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Genetic insights into biological mechanisms governing human ovarian ageing

Ruth, Katherine S. ; Day, Felix R. ; Hussain, Jazib ; Martínez-Marchal, Ana ; Aiken, Catherine E. ; Azad, Ajuna ; Thompson, Deborah J. ; Knoblochova, Lucie ; Abe, Hironori and Tarry-Adkins, Jane L. , et al. (2021) In Nature 596(7872). p.393-397
Abstract

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, 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 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key... (More)

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, 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 premutations3. 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.

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published
subject
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Nature
volume
596
issue
7872
pages
5 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:34349265
  • scopus:85112666642
ISSN
0028-0836
DOI
10.1038/s41586-021-03779-7
language
English
LU publication?
yes
id
608b9697-c791-4ae4-a921-b9fde67cf150
date added to LUP
2021-09-27 10:33:33
date last changed
2024-03-23 10:11:54
@article{608b9697-c791-4ae4-a921-b9fde67cf150,
  abstract     = {{<p>Reproductive longevity is essential for fertility and influences healthy ageing in women<sup>1,2</sup>, 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<sup>3</sup>. 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.</p>}},
  author       = {{Ruth, Katherine S. and Day, Felix R. and Hussain, Jazib and Martínez-Marchal, Ana and Aiken, Catherine E. and Azad, Ajuna and Thompson, Deborah J. and Knoblochova, Lucie and Abe, Hironori and Tarry-Adkins, Jane L. and Gonzalez, Javier Martin and Fontanillas, Pierre and Claringbould, Annique and Bakker, Olivier B. and Sulem, Patrick and Walters, Robin G. and Terao, Chikashi and Turon, Sandra and Horikoshi, Momoko and Lin, Kuang and Onland-Moret, N. Charlotte and Sankar, Aditya and Hertz, Emil Peter Thrane and Timshel, Pascal N. and Shukla, Vallari and Borup, Rehannah and Olsen, Kristina W. and Aguilera, Paula and Ferrer-Roda, Mònica and Huang, Yan and Stankovic, Stasa and Timmers, Paul R.H.J. and Ahearn, Thomas U. and Alizadeh, Behrooz Z. and Naderi, Elnaz and Andrulis, Irene L. and Arnold, Alice M. and Aronson, Kristan J. and Augustinsson, Annelie and Bandinelli, Stefania and Barbieri, Caterina M. and Beaumont, Robin N. and Becher, Heiko and Beckmann, Matthias W. and Benonisdottir, Stefania and Bergmann, Sven and Bochud, Murielle and Boerwinkle, Eric and Hall, Per and Olsson, Håkan and Perry, John R. B.}},
  issn         = {{0028-0836}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{7872}},
  pages        = {{393--397}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature}},
  title        = {{Genetic insights into biological mechanisms governing human ovarian ageing}},
  url          = {{http://dx.doi.org/10.1038/s41586-021-03779-7}},
  doi          = {{10.1038/s41586-021-03779-7}},
  volume       = {{596}},
  year         = {{2021}},
}