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

Diabetes. 2021 Apr;70(4):996-1005. doi: 10.2337/db20-0443. Epub 2021 Jan 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Diabetes Mellitus, Type 2 / genetics*
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study / methods
  • Homeodomain Proteins / genetics
  • Humans
  • KCNQ1 Potassium Channel / genetics
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics
  • Receptor, Melanocortin, Type 4 / genetics

Substances

  • Homeodomain Proteins
  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human
  • MC4R protein, human
  • PHF2 protein, human
  • Receptor, Melanocortin, Type 4

Associated data

  • figshare/10.2337/figshare.13607852

Grants and funding