Genetic admixture: a tool to identify diabetic nephropathy genes in African Americans

Diseases with an inherited component that demonstrate different prevalence in various ancestral populations can now be studied using admixture mapping in an appropriate admixed population. This strategy called mapping by admixture linkage disequilibrium or MALD utilizes polymorphic genetic markers that are spaced throughout the genome to identify genomic regions where the estimated admixture proportion is significantly different than its expected value. These genetic markers are selected based on their ancestry informativeness content. The MALD approach assumes that genomic regions showing excess ancestry from the ancestral population with higher disease prevalence, in the sample of admixed individuals, are more likely to harbor polymorphisms that confer higher risk to disease than others. Certain conditions including essential hypertension, type 2 diabetes mellitus and common complex forms of nephropathy demonstrate clear differences in disease frequency in individuals of African and European descent and appear particularly suited to this type of analysis. Genetic admixture can also cause confounding in association studies conducted on an admixed sample leading to inflated type I error rates and possible loss of power. This manuscript describes the background, methodologies and uses for admixture mapping in the search for genes that underlie type 2 diabetes mellitus and its associated nephropathy in the African American population, and statistical methods to address the confounding issues in genetic association tests.