Physiology helps GWAS take a step closer to mechanism

Abstract

Genome-wide association studies (GWAS) have been extremely successful at identifying replicable associations between common genetic variants and type 2 diabetes risk. The latest studies, including 35,000 European, 7,000 East Asian, 5,500 South Asian, and most recently 3,800 Latin American and 6,000 Japanese type 2 diabetes cases, bring the total number of associated variants to more than 70. There is strong evidence that many of the associated genetic variants lie in or close to genes important in type 2 diabetes etiology (e.g., the regions of the genome identified by GWAS are enriched for monogenic diabetes genes, such as HNF1A, HNF1B, and PPARG, and small noncoding regions of the genome [enhancers] critical for islet-specific gene expression). Nevertheless, the field has not moved from genetic associations to improved understanding of biology as quickly or as often as hoped.