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 quantify age-dependent genetic and environmental components of complex traits and diseases. When applying our approach to 16 UK Biobank quantitative traits (average N= 180K), we found environmental variance can accumulate with age, which leads to decreasing heritability with age, following an exposure accumulation model. We find heritability decreases with age for 5 traits, including systolic blood pressure and lung function (FEV1/FVC), with an average change of −17.8% with age per 10-years. When analyzing complex diseases, we found evidence that environmental variance in disease liability also accumulates with age for 5 of 9 diseases, with an average decrease of heritability −18.1% per 10 years. We found a liability threshold model with exposure accumulation explains 86% of decreasing PRS prediction power with age in 9 UK Biobank complex diseases (compared to 65% by the liability-threshold model alone, p = 3e-11). Finally, we show that both genetic and non-genetic predictors have decreasing prediction accuracy with age in 61 predictor-disease pairs, consistent with simulations. Our results suggest ascertaining younger cohorts is more powerful for training both genetic and non-genetic risk prediction models.