An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

TLDR

The study aimed to characterize T2D‑associated genetic variation across the allele frequency spectrum by meta‑analyzing GWAS data from 26,676 cases and 132,532 controls of European ancestry using 1000 Genomes imputation. The authors performed a meta‑analysis of GWAS data and then replicated promising signals in independent cohorts comprising up to 14,545 cases and 71,604 controls. The analysis identified 13 novel T2D loci, bringing the total to 128 independent signals, all driven by common variants, with credible sets larger than earlier panels and tissue‑specific enrichment indicating diverse biological mechanisms.

Abstract

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10-8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.