Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

Abstract

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to ~192,000 individuals, and used ~155,063 samples for independent replication. We identified 31 novel blood pressure or hypertension associated genetic regions in the general population, including three rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5mmHg/allele) than common variants. Multiple rare, nonsense and missense variant associations were found in A2ML1 and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.

Utilizing proteomics to understand and define hypertension: where are we and where do we go?

“…This has already been apparent in the first large genome-wide association study by the Wellcome Trust Case-Control Consortium [87] where the study of all other complex diseases resulted in significant and plausible hits whereas not a single genetic variant achieved genome-wide significance for hypertension. Only with changes in study designs [88] and further increased sample sizes [89] have genomic studies in hypertension evolved into a success story.…”

Csk Regulates Blood Pressure by Controlling the Synthetic Pathways of Aldosterone

“…[3][4][5][6][7] It is now evident that hypertension is a polygenic trait, wherein rare syndromes of hypertension Regulation of Aldosterone Synthesis by Csk…”

Genomics and Precision Medicine for Clinicians and Scientists in Hypertension

“…Further data with potential clinical significance have been generated by even larger meta-analyses published recently [15][16][17] . In one of these studies, Surendran et al, 15 genotyped nearly 350,000 individuals to identify 30 new blood pressure or hypertension-associated risk loci.…”

“…In one of these studies, Surendran et al, 15 genotyped nearly 350,000 individuals to identify 30 new blood pressure or hypertension-associated risk loci. These analyses provide insights into the pathophysiology of hypertension thus highlighting new potential for precision medicine and for druggable targets 15 .…”

“…In one of these studies, Surendran et al, 15 genotyped nearly 350,000 individuals to identify 30 new blood pressure or hypertension-associated risk loci. These analyses provide insights into the pathophysiology of hypertension thus highlighting new potential for precision medicine and for druggable targets 15 . The second study by Ehret et al, 16 performed association analyses on 340,000 individuals and identified 66 loci; of which 17 were novel, involved in BP regulation.…”