Study of biomarker for youth suicide risk through genome and epigenome-wide data

• Project/Area Number: 21K15712
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: Kobe University
• Principal Investigator: Otsuka Ikuo 神戸大学, 医学部附属病院, 助教 (40722880)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2022: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2021: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 若年自殺 / ゲノム / エピゲノム / バイオマーカー / リスクマーカー / メチル化年齢 / テロメア

Outline of Research at the Start

申請者らが網羅的ゲノム・エピゲノム解析により見出した、30歳代以下の自殺者における①末梢血テロメア異常短縮、②末梢血DNAメチル化年齢の異常老齢化、③自殺リスクに強く関連するGTF2IRD1遺伝子多型の存在、という予備的知見について、日本人若年自殺者及び、強い自殺念慮を有する若年者、さらには米国コロンビア大との連携による白人若年自殺行動者の追加試料を用いて多角的に追試し、臨床現場で真に有用な若年自殺リスクのバイオマーカーとなりうるかを検討する。

Outline of Final Research Achievements

Suicides (especially among young people) are increasing both in Japan and around the world. In this study, regarding youth suicide risk for which biomarkers and biological mechanisms have not yet been clarified, the novel preliminary findings "aberrant telomere shortening, abnormal acceleration of epigenetic age, and GTF2iRD1 SNP association in young suicides" that the applicant already identified were successfully replicated in an independent young suicide cohort. In addition, the applicant identified an aberrant increase in natural killer cells in juvenile suicides, and genetically mapped the correlation between suicidal behavior and other psychiatric traits classified into non-fatal suicide attempt and suicide death.

Academic Significance and Societal Importance of the Research Achievements

本研究の実施で、より強固なエビデンスが得られた「若年自殺リスクにおけるテロメア異常短縮・エピゲノム年齢異常老齢化・NK細胞異常増加」といったエピゲノムデータ由来の知見は、ケア介入によって可逆的な性質を有するものであり、また既に世界的に市販・流通しているアレイで容易に取得できる。本内容を引き続き大規模かつ経時的なデータで追試していくことで、「若年者の自殺リスクによる生物学的変化は、介入によって回復させることできる」というポジティブな科学的根拠に基づいて、新たなリスクマーカーパッケージやケアコンテンツ開発・創薬をスムーズに目指すことができる可能性がある。

