎 賢志, 松本 亜紀, 米田 一志

  大阪府済生会中津病院, Mar. 2012, 大阪府済生会中津病院年報, 22(2) (2), 203 - 206, Japanese


• 【サリヴァンの未来】若手に語る、サリヴァン

  杉林 稔, 中井 久夫, 島田 稔, 佐々木 雅明, 大山 文子, 平田 尚士, 岡崎 賢志, 玉田 有, 濱田 伸哉

  (株)星和書店, Dec. 2010, 治療の声, 11(1) (1), 19 - 29, Japanese

• 自殺のエピジェネティクス

  岡崎賢志, 大塚郁夫, 谷藤貴紀, 白井寿行, 毛利健太朗, 菱本明豊

  2024, 日本臨床精神神経薬理学会プログラム・抄録集, 34th (CD-ROM)


• アルコール依存症でのエピゲノム年齢加速

  白井寿行, 岡崎賢志, 大塚郁夫, 南陽香, 岡田将平, 宮地真生, 蓬莱政, 毛利健太朗, 菱本明豊

  2024, 日本精神科診断学会プログラム・抄録集, 43rd


• 未治療のうつ病患者におけるエピジェネティック年齢の加速とDNAメチル化に基づくナチュラルキラー細胞の減少

  岡崎賢志, 新藤良太, 谷藤貴紀, 大塚郁夫, 白井寿行, 毛利健太朗, 蓬莱政, 菱本明豊

  2024, 日本精神科診断学会プログラム・抄録集, 43rd


• 日本人の自殺既遂者における,マクロファージ遊走阻害因子(MIF)の低酸素応答因子における遺伝子研究

  宮地真生, 白井寿行, 岡崎賢志, 谷藤貴紀, 大塚郁夫, 岡田将平, 新藤良太, 蓬莱政, 毛利健太郎, 高橋玄倫, 近藤武史, 上野易弘, 菱本明豊

  2024, 日本生物学的精神医学会(Web), 46th


• メタンフェタミン依存症におけるエピゲノムワイド関連研究

  白井寿行, 岡崎賢志, 谷藤貴紀, 大塚郁夫, 蓬莱政, 毛利健太朗, 麻生克郎, 山本訓也, 菱本明豊

  2024, 日本生物学的精神医学会(Web), 46th


• DNAメチル化に代表される後天的遺伝子修飾と精神疾患の解明

  白井寿行, 岡崎賢志, 大塚郁夫, 谷藤貴紀, 宮地真生, 岡田将平, 蓬莱政, 毛利健太朗, 菱本明豊

  2024, 統合失調症研究(CD-ROM), 13(1) (1)


• 精神疾患とエピゲノム、そしてエピゲノム年齢

  白井 寿行, 岡崎 賢志, 谷藤 貴紀, 大塚 郁夫, 毛利 健太朗, 菱本 明豊

  (一財)仁明会, Sep. 2023, 仁明会精神医学研究, 21(1) (1), 51 - 71, Japanese


• Epigenetic clock解析により明らかとなった大うつ病性障害におけるDNAメチル化に基づくcystatin C値の上昇(Epigenetic clock analysis reveals increased cystatin C levels based on DNA methylation in major depressive disorder)

  谷藤 貴紀, 岡崎 賢志, 大塚 郁夫, 毛利 健太郎, 蓬莱 政, 新藤 良太, 白井 寿行, 菱本 明豊

  (一社)日本抗加齢医学会, Jun. 2023, 日本抗加齢医学会総会プログラム・抄録集, 23回, 252 - 252, English


• 胎児性アルコールスペクトラム障害児におけるEpigenetic Clock解析(Epigenetic Clock Analysis in Children with Fetal Alcohol Spectrum Disorder)

