Genetic susceptibility to earlier ovarian ageing increases de novo mutation rate in offspring

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by the Medical Research Council (Unit programs: MC\_UU\_12015/2, MC\_UU\_00006/2, MC\_UU\_12015/1, and MC\_UU\_00006/1). For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising. This research was conducted using the UK Biobank Resource under application 9905 (University of Cambridge) and 9072 and 871 (University of Exeter). Ajuna Azad and Eva Hoffmann were supported by the ERC (724718-ReCAP), Novo Nordisk Foundation (NNF15COC0016662), the Independent Research Foundation Denmark (0134-00299B), and a grant from the Danish National Research Foundation Centre (6110-00344B). Saleh Shekari was supported by the QUEX Institute (University of Exeter, UK and the University of Queensland, Australia). Anna Murray, Caroline Wright and Michael Weedon are supported by the Medical Research Council (MR/T00200X/1).The authors acknowledge the use of the University of Exeter High-Performance Computing facility in carrying out this work, funded by a MRC Clinical Research Infrastructure award (MRC Grant: MR/M008924/1). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: UK Biobank has approval from the North West Multi-centre Research Ethics Committee (MREC) as a Research Tissue Bank (RTB) approval. This approval means that researchers do not require separate ethical clearance and can operate under the RTB approval. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced using the UK Biobank resource will be returned to the UK Biobank returns catalogue upon publication.