Admixture mapping and subsequent finemapping suggests novel loci for type 2 diabetes in African Americans

Abstract

Type 2 diabetes (T2D) is a complex metabolic disease that disproportionately affects African Americans. Obesity is a major risk factor for T2D, and it is postulated that chronic inflammation possibly stemming from adipose tissue macrophages and T cells plays a key role. Genome-wide association studies (GWAS) have identified over 20 disease loci that contribute to T2D in European Americans but few studies have been performed in admixed populations. We first performed a GWAS of 1,563 African Americans from the Vanderbilt Genome-Electronic Records Project and Northwestern University NUgene Project as part of the electronic Medical Records and Genomics (eMERGE) network. We successfully replicate an association in TCF7L2, previously identified by GWAS in our African American dataset. We were unable to identify novel associations at p<5.0x10-8 by GWAS. Admixture mapping disease loci in recently admixed populations is a powerful method used to identify disease loci in African Americans. Using admixture mapping, we sought to identify novel disease loci in the genome with T2D. Our admixture scan revealed multiple candidate genes with T2D, including TCIRG1, a T-cell immune regulator expressed in the pancreas and liver and not previously implicated in T2D. We performed a subsequent fine-mapping analysis to further assess the association with TCIRG1 and T2D in >5,000 African Americans. We successfully identified 13 independent associations in TCIRG1, CHKA, and ALDH3B1 genes on chromosome 11. Our results suggest a novel region on chromosome 11 identified by admixture mapping associated with T2D in African Americans and warrants additional replication and validation in this region.