De novo mobile element insertions in mental disorders

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K15479
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Nishioka Masaki 国立研究開発法人理化学研究所, 脳神経科学研究センター, 研究員 (00780503)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 精神疾患 / 双極性障害 / 統合失調症 / 自閉症 / デノボ変異 / 転移因子 / エクソーム

Outline of Final Research Achievements

I analyzed de novo mutations using exome sequencing data derived from trios or quartets with major mental disorders: 171 trios with bipolar disorder, 1,726 trios with schizophrenia, and 9,044 individuals with autism or their unaffected family members). During the execution of this project, several reports on de novo mobile element insertions from patients with mental disorders were published. I pivoted this project to comprehensive detection of de novo mutations including those arising early in development as mosaic mutations in the probands with mental disorders. Several mosaic mutations on exons and mitochondrial DNA were detected as a novel de novo mutation class. I detected two dysfunctional mosaic mutations on the SRCAP gene from two independent the probands with bipolar disorder, and multiple de novo mitochondrial mutations from the probands with bipolar disorder or schizophrenia. The mosaic mutations were confirmed by independent molecular experiments.

Free Research Field

精神医学、ゲノム科学

Academic Significance and Societal Importance of the Research Achievements

双極性障害は遺伝因子と環境因子の2つが複合的に重なり発症されると考えられている。本計画により狭義の遺伝因子や環境因子とは異なる第3の因子として、発生発達過程で生じる後天的なゲノム変異も双極性障害・統合失調症に寄与している可能性を見出した。この知見は、双極性障害・統合失調症のゲノム構造や病態の理解に寄与するものと考えられる。特にミトコンドリアゲノムのデノボ変異解析はこれまで試みが少なく、本計画の新規性が高い。