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Identification of loci associated with paternal age effects of de novo mutations by analysis of large family genomic data

Research Project

Project/Area Number 22K20751
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0802:Biomedical structure and function and related fields
Research InstitutionInstitute of Physical and Chemical Research

Principal Investigator

Mizuno Shota  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, 特別研究員 (80962969)

Project Period (FY) 2022-08-31 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords父年齢効果 / デノボ変異 / GWAS / ゲノム / 遺伝学
Outline of Research at the Start

子のゲノムのみで検出される新規の遺伝子変異であるDe novo変異(DNM)は、集団における選択圧に影響されないことから、多様なヒト疾患で大きなリスクとなる。DNMは主に両親の生殖細胞での突然変異に由来するが、この約8割は父親の精子由来であり、父親の年齢依存的なDNM数の増加が知られている(父年齢効果;PAE)。このPAEによるDNM数増加には家系間での大きな差異が報告されているが、その要因は明らかとされていない。本研究では、約5000家系の大規模ゲノムデータベースを活用したPAEの大規模ゲノムワイド関連解析研究を実施する事で、PAEの大小に関与する新規関連遺伝子座の同定を目指す。

Outline of Final Research Achievements

In this project, we performed a genome-wide association study (GWAS) of the magnitude of paternal age effect (PAE) on de novo mutations (DNMs), genetic variants newly generated and detected only in the genome of the child. DNM calls were conducted by using data from approximately 3,000 families in the SPARK cohort during the project period, and a mean of 59 (SD ± 13) DNMs on autosomal chromosomes were identified. By using this dataset of DNM counts in children and the genotype data of approximately 8 million SNPs in fathers with appropriate data quality control, we performed a PAE GWAS and identified 95 SNPs that showed suggestive association (P<1E-5), whereas no SNPs reached the genome-wide significance (P<5E-8).

Academic Significance and Societal Importance of the Research Achievements

主に父親の生殖細胞での突然変異に由来するDNMは、集団における選択圧に影響されないことから、多様なヒト疾患で大きなリスクとなる。DNM数の父年齢依存的な増加には家系間での大きな差異が報告されているが、その要因は明らかとされていない。本研究が発展する事により、DNMの増減に関連する遺伝子座や関連する分子機構を明らかとされ、DNM発生リスクの推定やゲノム医療への貢献が期待される。

Report

(3 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • Research Products

    (6 results)

All 2024 2023 Other

All Journal Article (1 results) (of which Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (4 results) (of which Int'l Joint Research: 2 results) Remarks (1 results)

  • [Journal Article] Topologically associating domains define the impact of de novo promoter variants on autism spectrum disorder risk2024

    • Author(s)
      Nakamura Takumi、Ueda Junko、Mizuno Shota、Honda Kurara、Kazuno An-a、Yamamoto Hirona、Hara Tomonori、Takata Atsushi
    • Journal Title

      Cell Genomics

      Volume: 4 Issue: 2 Pages: 100488-100488

    • DOI

      10.1016/j.xgen.2024.100488

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] De novo promoter variants contribute to autism spectrum disorder risk through topologically associating domains2024

    • Author(s)
      Mizuno S.
    • Organizer
      The 47th Annual Meeting of Japanese Neuroscience Society
    • Related Report
      2023 Annual Research Report
  • [Presentation] Topologically associating domains define the impact of de novo promoter variants on autism spectrum disorder risk2023

    • Author(s)
      Mizuno S., Nakamura T., Ueda J., Honda K., Kazuno A. A., Yamamoto H., Hata T., & Takata A.
    • Organizer
      Human Genetics Asia 2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 自閉スペクトラム症におけるプロモーター領域de novo変異はクロマチン3次元構造を介した遺伝子制御によって疾患リスクに寄与する2023

    • Author(s)
      水野翔太、中村匠、上田順子、本田久楽々、数野安亜、山本明那、原伯徳、高田篤
    • Organizer
      第45回日本生物学的精神医学会年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Topologically associating domains define the impact of de novo promoter variants on autism spectrum disorder risk2023

    • Author(s)
      Mizuno S., Nakamura T., Ueda J., Honda K., Kazuno A. A., Yamamoto H., Hata T., & Takata A
    • Organizer
      The 52nd Annual Meeting of Society for Neuroscience
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Remarks] ゲノム変異における「バタフライエフェクト」

    • URL

      https://www.riken.jp/press/2024/20240127_1/index.html

    • Related Report
      2023 Annual Research Report

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Published: 2022-09-01   Modified: 2025-01-30  

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