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.

• Authors: Katherine S Ruth, Felix R Day, Jazib Hussain, Ana Martínez-Marchal, Catherine E Aiken, Ajuna Azad, Deborah J Thompson, Lucie Knoblochova, Hironori Abe, Jane L Tarry-Adkins, Javier Martin Gonzalez, Pierre Fontanillas, Annique Claringbould, Olivier B Bakker, Patrick Sulem, Robin G Walters, Chikashi Terao, Sandra Turon, Momoko Horikoshi, Kuang Lin, N Charlotte Onland-Moret, Aditya Sankar, Emil Peter Thrane Hertz, Pascal N Timshel, Vallari Shukla, Rehannah Borup, Kristina W Olsen, Paula Aguilera, 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 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, Laura Crisponi, Simon S Cross, Francesco Cucca, Kamila Czene, George Davey Smith, Eco J C N 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-Dominguez, Massimo Mezzavilla, Montserrat García-Closas, Christian Gieger, Graham G Giles, Harald Grallert, Daniel F Gudbjartsson, Vilmundur Gudnason, Pascal Guénel, Christopher A Haiman, Niclas Håkansson, Per Hall, Caroline Hayward, Chunyan He, Wei He, Gerardo Heiss, Miya K Høffding, John L Hopper, Jouke J Hottenga, Frank Hu, David Hunter, Mohammad A Ikram, Rebecca D Jackson, Micaella D R Joaquim, Esther M John, Peter K Joshi, David Karasik, Sharon L R Kardia, Christiana Kartsonaki, 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, Jian'an Luan, Reedik Mägi, 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 Murray, Mike A Nalls, Anne Newman, Raymond Noordam, Teresa Nutile, Dale R Nyholt, Andrew F Olshan, Håkan Olsson, Jodie N Painter, Alpa V Patel, Nancy L Pedersen, Natalia Perjakova, Annette Peters, Ulrike Peters, Paul D P 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, Chloé 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 Stöckl, Joyce B J van Meurs, Konstantin Strauch, Unnur Styrkarsdottir, Anthony J Swerdlow, Toshiko Tanaka, Lauren R Teras, Alexander Teumer, Unnur Þorsteinsdottir, Nicholas J Timpson, Daniela Toniolo, Michela Traglia, Melissa A Troester, Thérèse Truong, Jessica Tyrrell, André G Uitterlinden, Sheila Ulivi, Celine M Vachon, Veronique Vitart, Uwe Völker, Peter Vollenweider, Henry Völzke, Qin Wang, Nicholas J Wareham, Clarice R Weinberg, David R Weir, Amber N Wilcox, Ko Willems van Dijk, Gonneke Willemsen, James F Wilson, Bruce H R Wolffenbuttel, Alicja Wolk, Andrew R Wood, Wei Zhao, Marek Zygmunt, Biobank-based Integrative Omics Study (BIOS) Consortium, eQTLGen Consortium, Biobank Japan Project, China Kadoorie Biobank Collaborative Group, kConFab Investigators, LifeLines Cohort Study, InterAct consortium, 23andMe Research Team, Zhengming Chen, Liming Li, Lude Franke, Stephen Burgess, Patrick Deelen, Tune H Pers, Marie Louise Grøndahl, Claus Yding Andersen, Anna Pujol, Andres J Lopez-Contreras, Jeremy A Daniel, Kari Stefansson, Jenny Chang-Claude, Yvonne T van der Schouw, Kathryn L Lunetta, Daniel I Chasman, Douglas F Easton, Jenny A Visser, Susan E Ozanne, Satoshi H Namekawa, Petr Solc, Joanne M Murabito, Ken K Ong, Eva R Hoffmann, Anna Murray, Ignasi Roig, John R B Perry
• Journal: Nature (Nature) Vol. 596 Issue 7872 Pg. 393-397 (08 2021) ISSN: 1476-4687 [Electronic] England
• PMID: 34349265 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• FMR1 protein, human
• Fragile X Mental Retardation Protein
• Checkpoint Kinase 2
• Checkpoint Kinase 1
• Chek1 protein, mouse
• Chek2 protein, mouse

Topics

• Adult
• Aging (genetics)
• Alleles
• Animals
• Bone and Bones (metabolism)
• Checkpoint Kinase 1 (genetics)
• Checkpoint Kinase 2 (genetics)
• Diabetes Mellitus, Type 2
• Diet
• Europe (ethnology)
• Asia, Eastern (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