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 - Rennert, Gad
AU - Karasik, David
N1 - © 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.
KW - Adult
KW - Aging/genetics
KW - Alleles
KW - Animals
KW - Bone and Bones/metabolism
KW - Checkpoint Kinase 1/genetics
KW - Checkpoint Kinase 2/genetics
KW - Diabetes Mellitus, Type 2
KW - Diet
KW - Europe/ethnology
KW - Far East/ethnology
KW - Female
KW - Fertility/genetics
KW - Fragile X Mental Retardation Protein/genetics
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Healthy Aging/genetics
KW - Humans
KW - Longevity/genetics
KW - Menopause, Premature/genetics
KW - Menopause/genetics
KW - Mice
KW - Mice, Inbred C57BL
KW - Middle Aged
KW - Ovary/metabolism
KW - Primary Ovarian Insufficiency/genetics
KW - Uterus
UR - http://www.scopus.com/inward/record.url?scp=85112666642&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41586-021-03779-7
DO - https://doi.org/10.1038/s41586-021-03779-7
M3 - مقالة
C2 - 34349265
SN - 0028-0836
VL - 596
SP - 393
EP - 397
JO - Nature
JF - Nature
IS - 7872
ER -