Exposure accumulation drives age-dependent disease architectures and polygenic risk scores

Our understanding of the dependence of the genetic and environmental architecture of common diseases on age is incomplete. Here, we use longitudinal data to separate age-dependent genetic and environmental variance across complex traits and diseases. When applying our approach to 16 UK Biobank quantitative traits (average N=180K), we found environmental variance accumulates with age, leading to decreasing heritability with age, which follows an exposure accumulation model that is distinct from gene-age interaction model. Heritability decreases with age for 5 traits including systolic blood pressure and lung functon(FEV1/FVC), with an average change of −17.8% with age per 10-years. We demonstrated that majority of the decreasing heritability comes from exposure accumulation, instead of gene-age interaction, using longitudinal phenotypic correlations. For diseases, environmental variance in disease liability also accumulates with age for 5 of 9 diseases, with an average decrease in heritability of −18.1% per 10 years. A liability-threshold model with exposure accumulation explains 86% of decreasing PRS prediction R ² with age in 9 UK Biobank complex diseases. Finally, we show that both genetic and non-genetic predictors have decreasing prediction accuracy with age in 61 predictor-disease pairs. Taken together, our results demonstrate that the age-dependent liability- threshold model with exposure accumulation is a general disease model, suggesting ascertaining younger cohorts is more powerful for training both genetic and non-genetic risk prediction models.