Transcriptional control of glucose homeostasis and beta cell genesis and function is mediated by a closely-knit transcriptional regulatory pathway defined by specific transcription factors. The Mendelian phenotypes of maturity-onset diabetes of the young (MODY) are caused by separate lesions disrupting the coding sequences of each of these transcription factors (22). Interestingly, we observed clustering of common noncoding variants associated with abnormal glucose homeostasis, insulin and glycohemoglobin levels, and diabetic complications within recognition sites for the same six transcription factors (P < 0.029, binomial; 48% enrichment over random SNPs; Fig. 3A). This suggests that noncoding variants that predispose to dysregulation of glucose homeostasis perturb peripheral nodes of the same regulatory network responsible for Mendelian forms of Type 2 diabetes.
