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

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posted on 21.01.2021, 18:47 by Shylaja Srinivasan, Ling Chen, Jennifer Todd, Jasmin Divers, Samuel Gidding, Steven Chernausek, Rose A. Gubitosi-Klug, Megan M. Kelsey, Rachana Shah, Mary Helen Black, Lynne E. Wagenknecht, Alisa Manning, Jason Flannick, Giuseppina Imperatore, Josep M. Mercader, Dana Dabelea, Jose C. Florez, 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.

Funding

American Diabetes Association 1-19-ICTS-068 U.S. Department of Health and Human Services > National Institutes of Health > National Institute of Diabetes and Digestive and Kidney Diseases 1K23DK120932-01A

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