Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure

Abstract

Numerous genetic loci influence systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans 1-3. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N=74,064) and follow-up studies (N=48,607), we identified at genome-wide significance (P= 2.7×10-8 to P=2.3×10-13) four novel PP loci (at 4q12 near CHIC2/PDGFRAI, 7q22.3 near PIK3CG, 8q24.12 in NOV, 11q24.3 near ADAMTS-8), two novel MAP loci (3p21.31 in MAP4, 10q25.3 near ADRB1) and one locus associated with both traits (2q24.3 near FIGN) which has recently been associated with SBP in east Asians. For three of the novel PP signals, the estimated effect for SBP was opposite to that for DBP, in contrast to the majority of common SBP- and DBP-associated variants which show concordant effects on both traits. These findings indicate novel genetic mechanisms underlying blood pressure variation, including pathways that may differentially influence SBP and DBP.

Gene by stress genome-wide interaction analysis and path analysis identify EBF1 as a cardiovascular and metabolic risk gene

“…Two large GWASs of European Whites identified genome-wide significant variants in EBF1 associated with hypertension, systolic blood pressure, diastolic blood pressure, and mean arterial pressure. 26,27 The EBF1 gene was also identified as putative key regulatory gene for the coronary heart disease causal differential modules based on the global tissue-specific Bayesian and protein-protein interaction networks, 28 confirming the complex relationship between CVD and EBF1. However, the large consortia of GWASs -GIANT, MAGIC, DIAGRAM, and CARDIoGRAM -did not identify SNPs in EBF1.…”

The Influence of Known Genetic Variants on Subclinical Cardiovascular Outcomes in Childhood

“…The weighted risk scores were computed as sums of the number of outcome-increasing alleles, reflected by the dosage of the SNP, weighted by their effect sizes derived from the adult GWAS. [11][12][13] In line with the adult study, all 29 SNPs related to either SBP, or DBP, or both were incorporated into a single weighted genetic risk score, indicated as weighted adult blood pressure genetic risk score, and weighted by the average of the SBP and DBP effect estimates in adults. 12 We rescaled each weighted risk score to a score ranging from zero to the maximum number of outcome-increasing alleles, rounded to the nearest integer.…”

“…[11][12][13] One GWAS among a total sample of around 16 000 adults identified 2 SNPs related to LVEDD and 5 SNPs related to AoD.…”

“…[11][12][13] We examined whether genetic variants associated with subclinical cardiovascular outcomes in adults influence these outcomes from childhood onwards.…”

Vascular dysfunction precedes hypertension associated with a blood pressure locus on rat chromosome 12

“…Removal of chondroitin-dermatan sulfate-containing glycosaminoglycans from the arterial wall increases mesenteric vessel stiffness (17). Additionally, two human genomewide association studies in individuals of European ancestry (11,43) have suggestively associated a single-nucleotide polymorphism (rs2969070 [G]) that is intergenic of CHST12 and GRIFIN to hypertension. Interestingly, previous whole genome sequencing analysis of overlapping rat blood pressure loci within our candidate region found an ϳ86-kb region (chr12: 14,541,567-14,627,442 bp) containing single nucleotide variants near Chst12 and Grifin that were unique to the hypertensive SS strain compared with the normotensive BN, Dahl salt-resistant, and Wistar-Kyoto strains, suggesting that the SS-derived variant(s) within this region may be involved in BP regulation (38).…”