Genetic insights into biological mechanisms governing human ovarian ageing

Ruth, Katherine S, Day, Felix R, Hussain, Jazib, Martinez-Marchal, Ana, Aiken, Catherine E, Azad, Ajuna, Thompson, Deborah J, Knoblochova, Lucie, Abe, Hironori, Tarry-Adkins, Jane L, Gonzalez, Javier Martin, Fontanillas, Pierre, Claringbould, Annique, Bakker, Olivier B, Sulem, Patrick, Walters, Robin G, Terao, Chikashi, Turon, Sandra, Horikoshi, Momoko, Lin, Kuang, Onland-Moret, N Charlotte, Sankar, Aditya, Hertz, Emil Peter Thrane, Timshel, Pascal N, Shukla, Vallari, Borup, Rehannah, Olsen, Kristina W, Aguilera, Paula, Ferrer-Roda, Mònica, Huang, Yan, Stankovic, Stasa, Timmers, Paul R H J, Ahearn, Thomas U, Alizadeh, Behrooz Z, Naderi, Elnaz, Andrulis, Irene L, Arnold, Alice M, Aronson, Kristan J, Augustinsson, Annelie, Bandinelli, Stefania, Barbieri, Caterina M, Beaumont, Robin N, Becher, Heiko, Beckmann, Matthias W, Benonisdottir, Stefania, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E, Bolla, Manjeet K, Boomsma, Dorret I, Bowker, Nicholas, Brody, Jennifer A, Broer, Linda, Buring, Julie E, Campbell, Archie, Campbell, Harry, Castelao, Jose E, Catamo, Eulalia, Chanock, Stephen J, Chenevix-Trench, Georgia, Ciullo, Marina, Corre, Tanguy, Couch, Fergus J, Cox, Angela, Crisponi, Laura, Cross, Simon S, Cucca, Francesco, Czene, Kamila, Smith, George Davey, de Geus, Eco J C N, de Mutsert, Renée, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Dunning, Alison M, Dwek, Miriam, Eriksson, Mikael, Esko, Tõnu, Fasching, Peter A, Faul, Jessica D, Ferrucci, Luigi, Franceschini, Nora, Frayling, Timothy M, Gago-Dominguez, Manuela, Mezzavilla, Massimo, García-Closas, Montserrat, Gieger, Christian, Giles, Graham G, Grallert, Harald, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Guénel, Pascal, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hayward, Caroline, He, Chunyan, He, Wei, Heiss, Gerardo, Høffding, Miya K, Hopper, John L, Hottenga, Jouke J, Hu, Frank, Hunter, David, Ikram, Mohammad A, Jackson, Rebecca D, Joaquim, Micaella D R, John, Esther M, Joshi, Peter K, Karasik, David, Kardia, Sharon L R, Kartsonaki, Christiana, Karlsson, Robert, Kitahara, Cari M, Kolcic, Ivana, Kooperberg, Charles, Kraft, Peter, Kurian, Allison W, Kutalik, Zoltan, La Bianca, Martina, LaChance, Genevieve, Langenberg, Claudia, Launer, Lenore J, Laven, Joop S E, Lawlor, Deborah A, Le Marchand, Loic, Li, Jingmei, Lindblom, Annika, Lindstrom, Sara, Lindstrom, Tricia, Linet, Martha, Liu, YongMei, Liu, Simin, Luan, Jian'an, Mägi, Reedik, Magnusson, Patrik K E, Mangino, Massimo, Mannermaa, Arto, Marco, Brumat, Marten, Jonathan, , Mbarek, Hamdi, McKnight, Barbara, , Meisinger, Christa, Meitinger, Thomas, Menni, Cristina, Metspalu, Andres, Milani, Lili, Milne, Roger L, Montgomery, Grant W, Mook-Kanamori, Dennis O, Mulas, Antonella, Mulligan, Anna M, Murray, Alison, Nalls, Mike A, Newman, Anne, Noordam, Raymond, Nutile, Teresa, , Olshan, Andrew F, Olsson, Håkan, Painter, Jodie N, Patel, Alpa V, Pedersen, Nancy L, Perjakova, Natalia, Peters, Annette, Peters, Ulrike, Pharoah, Paul D P, Polasek, Ozren, Porcu, Eleonora, Psaty, Bruce M, Rahman, Iffat, Rennert, Gad, Rennert, Hedy S, Ridker, Paul M, Ring, Susan M, Robino, Antonietta, Rose, Lynda M, Rosendaal, Frits R, Rossouw, Jacques, Rudan, Igor, Rueedi, Rico, Ruggiero, Daniela, Sala, Cinzia F, Saloustros, Emmanouil, Sandler, Dale P, Sanna, Serena, Sawyer, Elinor J, Sarnowski, Chloé, Schlessinger, David, Schmidt, Marjanka K, Schoemaker, Minouk J, Schraut, Katharina E, Scott, Christopher, Shekari, Saleh, Shrikhande, Amruta, Smith, Albert V, Smith, Blair H, Smith, Jennifer A, Sorice, Rossella, Southey, Melissa C, Spector, Tim D, Spinelli, John J, Stampfer, Meir, Stöckl, Doris, van Meurs, Joyce B J, Strauch, Konstantin, Styrkarsdottir, Unnur, Swerdlow, Anthony J, Tanaka, Toshiko, Teras, Lauren R, Teumer, Alexander, Þorsteinsdottir, Unnur, Timpson, Nicholas J, Toniolo, Daniela, Traglia, Michela, Troester, Melissa A, Truong, Thérèse, Tyrrell, Jessica, Uitterlinden, André G, Ulivi, Sheila, Vachon, Celine M, Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Völzke, Henry, Wang, Qin, Wareham, Nicholas J, Weinberg, Clarice R, Weir, David R, Wilcox, Amber N, van Dijk, Ko Willems, Willemsen, Gonneke, Wilson, James F, Wolffenbuttel, Bruce H R, Wolk, Alicja, Wood, Andrew R, Zhao, Wei, Zygmunt, Marek, Chen, Zhengming, Li, Liming, Franke, Lude, Burgess, Stephen, Deelen, Patrick, Pers, Tune H, Grøndahl, Marie Louise, Andersen, Claus Yding, & Pujol, Anna (2021) Genetic insights into biological mechanisms governing human ovarian ageing. Nature, 596(7872), pp. 393-397.

