Genetic insights into biological mechanisms governing human ovarian ageing

Katherine S. Ruth, Felix R. Day, Jazib Hussain, Ana Martínez-Marchal, Catherine E. Aiken, Ajuna Azad, Deborah J. Thompson, Lucie Knoblochova, Hironori Abe, Jane L. Tarry-Adkins, Javier Martin Gonzalez, Pierre Fontanillas, Annique Claringbould, Olivier B. Bakker, Patrick Sulem, Robin G. Walters, Chikashi Terao, Sandra Turon, Momoko Horikoshi, Kuang LinN. Charlotte Onland-Moret, Aditya Sankar, Emil Peter Thrane Hertz, Pascal N. Timshel, Vallari Shukla, Rehannah Borup, Kristina W. Olsen, Paula Aguilera, Mònica 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, Stefania Bandinelli, Caterina M. Barbieri, Robin N. Beaumont, Heiko Becher, Matthias W. Beckmann, Stefania Benonisdottir, Sven Bergmann, Murielle Bochud, Eric Boerwinkle, Stig E. Bojesen, Blair H. Smith, John R. B. Perry

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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 (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 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
Number of pages5
JournalNature
Volume596
Issue number7872
Early online date4 Aug 2021
DOIs
Publication statusPublished - 19 Aug 2021

Keywords

  • Ageing
  • Endocrine reproductive disorders
  • Genome-wide association studies
  • Reproductive biology

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