Combinatorial epigenomic patterns define regulatory programs underlying disease heterogeneity
Complex diseases exhibit substantial variation in clinical presentation and outcome despite shared diagnoses. Current genetic models typically represent inherited risk as a single additive liability, obscuring the diverse biological mechanisms through which variants influence disease. Here, we show that disease-associated variants are organized into recurrent regulatory programs that reveal latent disease mechanisms. Using genome-scale epigenomic maps across human tissues and cell states, we identify regulatory programs that partition disease-associated variants without phenotypic or disease-specific priors. Variants assigned to different programs exert distinct biological effects that translate into divergent clinical outcomes. In type 2 diabetes, these programs reveal previously unrecognized disease subtypes with opposing cardiometabolic profiles that stratify future risk of myocardial infarction and non-alcoholic fatty liver disease. Together, our findings establish that inherited disease risk is organized into latent regulatory programs, revealing a fundamental layer of biological heterogeneity underlying complex disease.