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

The study analyzed whole-genome sequencing and clinical data from 374,973 All of Us program participants, of whom 42% had non-European ancestry. Researchers identified 370 carriers of pathogenic variants in MODY genes (maturity-onset diabetes of the young), representing 0.099% of participants, or approximately 1 in 1,013 individuals. Carrier prevalence was similar among European and African ancestry participants (0.105% in both groups). Diabetes penetrance was incomplete—occurring in 13.4% of carriers by age 40 and 43.5% by age 60. Penetrance varied by gene type: highest for GCK gene (56.0% by age 60), intermediate for HNF genes (45.4%), and lowest for other genes (29.0%). Carriers of variants in lower-penetrance genes had diabetes risk comparable to non-carriers with high genetic susceptibility to type 2 diabetes.