Trans-ethnic association study of blood pressure determinants in over 750,000 individuals

Abstract

In this trans-ethnic multi-omic study we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenome, and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in GWASs of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically-predicted gene expression of 840 genes in 45 tissues, and murine renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.

Biases in GWAS – the dog that did not bark

“…The genetic variant proxying interleukin-6 was, as expected, associated with lower risk of IHD [18], but had little effect on stroke or age at recruitment. For demonstration several blood pressure genetic variants [19] are shown with consistent associations with IHD and age at recruitment but no association with stroke.…”

“The Heidelberg Five” Personality Dimensions: Genome-wide Associations, Polygenic Risk for Neuroticism, and Psychopathology 20 Years after Assessment

“…They have been associated with neuropsychiatric disease [34] and coordinate both synaptic structure and function [35]. Furthermore, SNPs in the ITGB5 gene are associated with blood pressure [36] and coronary artery disease [37]. Interestingly, an association between ELAB and the incidence of CVD was previously identified in longitudinal analyses ( [6]) and thus may suggest a common genetic basis of both.…”

Rapid response to the Alpha-1 Adrenergic Agent Phenylephrine in the Perioperative Period is Impacted by Genomics and Ancestry

“…We identified two "non-responder" groups: patients who either had no increase in blood pressure in response to the bolus, or whose blood pressure paradoxically declined. The first group of non-responders was identified through the analysis performed on the EA population, which identified two rare SNPs, rs188427942 (MAF EA: 1.16%) and rs147664194 (MAF EA: 1.01%) located in or near gene CSNK1G3 (Casein Kinase 1 Gamma 3), in regions previously associated with SBP, DBP, and PP (pulse pressure) (Andreassen et al, 2014;Ehret et al, 2016;Giri et al, 2019;Liu et al, 2016). CSNK1G3, which encodes a member of a family of serine/threonine protein kinases that phosphorylate caseins and other acidic proteins, is mostly expressed in fibroblasts (GTEx Consortium, 2013) (Supplementary Figure 6).…”

“…AT: arterial tonometry (Andreassen et al, 2014;. Ehret et al, 2016;Evangelou et al, 2018;Giri et al, 2019;Kichaev et al, 2019;Levy et al, 2007;Liu et al, 2016;Nielsen et al, 2018;Roselli et al, 2018;Salvi et al, 2017;Taylor et al, 2016)…”