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Genetic insights into the biological mechanisms governing human ovarian ageing

By Katherine S Ruth, Felix R. Day, Jazib Hussain, Ana Martinez-Marchal, Catherine E Aiken, Ajuna Azad, Deborah J. Thompson, Hironori Abe, Jane L Tarry-Adkins, Javier Martin Gonzalez, Annique Claringbould, Olivier B. Bakker, Patrick Sulem, Sandra Turon, N. Charlotte Onland-Moret, Emil Peter Trane Hertz, Pascal N Timshel, Vallari Shukla, Rehannah Borup, Kristina W Olsen, Monica Ferrer-Roda, Yan Huang, Stasa Stankovic, Paul 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, 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, Renee de Mutsert, Immaculata De Vivo, Ellen W Demerath, Joe Dennis, Alison M Dunning, Miriam Dwek, Mikael Eriksson, Tonu Esko, Peter A. Fasching, Jessica D. Faul, Luigi Ferrucci, Nora Franceschini, Timothy M Frayling, Manuela Gago-Dominguez, Massimo Mezzavilla, Montserrat Garcia-Closas, Christian Gieger, Graham G Giles, Harald Grallert, Daniel F. Gudbjartsson, Vilmundur Gudnason, Pascal Guenel, Christopher A. Haiman, Niclas Hakansson, Per Hall, Caroline Hayward, Chunyan He, Wei He, Gerardo Heiss, Miya K Hoffding, John L Hopper, Jouke J. Hottenga, Frank Hu, David Hunter, Mohammad A Ikram, Rebecca D Jackson, Micaella DR Joaquim, Esther M. John, Peter Joshi, David Karasik, Sharon LR Kardia, Robert Karlsson, Cari M. Kitahara, Ivana Kolcic, Charles Kooperberg, Peter Kraft, Allison W. Kurian, Zoltan Kutalik, Martina La Bianca, Genevieve LaChance, Claudia Langenberg, Lenore J Launer, Joop S.E. Laven, Deborah A Lawlor, Loic Le Marchand, Jingmei Li, Annika Lindblom, Sara Lindstrom, Tricia Lindstrom, Martha Linet, YongMei Liu, Simin Liu, Jianan Luan, Reedik Magi, Patrik K.E. Magnusson, Massimo Mangino, Arto Mannermaa, Brumat Marco, Jonathan Marten, Nicholas G Martin, Hamdi Mbarek, Barbara McKnight, Sarah E. Medland, Christa Meisinger, Thomas Meitinger, Cristina Menni, Andres Metspalu, Lili Milani, Roger L. Milne, Grant W Montgomery, Dennis O. Mook-Kanamori, Antonella Mulas, Anna M. Mulligan, Alison E. Murray, Mike A Nalls, Anne Newman, Raymond Noordam, Teresa Nutile, Dale R Nyholt, Andrew F Olshan, Hakan Olsson, Jodie N Painter, Alpa V Patel, Nancy Pedersen, Natalia Perjakova, Annette Peters, Ulrike Peters, Paul DP. Pharoah, Ozren Polasek, Eleonora Porcu, Bruce M Psaty, Iffat Rahman, Gad Rennert, Hedy S. Rennert, Paul M Ridker, Susan M. Ring, Antonietta Robino, Lynda M. Rose, Frits R Rosendaal, Jacques Rossouw, Igor Rudan, Rico Rueedi, Daniela Ruggiero, Cinzia F Sala, Emmanouil Saloustros, Dale P Sandler, Serena Sanna, Elinor J. Sawyer, Chloe Sarnowski, David Schlessinger, Marjanka K. Schmidt, Minouk J. Schoemaker, Katharina E Schraut, Christopher Scott, Saleh Shekari, Amruta Shrikhande, Albert V. Smith, Blair H. Smith, Jennifer A. Smith, Rossella Sorice, Melissa C Southey, Tim D. Spector, John J. Spinelli, Meir Stampfer, Doris Stockl, Joyce B.J. van Meurs, Konstantin Strauch, Unnur Styrkarsdottir, Anthony J. Swerdlow, Toshiko Tanaka, Lauren R Teras, Alexander Teumer, Unnur Thorsteinsdottir, Nicholas J. Timpson, Daniela Toniolo, Michela Traglia, Melissa A. Troester, Therese Truong, Jessica Tyrrell, Andre G Uitterlinden, Sheila Ulivi, Celine M. Vachon, Veronique Vitart, Uwe Völker, Peter Vollenweider, Henry Volzke, Qin Wang, Nicholas J. Wareham, Clarice R. Weinberg, David R. Weir, Amber N. Wilcox, Ko Willems van Dijk, Gonneke Willemsen, James F Wilson, Bruce HR Wolffenbuttel, Alicja Wolk, Andrew R. Wood, Wei Zhao, Marek Zygmunt, Biobank-based Integrative Omics Study (BIOS) Consortium, eQTLGen Consortium, kConFab Investigators, The LifeLines Cohort Study, The InterAct consortium, Lude Franke, Stephen Burgess, Patrick Deelen, Tune H Pers, Marie Louise Grondahl, Claus Yding Andersen, Anna Pujol, Andres J Lopez-Contreras, Jeremy A Daniel, Kari Stefansson, Jenny Chang-Claude, Yvonne T. van der Schouw, Kathyrn L Lunetta, Daniel I. Chasman, Douglas F. Easton, Jenny A Visser, Susan E. Ozanne, Satoshi H Namekawa, Joanne M Murabito, Ken K. Ong, Eva R. Hoffmann, Anna Murray, Ignasi Roig, John R.B. Perry

Posted 15 Jan 2021
medRxiv DOI: 10.1101/2021.01.11.20248322

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.

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