Exome sequencing of multiplex families to elucidate pathophysiology of autism spectrum disorder

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K15512
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: Nagoya University
• Principal Investigator: KIMURA HIROKI 名古屋大学, 医学系研究科, 講師 (30612783)
• Project Period (FY): 2020-03-01 – 2022-03-31
• Keywords: 自閉スペクトラム症 / 統合失調症 / 多発家系 / エクソーム / 全ゲノムシークエンス / Gene ontology 解析 / ABCA13 / Trans synaptic signaling

Outline of Final Research Achievements

Autism spectrum disorder (ASD) is a highly heritable, complex disorder in which rare variants contribute significantly to disease risk. Although many genes have been associated with ASD, there have been few genetic studies of ASD in the Japanese population. In whole exomes from a Japanese ASD sample of 320 cases and 299 controls including 17 ASD multiplex families, rare variants were associated with ASD within specific neurodevelopmental gene sets, including highly constrained genes, fragile X mental retardation protein target genes, and genes involved in synaptic function, with the strongest enrichment in trans-synaptic signaling (p = 4.4 × 10-4, Q-value = 0.06). In particular, we strengthen the evidence regarding the role of ABCA13, a synaptic function& related gene, in Japanese ASD. The overall results of this exome study showed that rare variants related to synaptic function are associated with ASD susceptibility in the Japanese population.

Free Research Field

精神神経科学

Academic Significance and Societal Importance of the Research Achievements

自閉スペクトラム症（ASD）は、同一家系内に集積しうるが、これまでのASD遺伝研究は同一家系内にASDが存在しない家系を対象に新規突然変異を探すこと主であった。本研究では、日本人最大規模のASD患者さんのゲノムデータから、家系内で受け継がれた変異に着目し、ASDの同一家系内集積性の原因を探った。その結果、ASDの家系内集積に関わる様々なバリアントの同定が可能となり、新規のASD候補遺伝子となるABCA 13の同定に繋がった。本結果は、ASDが家系内に集積する原因の解明、ASDを含めた精神疾患の新規診断補助法の開発、さらにはASDの病態解明並びに新規の創薬につながることが期待された。