Genome-wide association study identifies eight loci associated with blood pressure

Abstract

Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

Figure 1

Regional association plots of eight blood pressure loci. For each locus, we show the region extending to within 500kb of a SNP with P < 10⁻⁴ on either side. Statistical significance of associated SNPs at each locus are illustrated on the - log₁₀(P) scale as a function of chromosomal position (NCBI Build 35). The sentinel SNP at each locus is shown in red. The correlation of the sentinel SNP to other SNPs at the locus is shown on a scale from minimal (gray and blue), to maximal (red). The meta-analysis result for stage 1 is shown with a red square. The joint analysis result (combined P) for stage 1+2a+2b is shown with an arrow. Fine-scale recombination rate from Myers et al is plotted in aqua.

Figure 2

Relationship of genome-wide significant loci to SBP, DBP and hypertension. Shown are the effects of each variant on continuous SBP and DBP and on the odds ratio for dichotomous hypertension compared to normotension (see Methods). For comparability, SBP and DBP effects are shown on the standard deviation scale (SBP SD = 16.6 mm Hg, DBP SD = 10.9 mm Hg). Alleles are coded as shown in Table 2.