Genome-wide association analysis of blood-pressure traits in African-ancestry individuals reveals common associated genes in African and non-African populations

Abstract

High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 × 10(-8)) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.

Figure 1

Overview of GWAS Meta-analysis for the COGENT Discovery and Replication Cohorts

Figure 2

Regional Interrogation of the EVX1-HOXA, SOX6, and ULK4 Loci (A–C) Associations between SBP, DBP, and HTN and homeobox genes on chromosome 7. Note the three independent SNPs (purple diamonds) in this region with multiple homeobox genes and EVX1 (Table 2). SNP rs17428471 is located in the middle peak. (D) Association between DBP and SOX6 on chromosome 11. p values of rs1401454 in both COGENT and all combined AA samples are shown. (E) Association between DBP and ULK4 on chromosome 3. One arrow points to the ICBP SNP rs3774372, which does not show evidence of association in COGENT samples. The most significant SNP is rs1717027. (F) Haplotype analysis of coding variants rs3774372, rs1716975, rs1717027, and rs2272007 in ULK4. The red and blue lines indicate haplotypes. The arrow points to a historical recombination breakpoint observed in AA, but not in EA (HapMap CEU), populations. The best model fitting the National Heart, Lung, and Blood Institute Candidate-gene Association Resource (“CARe”) data is TCCC versus (CTTT and TTTT), indicating that SNP rs3774372 reported in ICBP is unlikely to be a causal variant. In (A)–(E), the x axes show chromosomal positions, the left y axes show the p values, and the right y axes show the recombination rates across the region.

Figure 3

Pairwise Scatter Plots of the Effect Sizes of the 21 ICBP-Reported Variants among the COGENT, ICBP, South Asian, and East Asian Data Sets The figure is plotted on the basis of the variants after exclusion of eight monomorphic variants in HapMap CHB (Han Chinese in Beijing, China) and JPT (Japanese in Tokyo, Japan) samples. The Pearson correlation coefficients and the corresponding p values are r = 0.72 and p = 8.6 × 10⁻¹¹ (A), r = 0.69 and p = 2.1 × 10⁻⁹ (B), r = 0.64 and p = 8.6 × 10⁻⁷ (C), r = 0.76 and p = 1.4 × 10⁻¹³ (D), r = 0.8 and p = 3.2 × 10⁻¹⁷ (E), and r = 0.7 and p = 3.2 × 10⁻¹⁰ (F). We observed that the effect sizes are highly correlated across the different ethnic populations. These results strongly suggest that many common variants consistently contribute to BP variation across ethnicities, although replication is challenging because of variation in LD, sample size, and allele frequency.