  岡崎 賢志, 谷藤 貴紀, 大塚 郁夫, 蓬莱 政, 山木 愛久, 菱本 明豊

  (一社)日本抗加齢医学会, Jun. 2023, 日本抗加齢医学会総会プログラム・抄録集, 23回, 264 - 264, English


• 精神病性障害に対するブレクスピプラゾールの使用経験

  蓬莱 政, 青山 慎介, 木村 敦, 新名 尚史, 平田 尚士, 岡崎 賢志, 江口 典臣, 山木 愛久, 新光 穣, 曽良 一郎

  (公社)日本精神神経学会, Sep. 2021, 精神神経学雑誌, (2021特別号) (2021特別号), S572 - S572, Japanese


• メタボローム解析による統合失調症血液バイオマーカーの探究

  金 世賢, 岡崎 賢志, 大塚 郁夫, 新光 穣, 木村 敦, 蓬莱 政, 新名 尚史, 平田 尚士, 谷藤 貴紀, 山木 愛久, 青山 慎介, 菱本 明豊, 曽良 一郎

  日本神経精神薬理学会・日本生物学的精神医学会・日本精神薬学会, Aug. 2020, 日本神経精神薬理学会年会・日本生物学的精神医学会年会・日本精神薬学会総会・学術集会合同年会プログラム・抄録集, 50回・42回・4回, 190 - 190, Japanese


• 自殺完遂者の死後脳におけるケモカインの変化

  新光 穣, 大塚 郁夫, 岡崎 賢志, 蓬莱 政, 朴 秀賢, 高橋 玄倫, 上野 易弘, 曽良 一郎, 菱本 明豊

  日本神経精神薬理学会・日本生物学的精神医学会・日本精神薬学会, Aug. 2020, 日本神経精神薬理学会年会・日本生物学的精神医学会年会・日本精神薬学会総会・学術集会合同年会プログラム・抄録集, 50回・42回・4回, 197 - 197, Japanese


• ADHD患者由来の大脳皮質オルガノイドで見られた大脳皮質発達の遅延(Telencephalon organoid derived from ADHD patient showed delayed development of cerebral cortex)

  張 丹夢, 江口 典臣, 岡崎 賢志, 曽良 一郎

  日本神経精神薬理学会・日本生物学的精神医学会・日本精神薬学会, Aug. 2020, 日本神経精神薬理学会年会・日本生物学的精神医学会年会・日本精神薬学会総会・学術集会合同年会プログラム・抄録集, 50回・42回・4回, 201 - 201, English


• 統合失調症におけるマクロファージ遊走阻止因子(MIF)の血清濃度増加と遺伝子多型関連解析

  岡崎 賢志, 大塚 郁夫, 渡部 雄一郎, 朴 秀賢, 新名 尚史, 平田 尚士, 蓬莱 政, 染矢 俊幸, 曽良 一郎, 菱本 明豊

  (公社)日本精神神経学会, Jun. 2019, 精神神経学雑誌, (2019特別号) (2019特別号), S441 - S441, Japanese


• 統合失調症におけるY染色体モザイク欠損の検討

  平田 尚士, 菱本 明豊, 大塚 郁夫, 岡崎 賢志, 朴 秀賢, 木村 敦, 蓬莱 政, 曽良 一郎

  (公社)日本精神神経学会, Jun. 2019, 精神神経学雑誌, (2019特別号) (2019特別号), S473 - S473, Japanese


• 男性アルコール依存症患者の骨密度低下に関する横断的研究

  蓬莱 政, 菱本 明豊, 大塚 郁夫, 新名 尚史, 岡崎 賢志, 毛利 健太朗, 朴 秀賢, 曽良 一郎

  (公社)日本精神神経学会, Jun. 2019, 精神神経学雑誌, (2019特別号) (2019特別号), S749 - S749, Japanese


• 自殺既遂者の血液・脳組織におけるY染色体喪失の解析

  木村 敦, 菱本 明豊, 平田 尚士, 山本 愛久, 蓬莱 政, 新名 尚史, 大塚 郁夫, 岡崎 賢志, 朴 秀賢, 曽良 一郎

  (公社)日本精神神経学会, Jun. 2019, 精神神経学雑誌, (2019特別号) (2019特別号), S759 - S759, Japanese


• 統合失調症におけるマクロファージ遊走阻止因子(MIF)の血清濃度増加と遺伝子多型関連解析

  岡崎 賢志, 大塚 郁夫, 渡部 雄一郎, 朴 秀賢, 新名 尚史, 平田 尚士, 蓬莱 政, 染矢 俊幸, 曽良 一郎, 菱本 明豊

  (公社)日本精神神経学会, Jun. 2019, 精神神経学雑誌, (2019特別号) (2019特別号), S441 - S441, Japanese


• mtDNA copy number raises the potential of left frontopolar hemodynamic responses for distinguishing BD from MDD

