Abstract
Young-onset monogenic disorders often show variable penetrance, yet the underlying causes remain poorly understood. Uncovering these influences could reveal new biological mechanisms and enhance risk prediction for monogenic diseases. Here we show that polygenic background substantially shapes the clinical presentation of maturity-onset diabetes of the young (MODY), a common monogenic form of diabetes that typically presents in adolescence or early adulthood. We find strong enrichment of type 2 diabetes (T2D) polygenic risk, but not type 1 diabetes risk, in genetically confirmed MODY cases (n = 1,462). This T2D polygenic burden, primarily through beta-cell dysfunction pathways, is strongly associated with earlier age of diagnosis and increased diabetes severity. Common genetic variants collectively account for 24% (P < 0.0001) of the phenotypic variability. Using a large population cohort (n = 424,553), we demonstrate that T2D polygenic burden substantially modifies diabetes onset in individuals with pathogenic variants, with diabetes risk ranging from 11% to 81%. Finally, we show that individuals with MODY-like phenotypes (n = 300) without a causal variant have elevated polygenic burden for T2D and related traits, representing potential polygenic phenocopies. These findings reveal substantial influence of common genetic variation in shaping the clinical presentation of early-onset monogenic disorders. Incorporating these may improve risk estimates for individuals carrying pathogenic variants.