Large-Scale Association Analysis Provides Insights Into the Genetic Architecture and Pathophysiology of Type 2 Diabetes Mellitus

Abstract

We are amidst an epidemic of cardiometabolic diseases. Despite aggressive lifestyle modifications, the incidence of type 2 diabetes mellitus (T2DM), a potent risk factor for cardiovascular diseases, continues to rise. Simple family histories in patients demonstrate that there is a clustering of the disease in families, and prior studies using genome-wide association (GWA) approaches have identified 56 genetic loci that are associated with T2DM. In a recently published herculean effort, the authors stated that prior GWA study results captured 10% of familial aggregation of the disease. Therefore, to extend understanding of the genetic architecture and molecular basis of T2DM, the authors conducted a meta-analysis (34 840 cases and 114 981 controls) of genetic variants on the Metabochip, a custom array of 196 725 variants designed to facilitate cost-effective follow-up of nominal associations for T2DM, and other metabolic and cardiovascular traits and to enhance fine mapping of established loci. The authors asked whether characterization of increasing numbers of risk loci may provide evidence, at the functional level, that susceptibility to T2DM involves a limited set of molecular processes. The authors conducted a 2-stage meta-analysis: stage-1 meta-analysis consisted of 12 171 T2DM cases and 56 862 controls across 12 GWA studies of individuals of European descent, and the stage-2 meta-analysis consisted of 21 491 T2DM cases and 55 647 controls across 25 studies of individuals of European descent, and 1178 T2DM cases and 2472 controls from 1 study of individuals of Pakistani descent (PROMIS). These participants all underwent genotyping on the Metabochip, in which the T2DM component was comprised of 21 774 variants: 5057 replication single-nucleotide polymorphisms (SNPs) that capture the strongest independent 13 autosomal association signals from the GWA meta-analysis conducted by the Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium, and an additional 16 717 variants chosen from 1000 Genomes Project …