  菱本明豊, 辻井農亜, 大塚郁夫, 岡崎賢志, 柳雅也, 沼田周助, 山木愛久, 川久保善宏, 白川治

  2019, 日本うつ病学会総会プログラム・抄録集, 16th


• アストロサイトに着目した電気けいれん療法の作用機序の検討

  丸山 惣一郎, 岡崎 賢志, 朴 秀賢, 菊山 裕貴, 金沢 徹文, 米田 博

  (公社)日本精神神経学会, Jun. 2018, 精神神経学雑誌, (2018特別号) (2018特別号), S340 - S340, Japanese


• 日本人自殺既遂者におけるMIF遺伝子プロモーター領域機能的多型の関連解析(Association study of MIF promoter polymorphosms with suicide completers in the Japanese population)

  新名 尚史, 菱本 明豊, 大塚 郁夫, 岡崎 賢志, 朴 秀賢, 毛利 健太朗, 蓬莱 政, 江口 典臣, 木村 敦, 山木 愛久, 平田 尚士, 高橋 玄倫, 上野 易弘, 白川 治, 曽良 一郎

  日本生物学的精神医学会・日本神経精神薬理学会, Sep. 2017, 日本生物学的精神医学会・日本神経精神薬理学会合同年会プログラム・抄録集, 39回・47回, 190 - 190, English


• Possible role of CDH13 in nicotine dependence: Investigations on mouse neural progenitors and schizophrenia patients

  Ikuo Otsuka, Akitoyo Hishimoto, Shuken Boku, Satoshi Okazaki, Kentaro Mouri, Ichiro Sora

  Jun. 2016, INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, 19, 160 - 160, English

  Summary international conference


• 統合失調症におけるIL-19遺伝子の発現量的形質遺伝子座(eQTL)におけるハプロタイプ解析

  岡崎 賢志, 渡部 雄一郎, 大塚 郁夫, 吉田 正邦, 白岩 恭一, 毛利 健太朗, ウォラパット・ラッタアーパー, イルワン・スプリヤント, 江口 典臣, 笹田 徹, 福武 将映, 布川 綾子, 染矢 俊幸, 白川 治, 菱本 明豊, 曽良 一郎

  日本臨床精神神経薬理学会・日本神経精神薬理学会, Oct. 2013, 日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会プログラム・抄録集, 23回・43回, 230 - 230, Japanese


• 妄想性障害の経過中にレビー小体型認知症を発症した一例

  横山 紘子, 長谷川 雅史, 岡崎 賢志, 笹田 徹, 平良 勝, 田中 究

  (公社)日本精神神経学会, Aug. 2011, 精神神経学雑誌, 113(8) (8), 801 - 801, Japanese


• 再生不良性貧血による器質性精神障害を呈した一例

  佐々木 彩, 岡崎 賢志, 田宮 裕子, 菱本 明豊, 山本 泰司

  (公社)日本精神神経学会, Jul. 2011, 精神神経学雑誌, 113(7) (7), 727 - 727, Japanese


• 解離性(転換性)障害と統合失調症の鑑別を要した1例

  岡崎 賢志, 大塚 郁夫, 山本 泰司, 松井 裕介, 平良 勝, 田宮 裕子, 前田 潔

  (公社)日本精神神経学会, Jul. 2010, 精神神経学雑誌, 112(7) (7), 688 - 688, Japanese


• リスペリドンにより持続勃起症をきたしアリピプラゾールに薬剤変更を行った統合失調症の二例

  笹田 徹, 高橋 優, 岡崎 賢志, 福武 将映, 田宮 裕子, 菱本 明豊, 山本 泰司, 前田 潔

  (公社)日本精神神経学会, May 2010, 精神神経学雑誌, (2010特別) (2010特別), S - 330, Japanese


• 兵庫県の新精神科救急医療システムの現状

  岡崎 賢志, 田中 貞和, 青木 信生, 岩尾 俊一郎, 白井 豊, 幸地 芳郎

  (公社)日本精神神経学会, May 2009, 精神神経学雑誌, (2009特別) (2009特別), S - 264, Japanese

• Epigenetic clock analysis of blood samples from Japanese schizophrenia patients

