Genetic insights into the biological mechanisms governing human ovarian ageing

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.

From menarche to menopause: the impact of reproductive factors on the metabolic profile of over 65,000 women

“…Age at natural menopause Genetic instruments were selected from a GWAS of age at natural menopause conducted in 201,323 women of European ancestry (Supplementary table 4) 17 . Linear regression models were used to estimate the association between genetic variants and age at natural menopause (in years).…”

Menopause and cardiometabolic diseases: What we (don't) know and why it matters

“…[5,45,46] Alternative mechanisms, such as iron metabolism, the role of environmental factors, and the possible role of DNA damage response mechanisms in the association of menopausal and CVD, are some of the emerging hypotheses. [47,48] 4. Mechanisms underlying cardiometabolic risk in menopause…”

“…Genome wide association studies (GWAS) have identified between 56 to 290 single nucleotide polymorphisms (SNPs) associated with timing of menopause and uncovered new pathways involved in the genetic expression of menopausal traits. [47,48] Many of the SNPs associated with ANM, were linked with DNA damage response pathways. For example, missense mutations in FANC and FANCAB genes, which plays an important role in the response to replication stress (removal of interstrand crosslinks, DNA-protein crosslinks and R loops), were associated with EM.…”

“…In addition, results from pathway analyses implicate that some of the highlighted genes are involved in the meiotic phase of fetal oocytes, endocrine and metabolic mechanisms. [48] However, the role of these findings in the development and progression of CMD and/or CVD is still unknown.…”

“…Newer methodologies, such as MR analysis, have extracted evidence supporting the causal association between prolonged reproductive life and reduced risk of T2D, [48] however, causal associations between ANM and CVD and lipid levels have not been reported to date. [48] Some of the limitations of MR approaches implemented so far in menopause and CMD are their focus on estimating the total causal effects of combined pathways linked to early menopause, and limited attention on assessing individual pathways that might mediate the effect of menopause on CMD, if present. Future MR studies can explore whether genetic variants related to DNA damage can partially explain the association between menopause and CMD.…”