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

Abstract

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 multiethnic collaboration of three studies (TODAY, SEARCH, and T2D-GENES) with 3,006 youth case subjects with type 2 diabetes (mean age 15.1 ± 2.9 years) and 6,061 diabetes-free adult control subjects (mean age 54.2 ± 12.4 years). 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 seven genome-wide significant loci, including the novel locus rs10992863 in <i>PHF2</i> (<i>P</i> = 3.2 × 10^-8; odds ratio [OR] = 1.23). Known loci identified in our analysis include rs7903146 in <i>TCF7L2</i> (<i>P</i> = 8.0 × 10^-20; OR 1.58), rs72982988 near <i>MC4R</i> (<i>P</i> = 4.4 × 10^-14; OR 1.53), rs200893788 in <i>CDC123</i> (<i>P</i> = 1.1 × 10^-12; OR 1.32), rs2237892 in <i>KCNQ1</i> (<i>P</i> = 4.8 × 10^-11; OR 1.59), rs937589119 in <i>IGF2BP2</i> (<i>P</i> = 3.1 × 10^-9; OR 1.34), and rs113748381 in <i>SLC16A11</i> (<i>P</i> = 4.1 × 10^-8; OR 1.04). Secondary analysis with 856 diabetes-free youth control subjects uncovered an additional locus in <i>CPEB2</i> (<i>P</i> = 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 of youth-onset type 2 diabetes.