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 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 control subjects 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 of youth-onset type 2 diabetes.

Figure 1

A: QQ plot for case subjects with youth-onset T2D vs. adult control subjects without diabetes. The x-axis shows the expected distribution and the y-axis shows the observed distribution of findings. λ_GC = 1.08. B: QQ plot for case subjects with youth-onset T2D vs. youth control subjects without diabetes. The x-axis shows the expected distribution and the y-axis shows the observed distribution of findings. λ_GC = 1.09.

Figure 2

Manhattan plot for youth case subjects with T2D vs. adult control subjects without diabetes. The red horizontal line in the plot indicates the genome-wide significance P value threshold of 5 × 10⁻⁸. The closest genes for the seven genome-wide significant findings are shown circled in red.

Figure 3

Manhattan plot for youth case subjects with T2D vs. youth control subjects without diabetes. The red horizontal line in the plot indicates the genome-wide significance P value threshold of 5 × 10⁻⁸. The closest gene for the genome-wide significant finding is shown circled in red.