Skip to main content
construction release_alert
Scholars@Duke will be undergoing maintenance April 11-15. Some features may be unavailable during this time.
cancel
Journal cover image

Genetic insights into biological mechanisms governing human ovarian ageing.

Publication ,  Journal Article
Ruth, KS; Day, FR; Hussain, J; Martínez-Marchal, A; Aiken, CE; Azad, A; Thompson, DJ; Knoblochova, L; Abe, H; Tarry-Adkins, JL; Gonzalez, JM ...
Published in: Nature
August 2021

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

August 2021

Volume

596

Issue

7872

Start / End Page

393 / 397

Location

England

Related Subject Headings

  • Uterus
  • Primary Ovarian Insufficiency
  • Ovary
  • Middle Aged
  • Mice, Inbred C57BL
  • Mice
  • Menopause, Premature
  • Menopause
  • Longevity
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Ruth, K. S., Day, F. R., Hussain, J., Martínez-Marchal, A., Aiken, C. E., Azad, A., … Perry, J. R. B. (2021). Genetic insights into biological mechanisms governing human ovarian ageing. Nature, 596(7872), 393–397. https://doi.org/10.1038/s41586-021-03779-7
Ruth, Katherine S., Felix R. Day, Jazib Hussain, Ana Martínez-Marchal, Catherine E. Aiken, Ajuna Azad, Deborah J. Thompson, et al. “Genetic insights into biological mechanisms governing human ovarian ageing.Nature 596, no. 7872 (August 2021): 393–97. https://doi.org/10.1038/s41586-021-03779-7.
Ruth KS, Day FR, Hussain J, Martínez-Marchal A, Aiken CE, Azad A, et al. Genetic insights into biological mechanisms governing human ovarian ageing. Nature. 2021 Aug;596(7872):393–7.
Ruth, Katherine S., et al. “Genetic insights into biological mechanisms governing human ovarian ageing.Nature, vol. 596, no. 7872, Aug. 2021, pp. 393–97. Pubmed, doi:10.1038/s41586-021-03779-7.
Ruth KS, Day FR, Hussain J, Martínez-Marchal A, Aiken CE, Azad A, Thompson DJ, Knoblochova L, Abe H, Tarry-Adkins JL, Gonzalez JM, Fontanillas P, Claringbould A, Bakker OB, Sulem P, Walters RG, Terao C, Turon S, Horikoshi M, Lin K, Onland-Moret NC, Sankar A, Hertz EPT, Timshel PN, Shukla V, Borup R, Olsen KW, Aguilera P, Ferrer-Roda M, Huang Y, Stankovic S, Timmers PRHJ, Ahearn TU, Alizadeh BZ, Naderi E, Andrulis IL, Arnold AM, Aronson KJ, Augustinsson A, Bandinelli S, Barbieri CM, Beaumont RN, Becher H, Beckmann MW, Benonisdottir S, Bergmann S, Bochud M, Boerwinkle E, Bojesen SE, Bolla MK, Boomsma DI, Bowker N, Brody JA, Broer L, Buring JE, Campbell A, Campbell H, Castelao JE, Catamo E, Chanock SJ, Chenevix-Trench G, Ciullo M, Corre T, Couch FJ, Cox A, Crisponi L, Cross SS, Cucca F, Czene K, Smith GD, de Geus EJCN, de Mutsert R, De Vivo I, Demerath EW, Dennis J, Dunning AM, Dwek M, Eriksson M, Esko T, Fasching PA, Faul JD, Ferrucci L, Franceschini N, Frayling TM, Gago-Dominguez M, Mezzavilla M, García-Closas M, Gieger C, Giles GG, Grallert H, Gudbjartsson DF, Gudnason V, Guénel P, Haiman CA, Håkansson N, Hall P, Hayward C, He C, He W, Heiss G, Høffding MK, Hopper JL, Hottenga JJ, Hu F, Hunter D, Ikram MA, Jackson RD, Joaquim MDR, John EM, Joshi PK, Karasik D, Kardia SLR, Kartsonaki C, Karlsson R, Kitahara CM, Kolcic I, Kooperberg C, Kraft P, Kurian AW, Kutalik Z, La Bianca M, LaChance G, Langenberg C, Launer LJ, Laven JSE, Lawlor DA, Le Marchand L, Li J, Lindblom A, Lindstrom S, Lindstrom T, Linet M, Liu Y, Liu S, Luan J, Mägi R, Magnusson PKE, Mangino M, Mannermaa A, Marco B, Marten J, Martin NG, Mbarek H, McKnight B, Medland SE, Meisinger C, Meitinger T, Menni C, Metspalu A, Milani L, Milne RL, Montgomery GW, Mook-Kanamori DO, Mulas A, Mulligan AM, Murray A, Nalls MA, Newman A, Noordam R, Nutile T, Nyholt DR, Olshan AF, Olsson H, Painter JN, Patel AV, Pedersen NL, Perjakova N, Peters A, Peters U, Pharoah PDP, Polasek O, Porcu E, Psaty BM, Rahman I, Rennert G, Rennert HS, Ridker PM, Ring SM, Robino A, Rose LM, Rosendaal FR, Rossouw J, Rudan I, Rueedi R, Ruggiero D, Sala CF, Saloustros E, Sandler DP, Sanna S, Sawyer EJ, Sarnowski C, Schlessinger D, Schmidt MK, Schoemaker MJ, Schraut KE, Scott C, Shekari S, Shrikhande A, Smith AV, Smith BH, Smith JA, Sorice R, Southey MC, Spector TD, Spinelli JJ, Stampfer M, Stöckl D, van Meurs JBJ, Strauch K, Styrkarsdottir U, Swerdlow AJ, Tanaka T, Teras LR, Teumer A, Þorsteinsdottir U, Timpson NJ, Toniolo D, Traglia M, Troester MA, Truong T, Tyrrell J, Uitterlinden AG, Ulivi S, Vachon CM, Vitart V, Völker U, Vollenweider P, Völzke H, Wang Q, Wareham NJ, Weinberg CR, Weir DR, Wilcox AN, van Dijk KW, Willemsen G, Wilson JF, Wolffenbuttel BHR, Wolk A, Wood AR, Zhao W, Zygmunt M, 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 Z, Li L, Franke L, Burgess S, Deelen P, Pers TH, Grøndahl ML, Andersen CY, Pujol A, Lopez-Contreras AJ, Daniel JA, Stefansson K, Chang-Claude J, van der Schouw YT, Lunetta KL, Chasman DI, Easton DF, Visser JA, Ozanne SE, Namekawa SH, Solc P, Murabito JM, Ong KK, Hoffmann ER, Roig I, Perry JRB. Genetic insights into biological mechanisms governing human ovarian ageing. Nature. 2021 Aug;596(7872):393–397.
Journal cover image

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

August 2021

Volume

596

Issue

7872

Start / End Page

393 / 397

Location

England

Related Subject Headings

  • Uterus
  • Primary Ovarian Insufficiency
  • Ovary
  • Middle Aged
  • Mice, Inbred C57BL
  • Mice
  • Menopause, Premature
  • Menopause
  • Longevity
  • Humans