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Get Free AccessAbstract 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.
Katherine S. Ruth, Felix R. Day, Jazib Hussain, Ana Martínez-Marchal, Catherine Aiken, Ajuna Azad, Deborah J. Thompson, Hironori Abe, Jane L. Tarry‐Adkins, Javier Martín‐González, Annique Claringbould, Olivier B. Bakker, Patrick Sulem, Sandra Turon, N. Charlotte Onland‐Moret, Emil Peter Trane Hertz, Pascal Timshel, Vallari Shukla, Rehannah Borup, Kristina Wendelboe Olsen, 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 Barbieri, Robin N. Beaumont, Heiko Becher, Matthias W. Beckmann, Stefania Benónísdóttir, Sven Bergmann, Murielle Bochud, Eric Boerwinkle, Stig E. Bojesen, Manjeet K. Bolla, Dorret I. Boomsma, Nicholas Bowker, Jennifer A. Brody, Linda Broer, Julie E. Buring, Archie Campbell, Harry Campbell, Jose E. Castelao, Eulalia Catamo, Stephen J. Chanock, Georgia Chenevix‐Trench, Marina Ciullo, Tanguy Corre, Fergus J. Couch, Angela Cox, Simon S. Cross, Francesco Cucca, Kamila Czene, George Davey Smith, Eco JCN de Geus, Renée de Mutsert, Immaculata De Vivo, Ellen W. Demerath, Joe Dennis, Alison M. Dunning, Miriam Dwek, Mikael Eriksson, Tõnu Esko, Peter A. Fasching, Jessica D. Faul, Luigi Ferrucci, Nora Franceschini, Timothy M. Frayling, Manuela Gago-Domínguez, Massimo Mezzavilla, Montserrat García‐Closas, Christian Gieger, Graham G. Giles, Harald Grallert, Daníel F. Guðbjartsson, Vilmundur Guðnason, Pascal Guénel, Christopher A. Haiman, Niclas Håkansson, Per Hall, Caroline Hayward, Chunyan He, Wei He, Gerardo Heiss, Miya Kudo Høffding, John L. Hopper, Jouke‐Jan Hottenga, Frank B Hu, David J. Hunter, M. Arfan Ikram, Rebecca D. Jackson, Micaella Joaquim, Esther M. John (2021). Genetic insights into the biological mechanisms governing human ovarian ageing. , DOI: https://doi.org/10.1101/2021.01.11.20248322.
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Type
Preprint
Year
2021
Authors
100
Datasets
0
Total Files
0
Language
en
DOI
https://doi.org/10.1101/2021.01.11.20248322
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