Genetic Insights Into Biological Mechanisms Governing Human Ovarian Ageing

Abstract

Reproductive longevity is critical for fertility and impacts healthy ageing in women 1,2 , yet insights into the 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 ~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 3 . Identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR 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 increase fertility and extend reproductive life in mice. Causal inference analyses using the identified genetic variants indicates that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases risks of hormone-sensitive cancers. These findings provide insight into the mechanisms

Genetic insights into the age-specific biological mechanisms governing human ovarian ageing

“…Generally, our follow-up analyses support previous studies [9,13], but we demonstrate that almost all underlying pathways associated with variation in ANM act in an age-specific manner.…”

Genetic effects on the timing of parturition and links to fetal birth weight

“…We obtained summary statistics for several female reproductive traits from different sources (minimum sample size 10,000). We included summary statistics from the following traits: miscarriage 26 , gestational duration (fetal genome) 6 , age at first birth, age at menarche (Neale lab, http://www.nealelab.is), age at menopause 57 , number of live births (Neale lab, http://www.nealelab.is), testosterone 58 , CBAT 58 , SHBG 58 , estradiol (women, Neale lab, http://www.nealelab.is), pelvic organ prolapse (FinnGen), polycystic ovary syndrome ( 59 and FinnGen), endometriosis (Neale lab, http://www.nealelab.is), leiomyoma uterus (FinnGen) and pre-eclampsia 60 . For polycystic ovary syndrome, we meta-analyzed summary statistics from the largest published GWAS 59 and FinnGen.…”

Evidence for a fragile X messenger ribonucleoprotein 1 (FMR1) mRNA gain‐of‐function toxicity mechanism contributing to the pathogenesis of fragile X‐associated premature ovarian insufficiency

“…26,27,30 Of our candidate proteins, none have established connections to ovarian cell biology, thus we validated FUS and PA2G4 given their well-characterized roles in DNA damage repair 57 and cell proliferation 58 respectively, and TRA2β given its hypothesized involvement in FXTAS disease progression. 30 DNA damage repair is emerging as a key process in determining the ovarian lifespan, i.e., age at both premature and normal menopause 61,62 and overexpression of FUS in a drosophila model of FXTAS increased the toxicity phenotype of CGG-repeat RNA. 33 We hypothesized that sequestration of these proteins and subsequent deregulation of their function could be potentially detrimental for granulosa cells, and this could underlie the follicle loss that characterizes POI.…”