TY - JOUR

T1 - Genetic insights into biological mechanisms governing human ovarian ageing

AU - Ruth, Katherine S.

AU - Day, Felix R.

AU - Hussain, Jazib

AU - Martinez-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, Chikash

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, Monica

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 - Bojesen, Stig E.

AU - Hoffding, Miya K.

AU - Shrikhande, Amruta

AU - Pers, Tune H.

AU - Grøndahl, Marie Louise

AU - Andersen, Claus Yding

AU - Lopez-Contreras, Andres J.

AU - Daniel, Jeremy A.

AU - Hoffmann, Eva R.

AU - Biobank-based Integrative Omics St

AU - eQTLGen Consortium

AU - BioBank Japan Project

AU - China Kadoorie Biobank Collaborati

AU - kConFab Investigators

AU - LifeLines Cohort Study

AU - InterAct Consortium

AU - 23 Me Res Team

PY - 2021

Y1 - 2021

N2 - Reproductive longevity is essential for fertility and influences healthy ageing in women(1,2), 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 in approximately 200,000 women of European ancestry. These common alleles were associated with clinical extremes of age at natural menopause; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations(3). 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 women(1,2), 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 in approximately 200,000 women of European ancestry. These common alleles were associated with clinical extremes of age at natural menopause; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations(3). 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.

KW - MEIOTIC CELL-CYCLE

KW - DNA-DAMAGE

KW - MENDELIAN RANDOMIZATION

KW - CHROMOSOME SYNAPSIS

KW - EXPRESSION ANALYSIS

KW - EARLY MENOPAUSE

KW - GERMLINE

KW - VARIANTS

KW - DISEASE

KW - RISK

U2 - 10.1038/s41586-021-03779-7

DO - 10.1038/s41586-021-03779-7

M3 - Journal article

C2 - 34349265

VL - 596

SP - 393

EP - 397

JO - Nature

JF - Nature

SN - 0028-0836

ER -