Genetic risk for complex processes like CVD appears to involve interactions among multiple genes of small effect. Association mapping is much more powerful than linkage mapping in identifying such genes, but requires 200-500 times as many markers to scan the genome. Admixture mapping can extract much of the power of association studies but requires genotyping only a few thousand markers genome-wide. This application partners Jackson Heart Study (JHS) investigators with two leaders in the field of admixture mapping, Drs. David Reich and Nick Patterson. The studies proposed will exploit the genotyping and analytic power of the Broad Institute to perform admixture mapping in the largest cohort ever assembled to study CVD in African Americans. Several factors contribute to the timeliness of this study and show the strength of the proposed research team: (a) Our group has published the first practical genetic resource for admixture mapping: 2,154 markers with large frequency differences between Africans and Europeans, and methods to analyze the data. (b) We have assembled a unique cohort for the largest-ever genome-wide admixture scan for CVD risk genes: 3,796 unrelated African Americans rigorously characterized for a large number of CVD phenotypes, including HTN, coronary artery disease, stroke, diabetes mellitus, and heart failure. (c) Admixture mapping has had its first empiric successes, localizing genes for hypertension and multiple sclerosis. Admixture mapping works in practice, making it critically important to apply it to seek CVD genes in the JHS cohort. We propose three specific aims:
Specific Aim 1 : Whole-genome admixture scanning for CVD related genes. We will type 3,072 admixture mapping markers in DMA of 3,796 unrelated African American participants from the JHS cohort. We will concentrate our analyses on phenotypes with known differences in prevalence between African Americans and Europeans: hypertension, serum lipid levels, left ventricular hypertrophy, and low birth weight.
Specific Aim 2 : Follow-up and fine-mapping of the two strongest peaks of association. We will genotype 2,535 additional SNPs/peak in 940 participants (470 at each extreme for the selected phenotype).
Specific Aim 3 : Acquire all recorded birth weights for JHS participants. Birth weight will be analyzed both as a covariate for CVD phenotypes and as an independent phenotype, by admixture mapping. Lav language description: Finding genes that affect the risk of disease can identify new targets for drug treatment and lead to the development of important medical tests. These studies will seek genes of African and European origin that cause heart and blood vessel diseases in African Americans.
