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

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K20751
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0802:Biomedical structure and function and related fields
• Research Institution: Institute 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
• Keywords: 父年齢効果 / デノボ変異 / GWAS / ゲノム

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).

Free Research Field

ゲノム医科学

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。