Research Products

• [Int'l Joint Research] Columbia University(米国)
• [Int'l Joint Research] Columbia University(米国)
• [Journal Article] Epigenetic clock analysis reveals increased plasma cystatin C levels based on DNA methylation in major depressive disorder (2023)
  • Author(s): Tanifuji Takaki、Okazaki Satoshi、Otsuka Ikuo、Mouri Kentaro、Horai Tadasu、Shindo Ryota、Shirai Toshiyuki、Hishimoto Akitoyo
  • Journal Title: Psychiatry Research Volume: 322 Pages: 115103-115103
  • DOI: 10.1016/j.psychres.2023.115103
  • Peer Reviewed
• [Journal Article] Ribosomal DNA gene copies are increased in blood and brain of Japanese schizophrenia patients (2023)
  • Author(s): Li Sen、Otsuka Ikuo、Tanifuji Takaki、Okazaki Satoshi、Horai Tadasu、Takahashi Motonori、Kondo Takeshi、Ueno Yasuhiro、Hishimoto Akitoyo
  • Journal Title: PLOS ONE Volume: 18 Issue: 1 Pages: e0280694-e0280694
  • DOI: 10.1371/journal.pone.0280694
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of Novel, Replicable Genetic Risk Loci for Suicidal Thoughts and Behaviors Among US Military Veterans (2023)
  • Author(s): Kimbrel Nathan A.、Hishimoto Akitoyo、Okazaki Satoshi、Otsuka Ikuo、et al.
  • Journal Title: JAMA Psychiatry Volume: 80 Issue: 2 Pages: 135-135
  • DOI: 10.1001/jamapsychiatry.2022.3896
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epigenetic clock analysis in methamphetamine dependence (2022)
  • Author(s): Takemura Yukihiro、Tanifuji Takaki、Okazaki Satoshi、Shinko Yutaka、Otsuka Ikuo、Horai Tadasu、Shirai Toshiyuki、Aso Katsuro、Yamamoto Noriya、Hishimoto Akitoyo
  • Journal Title: Psychiatry Research Volume: 317 Pages: 114901-114901
  • DOI: 10.1016/j.psychres.2022.114901
  • Peer Reviewed
• [Journal Article] 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 (2022)
  • Author(s): Tanifuji Takaki、Otsuka Ikuo、Okazaki Satoshi、Horai Tadasu、So Ryuhei、Shiroiwa Kyoichi、Mouri Kentaro、Tanaka Motofumi、Ohmoto Nobuko、Sora Ichiro、Hirai Midori、Fukumoto Takumi、Ku Yonson、Hishimoto Akitoyo
  • Journal Title: Asian Journal of Psychiatry Volume: 78 Pages: 103282-103282
  • DOI: 10.1016/j.ajp.2022.103282
  • Peer Reviewed / Open Access
• [Journal Article] Successful electroconvulsive therapy for 22q11.2 deletion syndrome with Schizophrenia and Parkinson's disease (2022)
  • Author(s): Tanifuji Takaki、Otsuka Ikuo、Kimura Atsushi、Horai Tadasu、Okazaki Satoshi、Satake Wataru、Hishimoto Akitoyo
  • Journal Title: Psychiatry and Clinical Neurosciences Volume: 76 Issue: 11 Pages: 603-604
  • DOI: 10.1111/pcn.13467
  • Peer Reviewed
• [Journal Article] Improving polygenic prediction in ancestrally diverse populations (2022)
  • Author(s): Ruan Yunfeng、Lin Yen-Feng、Feng Yen-Chen Anne、Chen Chia-Yen、Lam Max、Guo Zhenglin、Ahn Yong Min、Akiyama Kazufumi、Arai Makoto、Baek Ji Hyun、Chen Wei J.、Chung Young-Chul、Feng Gang、Fujii Kumiko、et al. 50名、Stanley Global Asia Initiatives
  • Journal Title: Nature Genetics Volume: 54 Issue: 5 Pages: 573-580
  • DOI: 10.1038/s41588-022-01054-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epigenetic aging in Williams syndrome (2022)
  • Author(s): Okazaki Satoshi、Kimura Ryo、Otsuka Ikuo、Tomiwa Kiyotaka、Funabiki Yasuko、Hagiwara Masatoshi、Murai Toshiya、Hishimoto Akitoyo
  • Journal Title: Journal of Child Psychology and Psychiatry Volume: 63 Issue: 12 Pages: 1553-1562
  • DOI: 10.1111/jcpp.13613
  • Peer Reviewed
• [Journal Article] Polymorphisms in the hypoxia inducible factor binding site of the macrophage migration inhibitory factor gene promoter in schizophrenia (2022)
  • Author(s): Okazaki Satoshi、Boku Shuken、Watanabe Yuichiro、Otsuka Ikuo、Horai Tadasu、Morikawa Ryo、Kimura Atsushi、Shimmyo Naofumi、Tanifuji Takaki、Someya Toshiyuki、Hishimoto Akitoyo
  • Journal Title: PLOS ONE Volume: 17 Issue: 3 Pages: e0265738-e0265738
  • DOI: 10.1371/journal.pone.0265738
  • Peer Reviewed / Open Access
• [Journal Article] Novel missense SETD1A variants in Japanese patients with schizophrenia: Resequencing and association analysis (2022)
  • Author(s): Morikawa Ryo、Watanabe Yuichiro、Igeta Hirofumi、Arta Reza K.、Ikeda Masashi、Okazaki Satoshi、Hoya Satoshi、Saito Takeo、Otsuka Ikuo、Egawa Jun、Tanifuji Takaki、Iwata Nakao、Someya Toshiyuki
