The First Genome-Wide Association Study for Type 2 Diabetes in Youth: The Progress in Diabetes Genetics in Youth (ProDiGY) Consortium

The prevalence of type 2 diabetes in youth has increased substantially, yet the genetic underpinnings remain largely unexplored. To identify genetic variants predisposing to youth-onset type 2 diabetes, we formed ProDiGY, a multi-ethnic collaboration of three studies (TODAY, SEARCH, and T2D-GENES) with 3,006 youth type 2 diabetes cases (mean age 15.1±2.9 y) and 6,061 diabetes-free adult controls (mean age 54.2±12.4 y). After stratifying by principal component-clustered ethnicity, we performed association analyses on ~10 million imputed variants using a generalized linear mixed model incorporating a genetic relationship matrix to account for population structure and adjusting for sex. We identified 7 genome-wide significant loci, including the novel locus rs10992863 in PHF2 (P=3.2´10^-8, odds ratio [OR]=1.23). Known loci identified in our analysis include rs7903146 in TCF7L2 (P=8.0´10^-20, OR 1.58), rs72982988 near MC4R (P=4.4´10^-14, OR=1.53), rs200893788 in CDC123 (P=1.1´10^-12, OR= 1.32), rs2237892 in KCNQ1 (P=4.8´10^-11, OR=1.59), rs937589119 in IGF2BP2 (P=3.1´10^-9, OR=1.34) and rs113748381 in SLC16A11 (P=4.1´10^-8, OR=1.04). Secondary analysis with 856 diabetes-free youth controls uncovered an additional locus in CPEB2 (P=3.2´10^-8, OR=2.1) and consistent direction of effect for diabetes risk. In conclusion, we identified both known and novel loci in the first genome wide association study (GWAS) of youth-onset type 2 diabetes.