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Genetic Insights into Biological Mechanisms Governing Human Ovarian Ageing

Citation

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., et al. (2021). Genetic Insights into Biological Mechanisms Governing Human Ovarian Ageing. Nature, 596(7872), 393-397. PMCID: PMC7611832

Abstract

Reproductive longevity is essential for fertility and influences healthy ageing in women, 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 premutations. 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.

URL

http://dx.doi.org/10.1038/s41586-021-03779-7

Reference Type

Journal Article

Year Published

2021

Journal Title

Nature

Author(s)

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 A.
Bojesen, Stig Egil
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.
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 G.
Guénel, Pascal
Haiman, Christopher A.
Håkansson, Niclas
Hall, Per
Hayward, Caroline
He, Chunyan
He, Wei
Heiss, Gerardo M.
Høffding, Miya K.
Hopper, John L.
Hottenga, Jouke J.
Hu, Frank B.
Hunter, David J.
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 L.
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 Marie
Murray, Alison D.
Nalls, Mike A.
Newman, Anne B.
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, Timothy 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
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,
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.

Article Type

Regular

PMCID

PMC7611832

Race/Ethnicity

European

Sex/Gender

Ciswomen

ORCiD

Olshan - 0000-0001-9115-5128