Type 2 diabetes: new genes, new understanding

Abstract

Over the past two years, there has been a spectacular change in the capacity to identify common genetic variants that contribute to predisposition to complex multifactorial phenotypes such as type 2 diabetes (T2D). The principal advance has been the ability to undertake surveys of genome-wide association in large study samples. Through these and related efforts, approximately 20 common variants are now robustly implicated in T2D susceptibility. Current developments, for example in high-throughput resequencing, should help to provide a more comprehensive view of T2D susceptibility in the near future. Although additional investigation is needed to define the causal variants within these novel T2D-susceptibility regions, to understand disease mechanisms and to effect clinical translation, these findings are already highlighting the predominant contribution of defects in pancreatic beta-cell function to the development of T2D.

Figure 1. Schema for the pathogenesis of T2D.

T2D results, in most individuals, from concomitant defects in both insulin secretion and insulin action. It is likely that abnormalities in both β-cell mass and β-cell function contribute to the former, whereas obesity is a major cause of deficient insulin action. All processes are likely to involve contributions from both inherited and environmental effects. Examples of some of the genes and exposures implicated are shown in the yellow boxes.

Figure 2. Effect sizes of known T2D-susceptibility loci.

The T2D-susceptibility variants so far discovered have only modest individual effects. The x-axis gives the per-allele odds ratio (estimated for European-descent samples) for each locus listed on the y-axis. Loci are sorted by descending order of per-allele effect size from TCF7L2 (1.37) to ADAMTS9 (1.09) (Table 1). Loci shown in blue are those identified by GWA approaches, whereas those found by candidate-gene approaches and by large-scale association analyses are shown in yellow and red, respectively. Odds ratios are estimated from data in Refs [–7,24,25,43,45,44]. These figures are approximate estimates of the true effect sizes at each locus and might be either overestimates (owing to winner’s curse) or underestimates (because the causal variant in most cases is not known yet).

Figure 3. Future directions for T2D research.

The next wave of work to understand the underlying mechanisms and pathways of T2D physiology will focus on finding variants that remain undetected by GWA studies. In addition, analyses of the contribution of rare SNPs and structural variants will help identification of novel loci contributing to T2D risk. In parallel, defining the causal variant(s) in T2D loci will require large scale deep sequencing and fine mapping. A first layer of functional evaluation ofthevariants within associated loci through expression-quantitativetrait locus (eQTL) studies will combinethe geneticvariation in associated loci with expression analysis data to define regulatory relationships. Studies designed to understand the functional effect of any causal variants in relevant cell systems and animal models will give insight to physiological consequence. These advances will underpin efforts to translate the findings through development of diagnostic tests, risk evaluation and identification of novel drug targets.