Genetic insights into biological mechanisms governing human ovarian ageing

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  • Katherine S. Ruth
  • Felix R. Day
  • Hussain, Jazib
  • Ana Martinez-Marchal
  • Catherine E. Aiken
  • Ajuna Azad
  • Deborah J. Thompson
  • Lucie Knoblochova
  • Hironori Abe
  • Jane L. Tarry-Adkins
  • Martin Gonzalez, Javier
  • Pierre Fontanillas
  • Annique Claringbould
  • Olivier B. Bakker
  • Patrick Sulem
  • Robin G. Walters
  • Chikash Terao
  • Sandra Turon
  • Momoko Horikoshi
  • Kuang Lin
  • N. Charlotte Onland-Moret
  • Aditya Sankar
  • Hertz, Emil Peter Thrane
  • Pascal N. Timshel
  • Vallari Shukla
  • Rehannah Borup
  • Kristina W. Olsen
  • Paula Aguilera
  • Monica Ferrer-Roda
  • Yan Huang
  • Stasa Stankovic
  • Paul R. H. J. Timmers
  • Thomas U. Ahearn
  • Behrooz Z. Alizadeh
  • Elnaz Naderi
  • Irene L. Andrulis
  • Alice M. Arnold
  • Kristan J. Aronson
  • Annelie Augustinsson
  • Bojesen, Stig Egil
  • Miya K. Hoffding
  • Amruta Shrikhande
  • Pers, Tune H
  • Marie Louise Grøndahl
  • tcg964, tcg964
  • Lopez-Contreras, Andres
  • Jeremy A. Daniel
  • Hoffmann, Eva
  • Biobank-based Integrative Omics St
  • eQTLGen Consortium
  • BioBank Japan Project
  • China Kadoorie Biobank Collaborati
  • kConFab Investigators
  • LifeLines Cohort Study
  • InterAct Consortium
  • 23 Me Res Team

Reproductive longevity is essential for fertility and influences healthy ageing in women(1,2), 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 in approximately 200,000 women of European ancestry. These common alleles were associated with clinical extremes of age at natural menopause; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations(3). 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.

Original languageEnglish
Pages (from-to)393-397
Publication statusPublished - 2021

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