  • Journal Title: Psychiatry Research Volume: 310 Pages: 114481-114481
  • DOI: 10.1016/j.psychres.2022.114481
  • Peer Reviewed
• [Journal Article] Epigenetic clock analysis and increased plasminogen activator inhibitor-1 in high-functioning autism spectrum disorder (2022)
  • Author(s): Okazaki Satoshi、Kimura Ryo、Otsuka Ikuo、Funabiki Yasuko、Murai Toshiya、Hishimoto Akitoyo
  • Journal Title: PLOS ONE Volume: 17 Issue: 2 Pages: e0263478-e0263478
  • DOI: 10.1371/journal.pone.0263478
  • Peer Reviewed / Open Access
• [Journal Article] Accelerated epigenetic age and shortened telomere length based on DNA methylation in Nicolaides?Baraitser syndrome (2022)
  • Author(s): Shinko Yutaka、Okazaki Satoshi、Otsuka Ikuo、Horai Tadasu、Kim Saehyeon、Tanifuji Takaki、Hishimoto Akitoyo
  • Journal Title: Molecular Genetics & Genomic Medicine Volume: 10 Issue: 3
  • DOI: 10.1002/mgg3.1876
  • Peer Reviewed / Open Access
• [Journal Article] Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors (2022)
  • Author(s): Mullins N, Ikuo Otsuka, Akitoyo Hishimoto et al.
  • Journal Title: Biological Psychiatry Volume: 91 Issue: 3 Pages: 313-327
  • DOI: 10.1016/j.biopsych.2021.05.029
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mapping the genetic architecture of suicide attempt and suicide death using polygenic risk scores for clinically-related psychiatric disorders and traits (2021)
  • Author(s): Otsuka Ikuo、Galfalvy Hanga、Guo Jia、Akiyama Masato、Rujescu Dan、Turecki Gustavo、Hishimoto Akitoyo、Mann J. John
  • Journal Title: Psychological Medicine Volume: Epub Issue: 6 Pages: 1-9
  • DOI: 10.1017/s0033291721004700
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 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 (2021)
  • Author(s): Kim Saehyeon、Okazaki Satoshi、Otsuka Ikuo、Shinko Yutaka、Horai Tadasu、Shimmyo Naofumi、Hirata Takashi、Yamaki Naruhisa、Tanifuji Takaki、Boku Shuken、Sora Ichiro、Hishimoto Akitoyo
  • Journal Title: Neuropsychopharmacology Reports Volume: 42 Issue: 1 Pages: 42-51
  • DOI: 10.1002/npr2.12223
  • Peer Reviewed / Open Access
• [Journal Article] A preliminary genetic association study of GAD1 and GABAB receptor genes in patients with treatment-resistant schizophrenia (2021)
  • Author(s): Miyazawa Atsuhiro、Kanahara Nobuhisa、Kogure Masanobu、Otsuka Ikuo、Okazaki Satoshi、Watanabe Yoshinori、Yamasaki Fumiaki、Nakata Yusuke、Oda Yasunori、Hishimoto Akitoyo、Iyo Masaomi
  • Journal Title: Molecular Biology Reports Volume: 49 Issue: 3 Pages: 2015-2024
  • DOI: 10.1007/s11033-021-07019-z
  • Peer Reviewed
• [Journal Article] Association of Two Variable Number of Tandem Repeats in the Monoamine Oxidase A Gene Promoter with Schizophrenia (2021)
  • Author(s): Tanifuji Takaki、Okazaki Satoshi、Otsuka Ikuo、Horai Tadasu、Shinko Yutaka、Kim Saehyeon、Sora Ichiro、Hishimoto Akitoyo
  • Journal Title: Neuropsychiatric Disease and Treatment Volume: Volume 17 Pages: 3315-3323
  • DOI: 10.2147/ndt.s338854
  • Peer Reviewed / Open Access
• [Journal Article] Serum levels of glial cell line-derived neurotrophic factor as a biomarker for mood disorders and lithium response (2021)
  • Author(s): Keita Idemoto, Tamaki Ishima, Tomihisa Niitsu, Tatsuki Hata, Sumiko Yoshida, Kotaro Hattori, Tadasu Horai, Ikuo Otsuka, Hidenaga Yamamori, Shigenobu Toda etc
  • Journal Title: Psychiatric Res Volume: 301 Pages: 113967-113967
  • DOI: 10.1016/j.psychres.2021.113967
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 臨床での活用が期待される自殺の生物学的知見 (2021)
  • Author(s): 大塚郁夫, 菱本明豊.
  • Journal Title: 医学のあゆみ Volume: 279(1) Pages: 29-34
• [Journal Article] 自殺の神経生物学的異常 (2021)
  • Author(s): 大塚郁夫, 菱本明豊.
  • Journal Title: 臨床精神医学 Volume: 50(6) Pages: 577-583
• [Presentation] ゲノム/エピゲノム解析からみた自殺と細胞老化 (2022)
  • Author(s): 大塚郁夫
  • Organizer: BPCNPNPPP4学会合同年会（東京）
  • Invited
• [Presentation] 日本人自殺者のゲノムワイド関連解析 (2021)
  • Author(s): 大塚郁夫
  • Organizer: 第43回日本生物学的精神医学会・第51回日本神経精神薬理学会合同年会
• [Book] 臨床での活用が期待される自殺の生物学的知見（別冊・医学のあゆみ） (2022)
  • Author(s): 大塚郁夫、菱本明豊
  • Total Pages: 101
  • Publisher: 医歯薬出版株式会社
• [Book] 不安と自殺・自傷 ー特に遺伝学的知見の観点からー（臨床精神医学） (2022)
  • Author(s): 大塚郁夫、谷藤貴紀
  • Total Pages: 1088
  • Publisher: アークメディア