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

There is currently little evidence that the genetic basis of human
phenotype varies significantly across the lifespan. However, time-to-event
phenotypes are understudied and can be thought of as reflecting an
underlying hazard, which is unlikely to be constant through life when
values take a broad range. Here, we find that 74% of 245 genome-wide
significant genetic associations with age at natural menopause (ANM) in
the UK Biobank show a form of age-specific effect. Nineteen of these
replicated discoveries are identified only by our modelling framework,
which determines the time-dependency of DNA variant-age-at-onset
associations, without a significant multiple-testing burden. Across the
range of early to late menopause, we find evidence for significantly
different underlying biological pathways, changes in the sign of genetic
correlations of ANM to health indicators and outcomes, and differences in
inferred causal relationships. We find that DNA damage response processes
only act to shape ovarian reserve and depletion for women of early ANM.
Genetically mediated delays in ANM were associated with increased relative
risk of breast cancer and leiomyoma at all ages, and with high cholesterol
and heart failure for late-ANM women. These findings suggest that a better
understanding of the age-dependency of genetic risk factor relationships
among health indicators and outcomes is achievable through appropriate
statistical modelling of large-scale biobank data.