Common Genetic Variants Modify Disease Risk and Clinical Presentation in Monogenic Diabetes

The contribution of polygenic background in young onset monogenic disorders needs further exploration. Understanding this will provide new biological insights and may improve risk prediction of monogenic disease. Here we investigated the role of polygenic background in MODY--a common monogenic disorder with an age-dependent onset.We found strong enrichment of type 2 diabetes (T2D) polygenic risk, but not type 1 diabetes risk, in genetically confirmed MODY cases. This T2D polygenic burden, primarily through beta-cell dysfunction pathways, was strongly associated with earlier age of diagnosis and increased diabetes severity. Common genetic variants collectively accounted for 24% (p<0.0001) of the phenotypic variability. Using a large population cohort, we demonstrated 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 without a causal variant had 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 monogenic variants.