Genetic architecture and biology of youth-onset type 2 diabetes

The prevalence of youth-onset type 2 diabetes (T2D) and childhood obesity has been rising steadily 1 , producing a growing public health concern 1 that disproportionately affects minority groups 2 . The genetic basis of youth-onset T2D and its relationship to other forms of diabetes are unclear 3 . Here we report a detailed genetic characterization of youth-onset T2D by analysing exome sequences and common variant associations for 3,005 individuals with youth-onset T2D and 9,777 adult control participants matched for ancestry, including both males and females. We identify monogenic diabetes variants in 2.4% of individuals and three exome-wide significant ( P < 2.6 × 10 −6 ) gene-level associations ( HNF1A , MC4R , ATXN2L ). Furthermore, we report rare variant association enrichments within 25 gene sets related to obesity, monogenic diabetes and β-cell function. Many youth-onset T2D associations are shared with adult-onset T2D, but genetic risk factors of all frequencies—and rare variants in particular—are enriched within youth-onset T2D cases (5.0-fold increase in the rare variant and 3.4-fold increase in common variant genetic liability relative to adult-onset cases). The clinical presentation of participants with youth-onset T2D is influenced in part by the frequency of genetic risk factors within each individual. These findings portray youth-onset T2D as a heterogeneous disease situated on a spectrum between monogenic diabetes and adult-onset T2D.