Genetic insights into the biological mechanisms governing human ovarian ageing

Reproductive longevity is critical for fertility and impacts healthy ageing in women, yet insights into the underlying biological mechanisms and treatments to preserve it are limited. Here, we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in ∼200,000 women of European ancestry. These common alleles influence clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. Identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increase fertility and extend reproductive life in mice. Causal inference analyses using the identified genetic variants indicates that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases risks of hormone-sensitive cancers. These findings provide insight into the mechanisms governing ovarian ageing, when they act across the life-course, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Funding acknowledgements are available in the supplementary material ### 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: For studies included in the genome-wide analyses, within each of the studies, each participant provided written informed consent and the study protocol was approved by the institutional review board at the parent institution. Research on RNA expression in human eggs was carried out according to the Helsinki II declaration and was conducted in accordance with national regulation on research on human subjects and material. The research was approved by the Scientific Ethical Committee of the Capital Region of Denmark (Videnskabsetisk Komite) in accordance with Danish National regulation (H-2-2011-044; extension license amm. Nr. 51307; license holder: Claus Yding Andersen and H-1604473; license holder: Eva R. Hoffmann; H-16027088 granted to Marie Louise Grondahl). GDPR approval was obtained from the national data agency (SUND-2016-60, Eva R Hoffmann and HGH-2016_086 to Marie Louise Grondahl). All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. 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 genome-wide summary statistic data will be available at www.reprogen.org once the paper is published.