Genetic insights into biological mechanisms governing human ovarian ageing

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 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.

Metadata

Item Type:	Article
Authors/Creators:	This paper has 268 authors. You can scroll the list below to see them all or them all. Ruth, KS Day, FR Hussain, J Martínez-Marchal, A Aiken, CE Azad, A Thompson, DJ Knoblochova, L Abe, H Tarry-Adkins, JL Gonzalez, JM Fontanillas, P Claringbould, A Bakker, OB Sulem, P Walters, RG Terao, C Turon, S Horikoshi, M Lin, K Onland-Moret, NC Sankar, A Hertz, EPT Timshel, PN Shukla, V Borup, R Olsen, KW Aguilera, P Ferrer-Roda, M Huang, Y Stankovic, S Timmers, PRHJ Ahearn, TU Alizadeh, BZ Naderi, E Andrulis, IL Arnold, AM Aronson, KJ Augustinsson, A Bandinelli, S Barbieri, CM Beaumont, RN Becher, H Beckmann, MW Benonisdottir, S Bergmann, S Bochud, M Boerwinkle, E Bojesen, SE Bolla, MK Boomsma, DI Bowker, N Brody, JA Broer, L Buring, JE Campbell, A Campbell, H Castelao, JE Catamo, E Chanock, SJ Chenevix-Trench, G Ciullo, M Corre, T Couch, FJ Cox, A https://orcid.org/0000-0002-5138-1099 Crisponi, L Cross, SS https://orcid.org/0000-0003-2044-1754 Cucca, F Czene, K Smith, GD de Geus, EJCN de Mutsert, R De Vivo, I Demerath, EW Dennis, J Dunning, AM Dwek, M Eriksson, M Esko, T Fasching, PA Faul, JD Ferrucci, L Franceschini, N Frayling, TM Gago-Dominguez, M Mezzavilla, M García-Closas, M Gieger, C Giles, GG Grallert, H Gudbjartsson, DF Gudnason, V Guénel, P Haiman, CA Håkansson, N Hall, P Hayward, C He, C He, W Heiss, G Høffding, MK Hopper, JL Hottenga, JJ Hu, F Hunter, D Ikram, MA Jackson, RD Joaquim, MDR John, EM Joshi, PK Karasik, D Kardia, SLR Kartsonaki, C Karlsson, R Kitahara, CM Kolcic, I Kooperberg, C Kraft, P Kurian, AW Kutalik, Z La Bianca, M LaChance, G Langenberg, C Launer, LJ Laven, JSE Lawlor, DA Le Marchand, L Li, J Lindblom, A Lindstrom, S Lindstrom, T Linet, M Liu, Y Liu, S Luan, J Mägi, R Magnusson, PKE Mangino, M Mannermaa, A Marco, B Marten, J Martin, NG Mbarek, H McKnight, B Medland, SE Meisinger, C Meitinger, T Menni, C Metspalu, A Milani, L Milne, RL Montgomery, GW Mook-Kanamori, DO Mulas, A Mulligan, AM Murray, A Nalls, MA Newman, A Noordam, R Nutile, T Nyholt, DR Olshan, AF Olsson, H Painter, JN Patel, AV Pedersen, NL Perjakova, N Peters, A Peters, U Pharoah, PDP Polasek, O Porcu, E Psaty, BM Rahman, I Rennert, G Rennert, HS Ridker, PM Ring, SM Robino, A Rose, LM Rosendaal, FR Rossouw, J Rudan, I Rueedi, R Ruggiero, D Sala, CF Saloustros, E Sandler, DP Sanna, S Sawyer, EJ Sarnowski, C Schlessinger, D Schmidt, MK Schoemaker, MJ Schraut, KE Scott, C Shekari, S Shrikhande, A Smith, AV Smith, BH Smith, JA Sorice, R Southey, MC Spector, TD Spinelli, JJ Stampfer, M Stöckl, D van Meurs, JBJ Strauch, K Styrkarsdottir, U Swerdlow, AJ Tanaka, T Teras, LR Teumer, A Þorsteinsdottir, U Timpson, NJ Toniolo, D Traglia, M Troester, MA Truong, T Tyrrell, J Uitterlinden, AG Ulivi, S Vachon, CM Vitart, V Völker, U Vollenweider, P Völzke, H Wang, Q Wareham, NJ Weinberg, CR Weir, DR Wilcox, AN van Dijk, KW Willemsen, G Wilson, JF Wolffenbuttel, BHR Wolk, A Wood, AR Zhao, W Zygmunt, M Chen, Z Li, L Franke, L Burgess, S Deelen, P Pers, TH Grøndahl, ML Andersen, CY Pujol, A Lopez-Contreras, AJ Daniel, JA Stefansson, K Chang-Claude, J van der Schouw, YT Lunetta, KL Chasman, DI Easton, DF Visser, JA Ozanne, SE Namekawa, SH Solc, P Murabito, JM Ong, KK Hoffmann, ER Murray, A Roig, I Perry, JRB
Copyright, Publisher and Additional Information:	© 2021 The Authors. This is an author-produced version of a paper subsequently published in Nature. Uploaded in accordance with the publisher's self-archiving policy.
Dates:	Published: 19 August 2021 Published (online): 4 August 2021 Accepted: 29 June 2021
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Sheffield Teaching Hospitals
Depositing User:	Symplectic Sheffield
Date Deposited:	15 Oct 2021 12:34
Last Modified:	04 Feb 2022 01:38
Status:	Published
Publisher:	Springer Nature
Refereed:	Yes
Identification Number:	10.1038/s41586-021-03779-7
Related URLs:	Dataset
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:179281

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Genetic insights into biological mechanisms governing human ovarian ageing

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Genetic insights into biological mechanisms governing human ovarian ageing

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