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 sh..., We first restricted our analysis to a sample of European-ancestry UK Biobank individuals. To infer ancestry, we used both self-reported ethnic background (UK Biobank field 21000-0), selecting coding 1, and genetic ethnicity (UK Biobank field 22006-0), selecting coding 1. We projected the 488,377 genotyped participants onto the first two genotypic principal components (PC) calculated from 2,504 individuals of the 1,000 Genomes project. Using the obtained PC loadings, we then assigned each participant to the closest 1,000 Genomes project population, selecting individuals with PC1 projection < absolute value 4 and PC 2 projection < absolute value 3. Samples were also excluded based on UK Biobank quality control procedures with individuals removed of (i) extreme heterozygosity and missing genotype outliers; (ii) a genetically inferred gender that did not match the self-reported gender; (iii) putative sex chromosome aneuploidy; (iv) exclusion from kinship inference; (v) withdrawn conse...,