The overall goal of this project is to elucidate the genetic architecture of type 2 diabetes mellitus (T2D) among populations of Mexican ancestry by leveraging information from regulatory variants mapped in tissues relevant to insulin signaling. The prevalence of T2D is disproportionately high among Mexican Americans living in the U.S. and although T2D susceptibility in this population exhibits a pronounced genetic component, the majority of large-scale genetic studies have focused on individuals of European ancestry. Previous genome-wide association studies (GWAS) of Mexican Americans from Starr County, TX, and Mexicans from Mexico City provide evidence that many single nucleotide polymorphisms (SNPs) previously shown to significantly associate with T2D within European populations fail to reach genome-wide significance and present lower effect sizes within populations of Mexican ancestry. Furthermore, GWAS investigations are burdened by the problem of multiple testing and GWAS significant SNPs fail to explain the majority of T2D heritability. These findings indicate that the population-specific genetic basis for T2D among Mexican Americans is largely unexplained and requires further investigation. Recently, our laboratory has shown a significant enrichment of expression quantitative trait loci (eQTLs) mapped in human skeletal muscle and adipose tissue among the variants mostly highly associated with T2D and glucose homeostatic traits. Moreover, this enrichment is most prominent among variants that regulate gene expression at distances greater than 1Mb (trans eQTLs). This observation suggests a distal regulatory architecture for T2D and raises questions about the conventional practice of implicating T2D genes exclusively through physical proximity to linkage and association signals. This investigation will advance the understanding of the genetic architecture of T2D among populations of Mexican ancestry by testing the hypothesis that the majority of T2D heritability among Mexican Americans from Starr County, TX, and Mexicans from Mexico City, is explained by regulatory variants (including trans eQTLs) mapped in human tissues relevant to insulin signaling and/or glucose homeostasis (i.e. skeletal muscle, adipose, liver, pancreatic islet, and brain). The specific aims of this proposal are [1] to elucidae the minimum portion of genetic variation that explains the largest amount of T2D heritability among populations of Mexican Ancestry in the interest of developing more informative predictive scores for T2D liability and [2] to identify novel T2D genes and pathways with a gene-based approach that incorporates functional genetic information. This study will involve the application of powerful methods including a novel gene-based test that overcomes GWAS limitations and an approach to heritability estimation that incorporates all interrogated genetic variation to unique datasets and expand knowledge of T2D susceptibility among understudied, yet epidemiologically important populations.