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.
| Original language | English |
|---|---|
| Pages (from-to) | 393-397 |
| Number of pages | 5 |
| Journal | Nature |
| Volume | 596 |
| Issue number | 7872 |
| DOIs | |
| Publication status | Published - 19 Aug 2021 |
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In: Nature, Vol. 596, No. 7872, 19.08.2021, p. 393-397.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Genetic insights into biological mechanisms governing human ovarian ageing
AU - Ruth, Katherine S.
AU - Day, Felix R.
AU - Hussain, Jazib
AU - Martínez-Marchal, Ana
AU - Aiken, Catherine E.
AU - Azad, Ajuna
AU - Thompson, Deborah J.
AU - Knoblochova, Lucie
AU - Abe, Hironori
AU - Tarry-Adkins, Jane L.
AU - Gonzalez, Javier Martin
AU - Fontanillas, Pierre
AU - Claringbould, Annique
AU - Bakker, Olivier B.
AU - Sulem, Patrick
AU - Walters, Robin G.
AU - Terao, Chikashi
AU - Turon, Sandra
AU - Horikoshi, Momoko
AU - Lin, Kuang
AU - Onland-Moret, N. Charlotte
AU - Sankar, Aditya
AU - Hertz, Emil Peter Thrane
AU - Timshel, Pascal N.
AU - Shukla, Vallari
AU - Borup, Rehannah
AU - Olsen, Kristina W.
AU - Aguilera, Paula
AU - Ferrer-Roda, Mònica
AU - Huang, Yan
AU - Stankovic, Stasa
AU - Timmers, Paul R.H.J.
AU - Ahearn, Thomas U.
AU - Alizadeh, Behrooz Z.
AU - Naderi, Elnaz
AU - Andrulis, Irene L.
AU - Arnold, Alice M.
AU - Aronson, Kristan J.
AU - Augustinsson, Annelie
AU - Bandinelli, Stefania
AU - Barbieri, Caterina M.
AU - Beaumont, Robin N.
AU - Becher, Heiko
AU - Beckmann, Matthias W.
AU - Benonisdottir, Stefania
AU - Bergmann, Sven
AU - Bochud, Murielle
AU - Boerwinkle, Eric
AU - Bojesen, Stig E.
AU - Bolla, Manjeet K.
AU - Boomsma, Dorret I.
AU - Bowker, Nicholas
AU - Brody, Jennifer A.
AU - Broer, Linda
AU - Buring, Julie E.
AU - Campbell, Archie
AU - Campbell, Harry
AU - Castelao, Jose E.
AU - Catamo, Eulalia
AU - Chanock, Stephen J.
AU - Chenevix-Trench, Georgia
AU - Ciullo, Marina
AU - Corre, Tanguy
AU - Couch, Fergus J.
AU - Cox, Angela
AU - Crisponi, Laura
AU - Cross, Simon S.
AU - Cucca, Francesco
AU - Czene, Kamila
AU - Smith, George Davey
AU - de Geus, Eco J.C.N.
AU - de Mutsert, Renée
AU - De Vivo, Immaculata
AU - Demerath, Ellen W.
AU - Dennis, Joe
AU - Dunning, Alison M.
AU - Dwek, Miriam
AU - Eriksson, Mikael
AU - Esko, Tõnu
AU - Fasching, Peter A.
AU - Faul, Jessica D.
AU - Ferrucci, Luigi
AU - Franceschini, Nora
AU - Frayling, Timothy M.
AU - Gago-Dominguez, Manuela
AU - Mezzavilla, Massimo
AU - García-Closas, Montserrat
AU - Gieger, Christian
AU - Giles, Graham G.
AU - Grallert, Harald
AU - Gudbjartsson, Daniel F.
AU - Gudnason, Vilmundur
AU - Guénel, Pascal
AU - Haiman, Christopher A.
AU - Håkansson, Niclas
AU - Hall, Per
AU - Hayward, Caroline
AU - He, Chunyan
AU - He, Wei
AU - Heiss, Gerardo
AU - Høffding, Miya K.
AU - Hopper, John L.
AU - Hottenga, Jouke J.
AU - Hu, Frank
AU - Hunter, David
AU - Ikram, Mohammad A.
AU - Jackson, Rebecca D.
AU - Joaquim, Micaella D.R.
AU - John, Esther M.
AU - Joshi, Peter K.
AU - Karasik, David
AU - Kardia, Sharon L.R.
AU - Kartsonaki, Christiana
AU - Karlsson, Robert
AU - Kitahara, Cari M.
AU - Kolcic, Ivana
AU - Kooperberg, Charles
AU - Kraft, Peter
AU - Kurian, Allison W.
AU - Kutalik, Zoltan
AU - La Bianca, Martina
AU - LaChance, Genevieve
AU - Langenberg, Claudia
AU - Launer, Lenore J.
AU - Laven, Joop S.E.
AU - Lawlor, Deborah A.
