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000170226 005__ 20240229133709.0
000170226 0247_ $$2doi$$a10.1038/s41586-021-03779-7
000170226 0247_ $$2pmid$$apmid:34349265
000170226 0247_ $$2ISSN$$a0028-0836
000170226 0247_ $$2ISSN$$a1476-4687
000170226 0247_ $$2altmetric$$aaltmetric:111125337
000170226 037__ $$aDKFZ-2021-01834
000170226 041__ $$aEnglish
000170226 082__ $$a500
000170226 1001_ $$aRuth, Katherine S$$b0
000170226 245__ $$aGenetic insights into biological mechanisms governing human ovarian ageing.
000170226 260__ $$aLondon [u.a.]$$bNature Publ. Group$$c2021
000170226 3367_ $$2DRIVER$$aarticle
000170226 3367_ $$2DataCite$$aOutput Types/Journal article
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000170226 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000170226 3367_ $$00$$2EndNote$$aJournal Article
000170226 500__ $$a2021 Aug;596(7872):393-397
000170226 520__ $$aReproductive 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.
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