Type 2 diabetes is a major clinical and public health problem, especially in African Americans. The overall objective of this application is to identify novel loci that may partially account for excess risk of type 2 diabetes in African Americans compared to whites. We will employ Mapping by Admixture Linkage Disequilibrium (MALD) analysis, a specialized form of linkage disequilibrium mapping, to perform a genome-wide MALD analysis in a case-control study nested within the Atherosclerosis Risk in Communities (ARIC) study, a community-based prospective cohort study of the natural history of atherosclerosis. For the proposed MALD analysis, cases will be all African-American ARIC participants with type 2 diabetes (N = 1,238), and controls will be 1,238 age-matched African-American ARIC participants without type 2 diabetes. We hypothesize that some susceptibility alleles for type 2 diabetes are present at a higher frequency in African Americans than in whites and that specific regions of the genome in African Americans contain marker alleles that are in admixture linkage disequilibrium with type 2 diabetes susceptibility alleles. To test this hypothesis, we will: (1) genotyping 1,536 highly informative African-American MALD markers (~2 cM average spacing) in DNA from 2,476 African-American ARIC participants using the Center for Inherited Disease Research (CIDR) Human Custom Single Nucleotide Polymorphism (SNP) Genotyping Facility; (2) perform a genome-wide MALD analysis using the aforementioned scan to identify regions that are in admixture linkage disequilibrium with type 2 diabetes; and (3) follow up and confirm the most promising putative chromosomal regions with more densely-spaced SNPs. The proposed genetic analyses are innovative and complementary to the more traditional linkage and candidate gene techniques. The Principal Investigator has assembled a team of experts in all components of this research. This application explores the utility of MALD, a novel mapping technique, to identify type 2 diabetes susceptibility genes. Although this methodology is high risk, it also holds high promise for future genetics studies of type 2 diabetes and other complex traits. Detection of susceptibility genes for type 2 diabetes is a daunting challenge. Findings from this study will not only provide key insights into a new methodology for mapping genes, but will also lead to a better understanding of the genes that control type 2 diabetes susceptibility, a problem with high relevance in African Americans. ? ? ?
