Discovery and replication of novel blood pressure genetic loci in the Women's Genome Health Study

Abstract

Objectives: Genome-wide association meta-analyses have recently identified multiple loci associated with blood pressure. We sought to validate previously identified blood pressure loci by replication in a single large homogeneous population-based cohort and to identify new genome-wide significant loci using both conventional and expression-guided approaches.

Methods: We examined the associations of 18 single-nucleotide polymorphisms (SNPs) with genome-wide significance (P < 5.0 × 10⁻⁸, 'primary'), and 13 suggestive SNPs (5.0 × 10⁻⁸ < P < 5.6 × 10⁻⁵, 'secondary'), all from previously established genome-wide association studies, with self-reported blood pressure in 23 019 women from the Women's Genome Health Study. We then targeted for replication 12 gene expression-associated SNPs (eSNPs) that were also previously associated with blood pressure phenotypes.

Results: Using these replication strategies, we found confirmatory evidence for 13/18 primary SNPs, 3/13 secondary SNPs, and 4/12 eSNPs in the Women's Genome Health Study. Meta-analysis combining the Women's Genome Health Study results with prior study results revealed one previously unrecognized blood pressure locus with genome-wide significance: a BLK-GATA4-adjacent region (P = 3.2 × 10⁻⁸).

Conclusion: In this analysis, conventional and eSNP-guided strategies were complementary and illustrate two ways for extending initial genome-wide association results for discovery of new genes involved in human disease. Using this strategy, we report a newly identified blood pressure locus, BLK-GATA4, that may further understanding of the complex genetic pathways regulating blood pressure.

Figure 1. SBP and DBP risk scores

Aggregate effects of risk alleles on blood pressure phenotypes are summarized in a weighted risk score for SBP and DBP, respectively. The relationship between risk score and deviation from mean SBP or DBP are shown in the top panels. Black diamonds indicate the mean BP deviation for each risk score grouping, with black whiskers indicating the standard errors. The bottom panels show black diamonds to indicate the relationship between SBP (left) and DBP (right) risk score and odds ratios of HTN, with black whiskers representing 95% CIs. The p-values for slopes across risk score groups were all highly significant (P < 0.0001 for all 4 comparisons)