Admixture Mapping of Coronary Artery Calcification in the NHLBI Family Heart Study (FamHS)

Coronary artery calcification (CAC) is an important measure of subclinical coronary atherosclerosis. In European Americans meta-analyses of genome-wide association studies (GWAS) have identified ~30 independent regions associated with coronary artery disease.  However, there have been comparably few large studies conducted in African Americans. The largest African American GWAS meta-analysis failed to identify significant variants associated with CAC despite the non-trivial heritability (~30%) of CAC, and being powered to detect effects comparable to effects identified in European Americans.  Because CAC is differently prevalent and severe in African Americans and European Americans, admixture mapping may be a useful approach to gene mapping. Admixture mapping estimates local ancestry genome-wide and then looks for regions where ancestry is associated with a phenotype.  For this analysis we used LAMP-LD to estimate locus specific ancestry, and a kinship model to preform the association analysis. Our preliminary results suggest that the 622 African Americans in FamHS have more West African ancestry (~81.5%) than is often reported in the literature (~68%-74%).  Our analysis has identified a region of chromosome 15 that may be associated with CAC (p=9.48 x 10^-5).  This region includes several imprinted genes associated with neuro-genetic disorders. Our analysis further suggests that admixture mapping and GWAS of the same individuals does not detect similar CAC-associated regions of the genome. We also do not detect a signal where CAC-associated variants are found in European Americans. We suggest that admixture mapping is a useful hypothesis-generating tool to identify association signals that have not been identified by traditional GWAS.