Insights into the genetic basis of type 2 diabetes.

Type 2 diabetes is one of the most common complex diseases, of which considerable efforts have been made to unravel the pathophysiological mechanisms. Recently, large-scale genome-wide association (GWA) studies have successfully identified genetic loci robustly associated with type 2 diabetes by searching susceptibility variants across the entire genome in an unbiased, hypothesis-free manner. The number of loci has climbed from just three in 2006 to approximately 70 today. For the common type 2 diabetes-associated variants, three features have been noted. First, genetic impacts of individual variants are generally modest; mostly, allelic odds ratios range between 1.06 and 1.20. Second, most of the loci identified to date are not in or near obvious candidate genes, but some are often located in the intergenic regions. Third, although the number of loci is limited, there might be some population specificity in type 2 diabetes association. Although we can estimate a single or a few target genes for individual loci detected in GWA studies by referring to the data for experiments in vitro, biological function remains largely unknown for a substantial part of such target genes. Nevertheless, new biology is arising from GWA study discoveries; for example, genes implicated in β-cell dysfunction are over-represented within type 2 diabetes-associated regions. Toward translational advances, we have just begun to face new challenges - elucidation of multifaceted (i.e., molecular, cellular and physiological) mechanistic insights into disease biology by considering interaction with the environment. The present review summarizes recent advances in the genetics of type 2 diabetes, together with its realistic potential.