Genome-wide association study of blood pressure and hypertension

Abstract

Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 × 10(-7). The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P < 5 × 10(-8)) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.

Figure 1. Locus-specific association maps for systolic blood pressure

Locus-specific (-log₁₀p-values) maps in the CHARGE meta-analysis of systolic blood pressure for four loci with genome-wide significance in the joint analysis of CHARGE with Global BPgen. The four loci are represented by rs3184504 (SH2B3), rs2681492 (ATP2B1), rs381815 (PLEKHA7), and rs1004467 (CYP17A1). For each locus the sentinel SNP (lowest p value) is depicted in blue, SNPs in red have r² ≥0.8 with the sentinel SNP; SNPs in orange have r² ≥0.5; those in yellow have r² ≥0.2; those in white have r² < 0.2 with the sentinel SNP. Superimposed on the plot are gene locations (green) and recombination rates (blue).

Figure 2. Locus-specific association maps for diastolic blood pressure

Locus-specific (-log₁₀p-values) maps in the CHARGE meta-analysis of diastolic blood pressure for six loci with genome-wide significance in the joint analysis of CHARGE with Global BPgen. The six loci are represented by rs3184504 (SH2B3), rs2681472 (ATP2B1), rs6495122 (CSK), rs9815354 (ULK4), rs11014166 (CACNB2), and rs2384550 (TBX3/TBX5). For each locus the sentinel SNP (lowest p value) is depicted in blue, SNPs in red have r² ≥0.8 with the sentinel SNP; SNPs in orange have r² ≥0.5; those in yellow have r² ≥0.2; those in white have r² < 0.2 with the sentinel SNP. Superimposed on the plot are gene locations (green) and recombination rates (blue).

Figure 3. Systolic and Diastolic Blood Pressure Risk Scores

This figure shows deviation in blood pressure or odds ratio for hypertension as solid diamonds with whiskers extending to ±1 standard error. Sample sizes for blood pressure risk score groups are shown by the blue bars. The top panels present deviation from mean systolic (left panel) and diastolic blood pressure (right panel) in mm Hg according to weighted risk score. The bottom panels show odds ratios for hypertension in relation to systolic (left panel) and diastolic blood pressure (right panel) weighted risk score. DBP=diastolic blood pressure; HTN=hypertension; SBP=systolic blood pressure. The p values for slope across risk score groups were all highly significant: 1.8×10^-27 (systolic blood pressure vs. systolic blood pressure risk score), 1.7×10^-56 (diatolic blood pressure vs. diastolic blood pressure risk score), 1.4×10^-17 (hypertension vs. systolic blood pressure risk score), and 8.4×10^-10 (hypertension vs. diastolic blood pressure risk score).