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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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ID Code: 214298
Item Type: Contribution to Journal (Journal Article)
Refereed: Yes
ORCID iD:
Nyholt, Dale Rorcid.org/0000-0001-7159-3040
Additional Information: Acknowledgements: This research was conducted using the UK Biobank resource under application numbers 871 (Exeter) and 9797 (Cambridge). Full individual study acknowledgements can be found in the Supplementary Information. The authors wish to dedicate this work to the memory of Professor P. Solc. The QIMR cohort was supported by National Institutes of Health (NIH) Grants AA07535, AA07728, AA13320, AA13321, AA14041, AA11998, AA17688, DA012854, DA019951, AA010249, AA013320, AA013321, AA011998, AA017688, and DA027995; by Grants from the Australian National Health and Medical Research Council (NHMRC) (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498 and 1075175); by Grants from the Australian Research Council (ARC) (A7960034, A79906588, A79801419, DP0770096, DP0212016, and DP0343921); DRN (FT0991022, 613674) SEM (1103623) and GWM (619667) were supported by the ARC Future Fellowship and NHMRC Fellowship Schemes.
Measurements or Duration: 5 pages
Keywords: Adult, Aging/genetics, Alleles, Animals, Bone and Bones/metabolism, Checkpoint Kinase 1/genetics, Checkpoint Kinase 2/genetics, Diabetes Mellitus, Type 2, Diet, Europe/ethnology, Far East/ethnology, Female, Fertility/genetics, Fragile X Mental Retardation Protein/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Healthy Aging/genetics, Humans, Longevity/genetics, Menopause/genetics, Menopause, Premature/genetics, Mice, Mice, Inbred C57BL, Middle Aged, Ovary/metabolism, Primary Ovarian Insufficiency/genetics, Uterus
DOI: 10.1038/s41586-021-03779-7
ISSN: 0028-0836
Pure ID: 100038729
Divisions: Current > Research Centres > Centre for Genomics and Personalised Health
Current > QUT Faculties and Divisions > Faculty of Health
Current > Schools > School of Biomedical Sciences
Funding:
Copyright Owner: 2021. The Author(s), under exclusive licence to Springer Nature Limited
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Deposited On: 03 Nov 2021 07:28
Last Modified: 02 Aug 2024 14:46

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