  Satoshi Okazaki, Ikuo Otsuka, Shusuke Numata, Tadasu Horai, Kentaro Mouri, Shuken Boku, Tetsuro Ohmori, Ichiro Sora, Akitoyo Hishimoto

  7th Congress of Asian College of Neuropsychopharmacology (AsCNP) 2021, Oct. 2021, English

  Poster presentation


• Accelerated extrinsic epigenetic aging and increased natural killer cells in blood of suicide completers

  S. Okazaki, I. Otsuka, T. Horai, T. Hirata, M. Takahashi, Y. Ueno, S. Boku, I. Sora, A. Hishimoto

  The International College of Neuropsychopharmacology (CINP) 2021 VIRTUAL WORLD CONGRESS, English

  Poster presentation


• Mir-19b is increased in peripheral blood of schizophenic patients and a!ects proliferation and survival of hippocampal neural progenitor cells

  Boku S, Horai T, Okazaki S, Otsuka I, Mouri K, Hishimoto A

  Society for Neuroscience, Oct. 2019, English

  Poster presentation


• 統合失調症におけるマクロファージ遊走阻止因子(MIF)の血清濃度増加と遺伝子多型関連解析

  岡崎 賢志, 大塚 郁夫, 渡部 雄一郎, 朴 秀賢, 新名 尚史, 平田 尚士, 蓬莱 政, 染矢 俊幸, 曽良 一郎, 菱本 明豊

  日本精神神経学会, Jun. 2019, Japanese, Domestic conference

  Poster presentation


• 統合失調症におけるY染色体モザイク欠損の検討

  平田 尚士, 菱本 明豊, 大塚 郁夫, 岡崎 賢志, 朴 秀賢, 木村 敦, 蓬莱 政, 曽良 一郎

  日本精神神経学会, Jun. 2019, Japanese, Domestic conference

  Poster presentation


• 男性アルコール依存症患者の骨密度低下に関する横断的研究

  蓬莱 政, 菱本 明豊, 大塚 郁夫, 新名 尚史, 岡崎 賢志, 毛利 健太朗, 朴 秀賢, 曽良 一郎

  日本精神神経学会, Jun. 2019, Japanese, Domestic conference

  Poster presentation


• 自殺既遂者の血液・脳組織におけるY染色体喪失の解析

  木村 敦, 菱本 明豊, 平田 尚士, 山本 愛久, 蓬莱 政, 新名 尚史, 大塚 郁夫, 岡崎 賢志, 朴 秀賢, 曽良 一郎

  日本精神神経学会, Jun. 2019, Japanese, Domestic conference

  Poster presentation


• The cell cycle-related genes as biomarkers for schizophrenia

  Okazaki S, Boku S, Otsuka I, Eguchi N, Sora I, Hishimoto A

  Society for Neuroscience, Nov. 2018, English, International conference

  Poster presentation


• Loss of chromosome Y in blood, but not in brain, of suicide completers

  Otsuka I, Okazaki S, Kimura A, Horai T, Izumi T, Takahashi M, Ueno Y, Shirakawa O, Sora I, Hishimoto A

  WFSBP Asia Pacific Regional Congress of Biological Psychiatry, Sep. 2018, English, International conference

  Poster presentation


• Mosaic loss of chromosome Y in peripheral blood and its risk variants in men with schizophrenia

  Hirata T, Okazaki S, Otsuka I, Boku S, Aoyama S, Eguch N, Kimura A, Horai T, Sora I, Hishimoto A

  WFSBP Asia Pacific Regional Congress of Biological Psychiatry, Sep. 2018, English, International conference

  Poster presentation


• Increased serum levels and promoter polymorphisms of macrophage migration inhibitory factor in schizophrenia

  Okazaki S, Otsuka I, Wanatabe Y, Numata S, Boku S, Shimmyo N, Ormori T, Someya T, Sora I, Hishimoto A

