Physiology Helps GWAS Take a Step Closer to Mechanism

  1. Andrew T. Hattersley
  1. University of Exeter Medical School, University of Exeter, Exeter, U.K.
  1. Corresponding author: Timothy M. Frayling, t.m.frayling{at}

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 (1), 7,000 East Asian (2), 5,500 South Asian (3), and most recently 3,800 Latin American (4) and 6,000 Japanese (5) 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 [6]). Nevertheless, the field has not moved from genetic associations to improved understanding of biology as quickly or as often as hoped.

In this issue, Dimas et al. (7) present data that move the field a step closer to mechanisms. They tested the hypothesis that a systematic analysis of insulin secretion and insulin resistance measures in nondiabetic individuals would improve the understanding of the intermediate mechanisms by which genetic variants predispose to type 2 diabetes. They performed the most extensive analysis yet to group variants into categories based on their likely intermediate mechanism. The authors combined data from thousands of individuals with fasting-, oral-, and intravenous-based measures of insulin secretion and resistance. This approach has been used before for a smaller number of loci and individuals …

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