Population-Scale, Genotype-First Characterization of Monogenic Diabetes in 374,973 Multi-Ancestry Individuals from the All of Us Research Program

OBJECTIVE To characterize the prevalence and penetrance of maturity-onset diabetes of the young (MODY) in a multi-ancestry population using a genotype-first design. RESEARCH DESIGN AND METHODS We analyzed whole-genome sequencing and clinical data from 374,973 unrelated All of Us participants (42.0% non-European ancestry). We identified pathogenic or likely pathogenic (P/LP) variants in 10 established MODY genes and assessed carrier prevalence, diabetes penetrance, and glycemic profiles. We evaluated age-dependent diabetes risk by comparing carriers with non-carriers stratified by type 2 diabetes polygenic risk score (T2D PRS). RESULTS We identified 370 carriers of P/LP MODY gene variants (0.099%; 1 in 1,013), with similar carrier prevalence among European- and African-ancestry participants (0.105% in both groups). Diabetes penetrance was incomplete (13.4% by age 40; 43.5% by age 60) and varied by etiology: highest for GCK (56.0% by age 60), intermediate for HNF genes (HNF1A/HNF1B/HNF4A; 45.4%), and lowest for non-GCK/HNF genes (ABCC8/INS/KCNJ11/NEUROD1/PDX1/RFX6; 29.0%). In multivariable Cox models using non-carriers in the middle 80% of the T2D PRS as the reference, non-GCK/HNF gene variant carriers had modestly increased diabetes risk (HR, 1.57), similar to non-carriers in the top 10% of T2D PRS (HR, 1.64). These associations were observed in both European- and non-European-ancestry individuals. HbA1c profiles differed by etiology, with stable mild hyperglycemia in GCK variant carriers and greater variability among HNF and non-GCK/HNF gene variant carriers. CONCLUSIONS MODY gene variants showed incomplete, etiology-dependent penetrance across ancestries. Carriers of P/LP variants in lower-penetrance genes had diabetes risk comparable to that of non-carriers with high polygenic susceptibility.