Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney

Abstract

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project–based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits

“…We combined previously reported post-QC GWAS data from 54 studies (N=150,134)11,12,61, with newly available GWAS data from a further 23 independent studies (N=148,890) using a fixed effects inverse variance weighted meta-analysis. The 23 studies providing new data were: ASCOT-SC, ASCOT-UK, BRIGHT, Dijon 3C, EPIC-CVD, GAPP, HCS, GS:SFHS, Lifelines, JUPITER, PREVEND, TWINSUK, GWAS-Fenland, InterAct-GWAS, OMICS-EPIC, OMICS-Fenland, UKHLS, GoDARTS-Illumina and GoDarts-Affymetrix, NEO, MDC, SardiNIA, METSIM.…”

“…Here, we report genome-wide discovery analyses of BP traits - systolic (SBP), diastolic (DBP) and pulse pressure (PP) - in people of European ancestry drawn from UK Biobank (UKB)13 and the International Consortium of Blood Pressure-Genome Wide Association Studies (ICBP)11,12. We adopted a combination of a one- and two-stage study design to test common and low-frequency single nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) ≥ 1% associated with BP traits (Fig.…”

Genetic linkage analysis of a large family identifies FIGN as a candidate modulator of reduced penetrance in heritable pulmonary arterial hypertension

“…Among them, the aforementioned cardiorespiratory phenotypes remained on the list. Seven GWAS SNPs, located upstream from the FIGN gene, were responsible for this enrichment: rs16849225,36 37 rs1189140138 and rs144646839 for systolic blood pressure; rs1300257340 and rs1684921139 for pulse pressure measurement; rs76833157 and rs7576072 for both asthma and response to diisocyanate 41. Furthermore, one variant from a dbGAP study was associated with tunica media wall thickness of carotid arteries (rs1370493, pha003034-phs000221) 42.…”

Genome-Wide Association Scan of Serum Urea in European Populations Identifies Two Novel Loci

“…Furthermore, we examined eQTLs in donor kidney tissue in TransplantLines (detailed description of data and methods in online suppl. Note 11) [37,38].…”