The molecular analysis of a candidate gene as a cause of schizophrenia

• Project/Area Number: 16K10190
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Nagasaki University
• Principal Investigator: ONO Shinji 長崎大学, 原爆後障害医療研究所, 客員研究員 (70418820)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2017: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2016: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: 臨床精神医学 / 分子遺伝学 / 精神遺伝学 / 分子生物学 / 臨床精神科学 / 臨床精神分子遺伝学 / 遺伝学 / ゲノム / 精神神経科学

Outline of Final Research Achievements

Schizophrenia is a devastating, chronic neurodevelopmental disorder that affects approximately 1%. The pathogenesis is still unclear although it is one of the common diseases. In this study, we explored a new gene for schizophrenia in a three-generation family from Nagasaki prefecture utilizing whole-exome sequencing. As a result, we identified a new candidate gene for schizophrenia. We then generated a mouse model and performed expression and behavioral analysis to confirm the effect of this mutation. Results of these analyses supported that the mutation of this gene we identified could cause schizophrenia, which will lead to elucidation of the pathogenesis of this disease in the future.

Academic Significance and Societal Importance of the Research Achievements

これまで統合失調症をはじめとした精神神経疾患の遺伝的および生物学的要因の関与は明らかであったが、その詳細は不明な点が多かった。今回の研究成果はある一つの遺伝子が新たな統合失調症の原因であることを双方向的に証明したことが最も重要な点である。現段階ではこの遺伝子変異が脳機能に影響を与えるメカニズムの同定にはいたっていないが、今後解析を続けることにより統合失調症の病態解明につながるのみならず、診断の細分化や新たな治療標的の同定につながる可能性がある。このように本研究は医療行政上大変有意義であり、国民の保健・精神医療に多大なる貢献ができると考えられる。

Research Products

• [Journal Article] Nonsense mutation in CFAP43 causes normal pressure hydrocephalus with ciliary abnormalities (2019)
  • Author(s): Yoshiro Morimoto, Shintaro Yoshida, Akira Kinoshita, Chisei Satoh, Hiroyuki Mishima, Naohiro Yamaguchi, Katsuya Matsuda, Miako Sakaguchi, Takeshi Tanaka, Yoshihiro Komohara, Akira Imamura, Hiroki Ozawa, Masahiro Nakashima, Naohiro Kurotaki, Tatsuya Kishino, Koh-ichiro Yoshiura and Shinji Ono
  • Journal Title: Neurology Volume: 印刷中
  • NAID: 120006987711
  • Peer Reviewed / Open Access
• [Journal Article] Whole-exome sequencing and gene-based rare variant association tests suggest that PLA2G4E might be a risk gene for panic disorder. Transl Psychiatry. (2018)
  • Author(s): Morimoto Y, Shimada-Sugimoto M, Otowa T, Yoshida S, Kinoshita A, Mishima H, Yamaguchi N, Mori T, Imamura A, Ozawa H, Kurotaki N, Ziegler C, Domschke K, Deckert J, Umekage T, Tochigi M, Kaiya H, Okazaki Y, Tokunaga K, Sasaki T, Yoshiura KI, Ono S.
  • Journal Title: Transl Psychiatry Volume: 8 Issue: 1 Pages: 41-41
  • DOI: 10.1038/s41398-017-0088-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Deep sequencing reveals variations in somatic cell mosaic mutations between monozygotic twins with discordant psychiatric disease. (2017)
  • Author(s): Morimoto Y, Ono S, Imamura A, Okazaki Y, Kinoshita A, Mishima H, Nakane H, Ozawa H, Yoshiura KI, Kurotaki N.
  • Journal Title: Hum Genome Var. Volume: 4 Issue: 1 Pages: 17032-17032
  • DOI: 10.1038/hgv.2017.32
  • Peer Reviewed / Open Access
• [Journal Article] De novo non-synonymous TBL1XR1 mutation alters Wnt signaling activity (2017)
  • Author(s): Nishi Akira、Numata Shusuke、Tajima Atsushi、Zhu Xiaolei、Ito Koki、Saito Atsushi、Kato Yusuke、Kinoshita Makoto、Shimodera Shinji、Ono Shinji、Ochi Shinichiro、Imamura Akira、Kurotaki Naohiro、Ueno Shu-ichi、Iwata Nakao、Fukui Kiyoshi、Imoto Issei、Kamiya Atsushi、Ohmori Tetsuro
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 2887-2887
  • DOI: 10.1038/s41598-017-02792-z
  • NAID: 120006309984
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] De novo non-synonymous TBL1XR1 mutation alters Wnt signaling activity. (2017)
  • Author(s): Akira Nishi, Shusuke Numata, Atsushi Tajima, Xiaolei Zhu, Koki Ito, Atsushi Saito, Yusuke Kato, Makoto Kinoshita, Shinji Shimodera, Shinji Ono, Shinichiro Ochi, Akira Imamura, Naohiro Kurotaki, Shu-ichi Ueno, Nakao Iwata, Kiyoshi Fukui, Issei Imoto, Atsushi Kamiya, and Tetsuro Ohmori
  • Journal Title: Scientific Reports Volume: 印刷中
  • NAID: 120006309984
  • Peer Reviewed / Int'l Joint Research
• [Presentation] PLA2G4E遺伝子の希少変異はパニック障害のリスク因子の可能性がある (2017)
  • Author(s): 森本芳郎、吉田真太朗、木下晃、三嶋博之、山口尚宏、今村明、黒滝直弘、小澤寛樹、吉浦孝一郎、小野慎治
  • Organizer: 第62回日本人類遺伝学会
• [Presentation] Genetic projects of our department including panic disorder, schizophrenia and gender dysphoria. (2016)
  • Author(s): Shinji Ono
  • Organizer: International Alumni Symposium
  • Place of Presentation: Wuerzburg (Germany)
  • Invited
• [Presentation] Deep sequencing reveal variations in somatic cell mosaic mutations between monozygotic twins with discordant psychiatric disease. (2016)
  • Author(s): Yoshiro Morimoto, Shinji Ono,Hideyuki Nakane, Hiroki Ozawa, Naohiro Kurotaki, Koh-Ichiro Yoshiura
  • Organizer: ASHG annual meeting 2016
  • Place of Presentation: Vancouver (Canada)
  • Int'l Joint Research