Genetic insights into the biological mechanisms governing human ovarian ageing
Authors: Ruth Katherine S , Day Felix R , Hussain Jazib , Martínez-Marchal Ana , Aiken Catherine E , Azad Ajuna , Thompson Deborah J , Abe Hironori , Tarry-Adkins Jane L , Gonzalez Javier Martin , Claringbould Annique , Bakker Olivier B , Sulem Patrick , Turon Sandra , Onland-Moret N Charlotte , Hertz Emil Peter Trane , Timshel Pascal N , Shukla Vallari , Borup Rehannah , Olsen Kristina W , Ferrer-Roda Mònica , Huang Yan , Stankovic Stasa , Timmers Paul RHJ , 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 , Cross Simon S , Cucca Francesco , Czene Kamila , Davey-Smith George , de Geus Eco JCN , de Mutsert Renée , Vivo Immaculata De , 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 DR , John Esther M , Joshi Peter K , Karasik David , Kardia Sharon LR , Karlsson Robert , Kitahara Cari M , Kolcic Ivana , Kooperberg Charles , Kraft Peter , Kurian Allison W , Kutalik Zoltan , Bianca Martina La , LaChance Genevieve , Langenberg Claudia , Launer Lenore J , Laven Joop SE , Lawlor Deborah A , Marchand Loic Le , Li Jingmei , Lindblom Annika , Lindstrom Sara , Lindstrom Tricia , Linet Martha , Liu YongMei , Liu Simin , Luan Jian’an , Mägi Reedik , Magnusson Patrik KE , 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 DP , 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 BJ , 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 , Dijk Ko Willems van , Willemsen Gonneke , Wilson James F , Wolffenbuttel Bruce HR , Wolk Alicja , Wood Andrew R , Zhao Wei , Zygmunt Marek ,   Biobank-based Integrative Omics Study (BIOS) Consortium,   eQTLGen Consortium,   kConFab Investigators,   The LifeLines Cohort Study,   The InterAct consortium, 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 Kathyrn L , Chasman Daniel I , Easton Douglas F , Visser Jenny A , Ozanne Susan E , Namekawa Satoshi H , Murabito Joanne M , Ong Ken K , Hoffmann Eva R , Murray Anna , Roig Ignasi , Perry John RB 
Published: January 2021

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 monogenicFMR1premutations. 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.