Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk

Abstract

Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.

Figure 1

Study design schematic for discovery and validation of loci. N: sample size; QC: Quality Control; PCA: Principal Component Analysis; BP: blood pressure; SBP: systolic BP; DBP: diastolic BP; PP: pulse pressure; SNVs: single nucleotide variants; BMI: body mass index; UKB: UK Biobank; UKBL: UK BiLEVE; GWAS: Genome-wide association study; MAF: Minor Allele Frequency; P: P-value; LD: Linkage Disequilibrium; 1000G: 1000 Genomes. UKBBvsUKBL: a binary indicator variable for UK Biobank vs UK BiLEVE to adjust for the different genotyping chips

Figure 2

Venn diagram of 107 validated loci from our study. This shows concordance of significant associations across the three blood pressure phenotypes for the 107 validated sentinel variants (Tables 1-3) from both the GWAS and exome analyses, according to genome-wide significance in the combined meta-analysis. The locus names labelled within the Venn Diagram correspond to Tables 1-3, and relate to the nearest annotated gene. The loci names in bold font highlight the 32 novel loci which are reported for the first time in our study.

Figure 3

Distribution of Genetic Risk Score (GRS) and its relationship with blood pressure, hypertension and CVD outcomes. The GRS is based on all reported loci: both previously reported loci at the time of analysis; and all validated blood pressure variants from this study. (a) Distribution of GRS in Airwave and sex-adjusted odds ratio of hypertension in age 50+ comparing each of the upper four GRS quintiles with the lowest quintile; dotted lines represent the upper 95% confidence intervals. (b) Mean blood pressures and standard deviation in bracket in Airwave age 50+ across GRS quintiles. (c) Distribution of GRS in UKB and sex-adjusted odds ratio of CVD, CAD and stroke comparing each of the upper four GRS quintiles with the lowest quintile; dotted lines represent the upper 95% confidence intervals. (d) Count of CVD, CAD and stroke (events and deaths) across GRS quintiles in UKB participants

Figure 4

Summary of gene cardiovascular expression from validated loci. Genes are shown on the basis of their tissue expression and supporting evidence summarised in Supplementary Table 16, based on Knockout (KO) phenotype, previously reported blood pressure biology or a strong functional rationale: eQTL (expression Quantitative Trait Loci), nsSNV (non-synonymous SNV), Hi-C. Multiple lines of evidence indicate the central importance of the vasculature in blood pressure regulation and we thus highlight existing drugged (*) and druggable (#) targets among these genes. Illustrations used elements with permission from Servier Medical Art. We note that some druggable genes may carry a safety liability, such as GJA1, which has known association with QT interval