  WFSBP Asia Pacific Regional Congress of Biological Psychiatry, Sep. 2018, English, International conference

  Poster presentation


• アストロサイトに着目した電気けいれん療法の作用機序の検討

  丸山 惣一郎, 岡崎 賢志, 朴 秀賢, 菊山 裕貴, 金沢 徹文, 米田 博

  日本精神神経学会, Jun. 2018, Japanese, Domestic conference


• Mechanism of modified electroconvulsive therapy electrical stimulation to neurogenesis

  Maruyama S, Bo ku S, Okazaki S, Kikuyama H, Kanazawa T, Yoneda H

  World Psychiatric Association’s Thematic Congress ., Feb. 2018, English, International conference

  Poster presentation


• Shorter telomere length in suicide completers

  大塚 郁夫, 菱本 明豊, 泉 剛, 朴 秀賢, 木村 敦, 張 園, 毛利 健太朗, 岡崎 賢志, 高橋 玄倫, 上野 易弘, 白川 治, 曽良 一郎

  日本生物学的精神医学会・日本神経精神薬理学会合同年会, Sep. 2017, Japanese, Domestic conference

  Oral presentation


• Association study of MIF promoter polymorphosms with suicide completers in the Japanese population

  新名 尚史, 菱本 明豊, 大塚 郁夫, 岡崎 賢志, 朴 秀賢, 毛利 健太朗, 蓬莱 政, 江口 典臣, 木村 敦, 山木 愛久, 平田 尚士, 高橋 玄倫, 上野 易弘, 白川 治, 曽良 一郎

  日本生物学的精神医学会・日本神経精神薬理学会合同年会, Sep. 2017, Japanese, Domestic conference

  Poster presentation


• Possible role of CDH13 in nicotine dependence: Investigations on mouse neural progenitors and schizophrenia patients

  大塚 郁夫, 菱本 明豊, 朴 秀賢, 岡崎 賢志, 毛利 健太朗, 曽良 一郎

  日本神経精神薬理学会年会, Jul. 2016, Japanese, Domestic conference


• アルコール・薬物依存症の神経生物学・遺伝学的研究の動向 若手精神科医を中心に 細胞接着因子と精神疾患

  菱本 明豊, 大塚 郁夫, 岡崎 賢志, 朴 秀賢

  日本アルコール・薬物医学会, Oct. 2015, Japanese, Domestic conference

  Oral presentation


• 危険ドラッグの臨床症状への影響および遺伝子多型との関連の検討

  岡崎 賢志, 菱本 明豊, 朴 秀賢, 毛利 健太朗, 竹村 幸洋, 麻生 克郎, 山本 訓也, 曽良 一郎

  日本アルコール・薬物医学会, Oct. 2015, Japanese, Domestic conference

  Oral presentation


• A three-stage mRNA expression study to identify cell cycle-related genes associated with schizophrenia

  岡崎 賢志, 菱本 明豊, 朴 秀賢, 毛利 健太朗, 白岩 恭一, 大塚 郁夫, 白井 豊, 藤田 愛子, 白川 治, 湖海 正尋, 曽良 一郎

  日本生物学的精神医学会・日本神経精神薬理学会合同年会, Sep. 2015, Japanese, Domestic conference

  Poster presentation


• Association analysis of the Cadherin 13 gene with schizophrenia in the Japanese population

  大塚 郁夫, 渡部 雄一郎, 菱本 明豊, 朴 秀賢, 毛利 健太朗, 白岩 恭一, 岡崎 賢志, 布川 綾子, 白川 治, 染矢 俊幸, 曽良 一郎

  日本生物学的精神医学会・日本神経精神薬理学会合同年会, Sep. 2015, Japanese, Domestic conference

  Poster presentation


• 統合失調症におけるIL-19遺伝子の発現量的形質遺伝子座(eQTL)におけるハプロタイプ解析

  岡崎 賢志, 渡部 雄一郎, 大塚 郁夫, 吉田 正邦, 白岩 恭一, 毛利 健太朗, ウォラパット・ラッタアーパー, イルワン・スプリヤント, 江口 典臣, 笹田 徹, 福武 将映, 布川 綾子, 染矢 俊幸, 白川 治, 菱本 明豊, 曽良 一郎

