Genome-wide analysis of blood pressure variability and ischemic stroke

Abstract

Background and purpose: Visit-to-visit variability in blood pressure (vBP) is associated with ischemic stroke. We sought to determine whether such variability has genetic causes and whether genetic variants associated with BP variability are also associated with ischemic stroke.

Methods: A Genome Wide Association Study (GWAS) for loci influencing BP variability was undertaken in 3802 individuals from the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) study, in which long-term visit-to-visit and within-visit BP measures were available. Because BP variability is strongly associated with ischemic stroke, we genotyped the sentinel single nucleotide polymorphism in an independent ischemic stroke population comprising 8624 cases and 12 722 controls and in 3900 additional (Scandinavian) participants from the ASCOT study to replicate our findings.

Results: The ASCOT discovery GWAS identified a cluster of 17 correlated single nucleotide polymorphisms within the NLGN1 gene (3q26.31) associated with BP variability. The strongest association was with rs976683 (P=1.4×10(-8)). Conditional analysis of rs976683 provided no evidence of additional independent associations at the locus. Analysis of rs976683 in patients with ischemic stroke found no association for overall stroke (odds ratio, 1.02; 95% CI, 0.97-1.07; P=0.52) or its subtypes: cardioembolic (odds ratio, 1.07; 95% CI, 0.97-1.16; P=0.17), large vessel disease (odds ratio, 0.98; 95% CI, 0.89-1.07; P=0.60), and small vessel disease (odds ratio, 1.07; 95% CI, 0.97-1.17; P=0.19). No evidence for association was found between rs976683 and BP variability in the additional (Scandinavian) ASCOT participants (P=0.18).

Conclusions: We identified a cluster of single nucleotide polymorphisms at the NLGN1 locus showing significant association with BP variability. Follow-up analyses did not support an association with risk of ischemic stroke and its subtypes.

Keywords: GWAS; blood pressure variability; genes; polymorphism; stroke.

Figure 1

Genome-wide Manhattan plot for the ASCOT Anglo IR-UK GWAS showing a cluster of 17 SNPs in/near NLGN1 associated with BP variability (P < 5 × 10⁻⁷). Individual –log₁₀ p values are plotted against their genomic position by chromosome. The dotted line at 10⁻⁶ marks the threshold for promising SNPs and the solid line at 10⁻⁸ marks the genome-wide significance threshold.

Figure 2

Regional association and LD plots for the 17 correlated SNP's within the Neuroligin-1 (NLGN1) gene (3q26.31). The plots A & B are conditioned on the imputed sentinel SNP rs976683 and C & D are conditioned on the top genotyped SNP rs9830510. In plot 2A & C, each coloured square represents a SNP p value, with the colour scale correlating the r² values for that SNP to the target SNP (red diamond) taken from the HapMap phase 2 CEU panel. In plot 2B & C, the target SNP (orange diamond) is represented in linkage disequilibrium with the cluster of 16 SNPs and other SNPs in the HapMap phase 2 CEU panel.