The First Genome-Wide Association Study (GWAS) for Type 2 Diabetes in Youth from the Progress in Diabetes Genetics in Youth (ProDiGY) Collaboration

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The prevalence of type 2 diabetes is increasing in youth, particularly in certain ethnic groups, and studies have highlighted differences between youth- and adult-onset disease. However, its genetic determinants remain largely unexplored. To identify genetic variants predisposing to type 2 diabetes in youth, we formed ProDiGY, a multi-ethnic collaboration of the TODAY, SEARCH for Diabetes in Youth, and T2D-GENES studies, with 30young cases (mean age= 15.1 y ±2.8, 63% female, 22% white, 36% African American, 42% Hispanic) and 6061 diabetes-free adult controls (mean age = 54.2 y ±12.4; 57% female, 24% white, 18% African American, 58% Hispanic). After stratifying by self-reported and principal component-clustered ethnicity, we performed association analyses on 206,928 directly genotyped variants using a generalized linear mixed model using a genetic relationship matrix to account for population structure. We identified 5 genome-wide significant loci, including the novel locus rs13130484 in GNPDA2 (P= 1.4 ×10-8, odds ratio [OR]= 1.24), which has nominal association with type 2 diabetes in adults. Known loci identified in our analysis include rs4132670 in the well-known type 2 diabetes locus TCF7L2 (P= 4.2×10-13, OR 1.35) in high linkage disequilibrium with causal SNP rs7903146 (R2=0.83), rs11662368 near the obesity locus MC4R (P= 3.9×10-9, OR =1.31), rs11257655 in RN7SL232P (P= 5.7×10-12, OR= 1.33), and rs7075724 in CDC123 (P= 8.3×10-11, OR= 1.29); effect sizes are greater for these latter three loci than those found in adults (Pdiff= 8.2×10-5, 2.4×10-5, and 1.7×10-6, respectively). Secondary analysis with 856 diabetes-free youth controls demonstrated consistent direction of effect but no additional loci. In conclusion, we identified known and novel genetic loci predisposing to type 2 diabetes in youth. Our future analysis of ∼10 million variants holds the potential to uncover additional new type 2 diabetes susceptibility loci. Disclosure S. Srinivasan: None. J. Todd: None. L. Chen: None. J. Divers: None. S. Gidding: None. S. Chernausek: Advisory Panel; Self; Novo Nordisk Inc.. R. Gubitosi-Klug: None. M.M. Kelsey: Other Relationship; Self; Daiichi Sankyo Company, Limited, Merck Sharp & Dohme Corp.. R. Shah: None. M. Black: None. L.E. Wagenknecht: None. J.M. Mercader: None. A. Manning: None. J. Flannick: None. D. Dabelea: None. J.C. Florez: Consultant; Self; Intarcia Therapeutics, Inc.. Consultant; Spouse/Partner; Santen.

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