Genome-wide association studies of quantitative glycaemic traits

Abstract

Genome-wide association studies (GWASs) of patients with type 2 diabetes (T2D) and unaffected control participants (case-control studies) are designed to identify genetic variants that predispose to T2D, although the mechanisms by which these variants predispose to T2D are unclear. In 2008, the Meta-Analysis of Glucose and Insulin-related traits Consortium (MAGIC) was established to facilitate meta-analysis of GWAS data of quantitative glycaemic traits (including fasting and post-challenge glycaemic measures) from persons without diabetes. These traits are associated with cardiovascular outcomes even below the diabetic threshold and are important in and of themselves. Our aims were threefold: (a) to identify loci influencing glycaemic traits as a way to understand the similarities and differences between loci influencing glucose regulation within the normal physiological range and those affecting pathophysiological states (T2D); (b) to identify new loci impacting T2D risk using an alternative approach; and (c) to use glycaemic traits to begin to elucidate disease mechanism, i.e. how loci impact biological pathways to promote disease. Here, we describe the approaches used in MAGIC, what we have learned about the genetic architecture of glycaemic traits and T2D itself, and how we see future genomic studies further refining disease aetiology.