Youth-onset type 2 diabetes (T2D) has a strong genetic predisposition and is regarded as a phenotypic extreme of adult-onset T2D. In this study, we aimed to investigate the contribution of rare coding variants to the genetic basis of youth-onset T2D by analyzing whole-exome sequences of 3,005 persons with youth-onset T2D (diagnosed before 20 years of age) from the Progress in Diabetes Genetics in Youth (ProDiGY) consortium and 9,777 ancestry matched adult controls. We identified three genes with aggregate rare variant associations reaching exome-wide significance (P<2.6×10-6). In addition, we were able to identify eight genes previously linked to diabetes that were included in the top 20 (P<2.0×10-6) overlapping biologically characterized gene sets. These 11 genes were classified into three groups: 1) monogenic diabetes-related genes (HNF1A, GCK, and RFX6), 2) obesity-related genes (MC4R, ATXN2L, GHRL, and CPQ), and 3) β-cell function related genes (SLC30A8, ABCC8, PAM, and SIX3). A novel exome-wide significant gene burden association was observed for ATXN2L with odds ratio (OR) 1.26, P=1.1×10-6. For known diabetes genes, the effect sizes of gene burden analysis in youth-onset T2D were much larger than that of adult-onset T2D: examples include MC4R (OR 3.5, P=1.7×10-11 vs. OR 2.1, P=2.7×10-10 in adults) and HNF1A (OR 7.5, P=1.2×10-10 vs. OR 1.2, P=0.022). In terms of liability variance explained, both common and rare variants contributed more to youth-onset T2D than they did to adult-onset T2D (3.1-fold enrichment for common variants, 5.3-fold enrichment for rare variants). However, greater enrichment of rare variants in youth-onset T2D caused the liability variance explained by rare variants to approach 28% of that explained by common variants, in contrast to 17% for adult-onset T2D. These data paint a picture of youth-onset T2D as a disease intermediate in extremity between monogenic diabetes and T2D, in which genetic variants in both insulin secretion and insulin response pathways are implicated.
S. Kwak: None. L. M. Laffel: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompe, Insulogic LLC, Janssen Pharmaceuticals, Inc., Laxmi Therapeutic Devices, LifeScan, Lilly Diabetes, Medtronic, Provention Bio, Inc. E. M. Isganaitis: None. M. W. Haymond: Advisory Panel; Self; Daiichi Sankyo, Zealand Pharma A/S, Other Relationship; Self; AstraZeneca, Stock/Shareholder; Self; Xeris Pharmaceuticals, Inc. L. L. Levitsky: Consultant; Self; Eli Lilly and Company. T. I. Pollin: None. J. C. Florez: Consultant; Self; Goldfinch Bio, Inc., Other Relationship; Self; Novo Nordisk. J. Flannick: None. On behalf of the prodigy consortium: n/a. S. Srinivasan: None. L. Chen: None. J. Todd: None. E. T. Jensen: None. J. Divers: None. A. K. Mottl: Advisory Panel; Self; Bayer U. S. C. Pihoker: None. R. Gandica: None.
National Institutes of Health (1R01DK125490-01)