Genome-wide association study of coronary heart disease and its risk factors in 8,090 African Americans: the NHLBI CARe Project

Abstract

Coronary heart disease (CHD) is the leading cause of mortality in African Americans. To identify common genetic polymorphisms associated with CHD and its risk factors (LDL- and HDL-cholesterol (LDL-C and HDL-C), hypertension, smoking, and type-2 diabetes) in individuals of African ancestry, we performed a genome-wide association study (GWAS) in 8,090 African Americans from five population-based cohorts. We replicated 17 loci previously associated with CHD or its risk factors in Caucasians. For five of these regions (CHD: CDKN2A/CDKN2B; HDL-C: FADS1-3, PLTP, LPL, and ABCA1), we could leverage the distinct linkage disequilibrium (LD) patterns in African Americans to identify DNA polymorphisms more strongly associated with the phenotypes than the previously reported index SNPs found in Caucasian populations. We also developed a new approach for association testing in admixed populations that uses allelic and local ancestry variation. Using this method, we discovered several loci that would have been missed using the basic allelic and global ancestry information only. Our conclusions suggest that no major loci uniquely explain the high prevalence of CHD in African Americans. Our project has developed resources and methods that address both admixture- and SNP-association to maximize power for genetic discovery in even larger African-American consortia.

Figure 1. Quantile-quantile (QQ) plots of the meta-analyses for coronary heart disease, HDL-C, hypertension, LDL-C, smoking, and type-2 diabetes analyzed in the CARe African-American samples (N = 8,090).

Each black circle represents an observed statistic for all genotypes and imputed SNPs (defined as the −log₁₀(P-value)) against the corresponding expected statistic. The grey area corresponds to the 90% confidence intervals calculated empirically using permutations. The meta-analysis inflation factors are: coronary heart disease (λ_s = 0.991), HDL-C (λ_s = 1.030), hypertension (λ_s = 1.024), LDL-C (λ_s = 1.023), smoking (λ_s = 1.008), and type-2 diabetes (λ_s = 1.017). Data shown are genomic controlled before (for each study) and after the meta-analysis.

Figure 2. HDL-C association results in Caucasians (top panel) and in the CARe African Americans (bottom panel) at the FADS locus.

Plots were generated using LocusZoom . Under the top panel, the light blue box corresponds to the chromosomal interval flanked by the leftmost and rightmost SNPs with a r²≥0.3 with the index SNP rs174547 in HapMap CEU. In the bottom panel, there is no light blue box because the top CARe SNPs at this locus, rs1535, is not in strong LD with any markers in HapMap YRI.