AU - Le Marchand, Loic
AU - Li, Jingmei
AU - Lindblom, Annika
AU - Lindstrom, Sara
AU - Lindstrom, Tricia
AU - Linet, Martha
AU - Liu, Yong Mei
AU - Liu, Simin
AU - Luan, Jian’an
AU - Mägi, Reedik
AU - Magnusson, Patrik K.E.
AU - Mangino, Massimo
AU - Mannermaa, Arto
AU - Marco, Brumat
AU - Marten, Jonathan
AU - Martin, Nicholas G.
AU - Mbarek, Hamdi
AU - McKnight, Barbara
AU - Medland, Sarah E.
AU - Meisinger, Christa
AU - Meitinger, Thomas
AU - Menni, Cristina
AU - Metspalu, Andres
AU - Milani, Lili
AU - Milne, Roger L.
AU - Montgomery, Grant W.
AU - Mook-Kanamori, Dennis O.
AU - Mulas, Antonella
AU - Mulligan, Anna M.
AU - Murray, Alison
AU - Nalls, Mike A.
AU - Newman, Anne
AU - Noordam, Raymond
AU - Nutile, Teresa
AU - Nyholt, Dale R.
AU - Olshan, Andrew F.
AU - Olsson, Håkan
AU - Painter, Jodie N.
AU - Patel, Alpa V.
AU - Pedersen, Nancy L.
AU - Perjakova, Natalia
AU - Peters, Annette
AU - Peters, Ulrike
AU - Pharoah, Paul D.P.
AU - Polasek, Ozren
AU - Porcu, Eleonora
AU - Psaty, Bruce M.
AU - Rahman, Iffat
AU - Rennert, Gad
AU - Rennert, Hedy S.
AU - Ridker, Paul M.
AU - Ring, Susan M.
AU - Robino, Antonietta
AU - Rose, Lynda M.
AU - Rosendaal, Frits R.
AU - Rossouw, Jacques
AU - Rudan, Igor
AU - Rueedi, Rico
AU - Ruggiero, Daniela
AU - Sala, Cinzia F.
AU - Saloustros, Emmanouil
AU - Sandler, Dale P.
AU - Sanna, Serena
AU - Sawyer, Elinor J.
AU - Sarnowski, Chloé
AU - Schlessinger, David
AU - Schmidt, Marjanka K.
AU - Schoemaker, Minouk J.
AU - Schraut, Katharina E.
AU - Scott, Christopher
AU - Shekari, Saleh
AU - Shrikhande, Amruta
AU - Smith, Albert V.
AU - Smith, Blair H.
AU - Smith, Jennifer A.
AU - Sorice, Rossella
AU - Southey, Melissa C.
AU - Spector, Tim D.
AU - Spinelli, John J.
AU - Stampfer, Meir
AU - Stöckl, Doris
AU - van Meurs, Joyce B.J.
AU - Strauch, Konstantin
AU - Styrkarsdottir, Unnur
AU - Swerdlow, Anthony J.
AU - Tanaka, Toshiko
AU - Teras, Lauren R.
AU - Teumer, Alexander
AU - Þorsteinsdottir, Unnur
AU - Timpson, Nicholas J.
AU - Toniolo, Daniela
AU - Traglia, Michela
AU - Troester, Melissa A.
AU - Truong, Thérèse
AU - Tyrrell, Jessica
AU - Uitterlinden, André G.
AU - Ulivi, Sheila
AU - Vachon, Celine M.
AU - Vitart, Veronique
AU - Völker, Uwe
AU - Vollenweider, Peter
AU - Völzke, Henry
AU - Wang, Qin
AU - Wareham, Nicholas J.
AU - Weinberg, Clarice R.
AU - Weir, David R.
AU - Wilcox, Amber N.
AU - van Dijk, Ko Willems
AU - Willemsen, Gonneke
AU - Wilson, James F.
AU - Wolffenbuttel, Bruce H.R.
AU - Wolk, Alicja
AU - Wood, Andrew R.
AU - Zhao, Wei
AU - Zygmunt, Marek
AU - Chen, Zhengming
AU - Li, Liming
AU - Franke, Lude
AU - Burgess, Stephen
AU - Deelen, Patrick
AU - Pers, Tune H.
AU - Grøndahl, Marie Louise
AU - Andersen, Claus Yding
AU - Pujol, Anna
AU - Biobank-based Integrative Omics Study (BIOS) Consortium
AU - eQTLGen Consortium
AU - The Biobank Japan
AU - China Kadoorie Biobank Collaborative Group
AU - kConFab Investigators
AU - The LifeLines Cohort Study
AU - The InterAct Consortium
AU - 23andMe Research Team
N1 - Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/8/19
Y1 - 2021/8/19
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85112666642&partnerID=8YFLogxK
U2 - 10.1038/s41586-021-03779-7
DO - 10.1038/s41586-021-03779-7
M3 - Article
C2 - 34349265
AN - SCOPUS:85112666642
SN - 0028-0836
VL - 596
SP - 393
EP - 397
JO - Nature
JF - Nature
IS - 7872
ER -