Genetic susceptibility to earlier ovarian ageing increases de novo mutation rate in offspring
Genetic susceptibility to earlier ovarian ageing increases de novo mutation rate in offspring
Abstract Human genetic studies have provided substantial insight into the biological mechanisms governing ovarian ageing, yet previous approaches have been largely restricted to assessing common genetic variation. Here we report analyses of rare (MAF<0.1%) protein-coding variants in the exomes of 106,973 women from the UK Biobank study, implicating novel genes with effect sizes up to ～5 times larger than previously discovered in analyses of common variants. These include protein truncating variants in ZNF518A, which shorten reproductive lifespan by promoting both earlier age at natural menopause (ANM, 5.61 years [4.04-7.18], P=2*10-12) and later puberty timing in girls (age at menarche, 0.56 years [0.15-0.97], P=9.2*10-3). By integrating ChIP-Seq data, we demonstrate that common variants associated with ANM and menarche are enriched in the binding sites of ZNF518A. We also identify further links between ovarian ageing and cancer susceptibility, highlighting damaging germline variants in SAMHD1 that delay ANM and increase all-cause cancer risk in both males (OR=2.1 [1.7-2.6], P=4.7*10-13) and females (OR=1.61 [1.31-1.96], P=4*10-6). Finally, we demonstrate that genetic susceptibility to earlier ovarian ageing in women increases de novo mutation rate in their offspring. This provides direct evidence that female mutation rate is heritable and highlights an example of a mechanism for the maternal genome influencing child health.
Gardner Eugene J.、Azad Ajuna、Murray Anna、Ong Ken K.、The Genomics England Research Consortium、Kentistou Katherine A.、Day Felix R.、Wright Caroline F.、Perry John R. B.、Beaumont Robin N.、Wood Andrew R.、Weedon Michael N.、Zhao Yajie、Kennedy Kitale、Hurles Matthew E.、Martin Hilary C.、Hawkes Gareth、Ruth Katherine S.、Owens Nick D. L.、Hoffmann Eva R.、Shekari Saleh、Stankovic Stasa、Huang Qin Qin
MRC Epidemiology Unit, Wellcome¨CMRC Institute of Metabolic Science, University of CambridgeDNRF Center for Chromosome Stability, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of CopenhagenUniversity of Exeter Medical School, University of ExeterMRC Epidemiology Unit, Wellcome¨CMRC Institute of Metabolic Science, University of Cambridge||Department of Paediatrics, University of CambridgeGenomics England||William Harvey Research Institute, Queen Mary University of LondonMRC Epidemiology Unit, Wellcome¨CMRC Institute of Metabolic Science, University of CambridgeMRC Epidemiology Unit, Wellcome¨CMRC Institute of Metabolic Science, University of CambridgeUniversity of Exeter Medical School, University of ExeterMRC Epidemiology Unit, Wellcome¨CMRC Institute of Metabolic Science, University of Cambridge||Metabolic Research Laboratory, Wellcome¨CMRC Institute of Metabolic Science, University of CambridgeUniversity of Exeter Medical School, University of ExeterUniversity of Exeter Medical School, University of ExeterUniversity of Exeter Medical School, University of ExeterMRC Epidemiology Unit, Wellcome¨CMRC Institute of Metabolic Science, University of CambridgeUniversity of Exeter Medical School, University of ExeterWellcome Sanger InstituteWellcome Sanger InstituteUniversity of Exeter Medical School, University of ExeterUniversity of Exeter Medical School, University of ExeterUniversity of Exeter Medical School, University of ExeterDNRF Center for Chromosome Stability, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of CopenhagenUniversity of Exeter Medical School, University of Exeter||School of Public Health, Faculty of Medicine, University of QueenslandMRC Epidemiology Unit, Wellcome¨CMRC Institute of Metabolic Science, University of CambridgeWellcome Sanger Institute
遗传学妇产科学基础医学
Gardner Eugene J.,Azad Ajuna,Murray Anna,Ong Ken K.,The Genomics England Research Consortium,Kentistou Katherine A.,Day Felix R.,Wright Caroline F.,Perry John R. B.,Beaumont Robin N.,Wood Andrew R.,Weedon Michael N.,Zhao Yajie,Kennedy Kitale,Hurles Matthew E.,Martin Hilary C.,Hawkes Gareth,Ruth Katherine S.,Owens Nick D. L.,Hoffmann Eva R.,Shekari Saleh,Stankovic Stasa,Huang Qin Qin.Genetic susceptibility to earlier ovarian ageing increases de novo mutation rate in offspring[EB/OL].(2025-03-28)[2025-06-12].https://www.medrxiv.org/content/10.1101/2022.06.23.22276698.点此复制
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