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Genetic insights into biological mechanisms governing human ovarian ageing.

TitleGenetic insights into biological mechanisms governing human ovarian ageing.
Publication TypeJournal Article
Year of Publication2021
AuthorsRuth KS, Day FR, Hussain J, et al.
Corporate AuthorsBiobank-based Integrative Omics Study(BIOS) Consortium, eQTLGen consortium, BioBank Japan Project, China Kadoorie Biobank Collaborative Group, kConFab Investigators, LifeLines Cohort Study, InterAct Consortium, 23andMe Research Team
JournalNature
Volume596
Issue7872
Pagination393-397
Date Published2021 08
ISSN1476-4687
Abstract

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its 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 about 200,000 women of European ancestry. These common alleles were associated with 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. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated 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 increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

DOI10.1038/s41586-021-03779-7
Alternate JournalNature
PubMed ID34349265
Grant ListR01 HL105756 / HL / NHLBI NIH HHS / United States
U01 HL130114 / HL / NHLBI NIH HHS / United States