  日本臨床精神神経薬理学会・日本神経精神薬理学会合同年会, Oct. 2013, Japanese, Domestic conference

  Poster presentation


• 妄想性障害の経過中にレビー小体型認知症を発症した一例

  横山 紘子, 長谷川 雅史, 岡崎 賢志, 笹田 徹, 平良 勝, 田中 究

  精神神経学雑誌, Aug. 2011, Japanese


• 再生不良性貧血による器質性精神障害を呈した一例

  佐々木 彩, 岡崎 賢志, 田宮 裕子, 菱本 明豊, 山本 泰司

  精神神経学雑誌, Jul. 2011, Japanese


• 解離性(転換性)障害と統合失調症の鑑別を要した1例

  岡崎 賢志, 大塚 郁夫, 山本 泰司, 松井 裕介, 平良 勝, 田宮 裕子, 前田 潔

  精神神経学雑誌, Jul. 2010, Japanese


• リスペリドンにより持続勃起症をきたしアリピプラゾールに薬剤変更を行った統合失調症の二例

  笹田 徹, 高橋 優, 岡崎 賢志, 福武 将映, 田宮 裕子, 菱本 明豊, 山本 泰司, 前田 潔

  精神神経学雑誌, May 2010, Japanese


• 兵庫県の新精神科救急医療システムの現状

  岡崎 賢志, 田中 貞和, 青木 信生, 岩尾 俊一郎, 白井 豊, 幸地 芳郎

  日本精神神経学会, May 2009, Japanese, Domestic conference

  Oral presentation

• Society for Neuroscience


• 日本神経精神薬理学会


• 日本臨床精神神経薬理学会


• 日本生物学的精神医学会


• 日本精神神経学会

• MIFに着目した低酸素暴露と統合失調症を結ぶ分子メカニズムの解明

  岡崎 賢志, 江口 典臣, 蓬莱 政

  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, 01 Apr. 2021 - 31 Mar. 2024

  統合失調症は世界的に有病率約1%のありふれた疾患であるが、その生物学的基盤は明らかでなく、診断や治療は症状と経過に依存している。本研究の目的は、統合失調症の病態機序において、低酸素―低酸素誘導因子（HIF）―マクロファージ遊走阻止因子（MIF）経路の役割を明らかにし、治療標的やバイオマーカーとして臨床応用へ展開するための研究基盤を確立することである。 R3年度の実験としては、統合失調症患者と健常対照者の末梢血由来DNAを用いて、MIF遺伝子プロモーター領域に存在する、HIF結合部位である低酸素応答領域（HRE）に存在するSNPの多型解析を行った。その結果、このSNPのマイナーアレルが統合失調症患者群では有意に多く、リスクアレルであることを見出した。性別によるサブグループ解析を行ったところ、これらの結果は女性において男性よりも顕著であった。さらに新生仔C57BL/6マウス皮質由来アストロサイトの初代培養系を用いて、低酸素によるアストロサイトのMIF発現機構の解析を進めた。HIF活性化因子であるML228によるMIF mRNAの有意な増加を見出した。さらに低酸素処置による実験を行い、MIF mRNAとMIF蛋白が低酸素条件で有意に増加することを見出した。マウスMIF遺伝子プロモーター領域においても、ヒトMIF遺伝子と相同するHRE領域が存在する。低酸素応答におけるMIF遺伝子発現機構について、ルシフェラーゼアッセイ法を用いて、プロモーター活性に変化の解析を進めている。新生仔マウス海馬由来神経幹細胞の初代培養系も維持継続している。また患者および健常者由来iPS細胞の樹立と長期培養維持継代も継続して行っている。


• MIFから考える統合失調症の分子病態と抗精神病薬の新たな作用機序

  岡﨑 賢志

  日本学術振興会科学研究費, 若手研究, Apr. 2018 - Mar. 2021, Principal investigator

  Competitive research funding


• 統合失調症の神経免疫仮説におけるマクロファージ遊走阻止因子（MIF）の役割

  岡﨑 賢志

  日本学術振興会科学研究費, 若手研究(B), Apr. 2015 - Mar. 2018, Principal investigator

  Competitive research funding