No abstract

Reproductive longevity is critical for fertility and impacts healthy ageing in women, 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 influence 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. 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 governing ovarian ageing, when they act across the life-course, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

Human genetic studies have provided substantial insight into the biological mechanisms governing ovarian ageing, yet previous approaches have been largely restricted to assessing common genetic variation. Here we report analyses of rare (MAF<0.1%) protein-coding variants in the exomes of 106,973 women from the UK Biobank study, implicating novel genes with effect sizes up to ~5 times larger than previously discovered in analyses of common variants. These include protein truncating variants in ZNF518A, which shorten reproductive lifespan by promoting both earlier age at natural menopause (ANM, 5.61 years [4.04-7.18], P=2*10-12) and later puberty timing in girls (age at menarche, 0.56 years [0.15-0.97], P=9.2*10-3). By integrating ChIP-Seq data, we demonstrate that common variants associated with ANM and menarche are enriched in the binding sites of ZNF518A. We also identify further links between ovarian ageing and cancer susceptibility, highlighting damaging germline variants in SAMHD1 that delay ANM and increase all-cause cancer risk in both males (OR=2.1 [1.7-2.6], P=4.7*10-13) and females (OR=1.61 [1.31-1.96], P=4*10-6). Finally, we demonstrate that genetic susceptibility to earlier ovarian ageing in women increases de novo mutation rate in their offspring. This provides direct evidence that female mutation rate is heritable and highlights an example of a mechanism for the maternal genome influencing child health.

Premature ovarian insufficiency (POI) affects 1% of women and is a leading cause of infertility. It is often considered to be a monogenic disorder, with pathogenic variants in ~100 genes described in the literature. We sought to systematically evaluate the penetrance of variants in these genes using exome sequence data in 104,733 women from the UK Biobank, 2,231 (1.14%) of whom reported natural menopause under the age of 40. We found limited evidence to support any previously reported autosomal dominant effect. For nearly all heterozygous effects on previously reported POI genes we ruled out even modest penetrance, with 99.9% (13,699/13,708) of all protein truncating variants found in reproductively healthy women. We found evidence of haploinsufficiency effects in several genes, including TWNK (1.54 years earlier menopause, P=1.59*10 -6 ) and SOHLH2 (3.48 years earlier menopause, P=1.03*10 -4 ). Collectively our results suggest that for the vast majority of women, POI is not caused by autosomal dominant variants either in genes previously reported or currently evaluated in clinical diagnostic panels. Our findings, plus previous studies, suggest that the majority of POI cases are likely oligogenic or polygenic in nature, which has major implications for future clinical genetic studies, and genetic counselling for families affected by POI.