. 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 | Ruth, Katherine S; Day, Felix R; Hussain, Jazib; Martínez-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; Martin, Nicholas G; Mbarek, Hamdi; McKnight, Barbara; Medland, Sarah E; 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; Nyholt, Dale R; 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; Lopez-Contreras, Andres J; Daniel, Jeremy A; Stefansson, Kari; Chang-Claude, Jenny; van der Schouw, Yvonne T; Lunetta, Kathryn L; Chasman, Daniel I; Easton, Douglas F; Visser, Jenny A; Ozanne, Susan E; Namekawa, Satoshi H; Solc, Petr; Murabito, Joanne M; Ong, Ken K; Hoffmann, Eva R; Murray, Anna; Roig, Ignasi; Perry, John R B |
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| Journal | NATURE |
| Pages | 393-397 |
| Volume | 596 |
| Date | 1/01/2021 |
| Grant ID | |
| Funding Body | |
| URL | http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1038/s41586-021-03779-7 |