How inherited variation shapes human disease trajectories

Although inherited variation is fixed at birth, its effects on health change with age and differ between common and rare variants. Here, we introduce Mendelnoulli, a longitudinal model that combines the age-dependent effects of polygenic and monogenic variation on health records, separating how much disease each individual accumulates overall from diseases to which they are prone. Mendelnoulli further allows polygenic and monogenic components to exert different influences on latent disease trajectories. We apply the model to 348 diseases, 36 polygenic scores, and 34 monogenic conditions across three biobanks and provide an atlas of the age-dependent effects of inherited variation on common human diseases. We show that polygenic effects change significantly with age, with Mendelnoulli improving held-out one-year discrimination for all 28 diseases tested compared with a model whose polygenic effects are constant over age (median AUC 0.95 vs 0.92). For individuals with no prior diagnoses, Mendelnoulli identified 8.6 more of every 100 new cases than that model, when each flagged the 5\% at highest risk. For genes with an established disease, Mendelnoulli selected that disease for 27 of 30 genes and ranked it first for 17 (7 expected by chance), and recovered known differences in timing, such as earlier breast cancer effects for BRCA1 than BRCA2 (peak 48 vs 66 years). Mendelnoulli provides a unified model of common and rare genetic influences on disease trajectories across the life course.