Analysis of 200,000 Exome-Sequenced UK Biobank Subjects Implicates Genes Involved in Increased and Decreased Risk of Hypertension

Abstract

<b><i>Background:</i></b> Previous analyses have identified common variants along with some specific genes and rare variants which are associated with risk of hypertension, but much remains to be discovered. <b><i>Methods and Results:</i></b> Exome-sequenced UK Biobank participants were phenotyped based on having a diagnosis of hypertension or taking anti-hypertensive medication to produce a sample of 66,123 cases and 134,504 controls. Variants with minor allele frequency (MAF) <0.01 were subjected to a gene-wise weighted burden analysis, with higher weights assigned to variants which are rarer and/or predicted to have more severe effects. Of 20,384 genes analysed, 2 genes were exome-wide significant, <i>DNMT3A</i> and <i>FES</i>. Also strongly implicated were <i>GUCY1A1</i> and <i>GUCY1B1</i>, which code for the subunits of soluble guanylate cyclase. There was further support for the previously reported effects of variants in <i>NPR1</i> and protective effects of variants in <i>DBH</i>. An inframe deletion in <i>CACNA1D</i> with MAF = 0.005, rs72556363, is associated with modestly increased risk of hypertension. Other biologically plausible genes highlighted consist of <i>CSK</i>, <i>AGTR1</i>, <i>ZYX</i>, and <i>PREP</i>. All variants implicated were rare, and cumulatively they are not predicted to make a large contribution to the population risk of hypertension. <b><i>Conclusions:</i></b> This approach confirms and clarifies previously reported findings and also offers novel insights into biological processes influencing hypertension risk, potentially facilitating the development of improved therapeutic interventions. This research has been conducted using the UK Biobank Resource.

Whole-exome sequencing study identifies rare variants and genes associated with intraocular pressure and glaucoma

“…From the pan-ancestry single-variant association results, we selected rare variants with P < 5 × 10 −7 excluding intronic and synonymous variants. We assigned weights to these variants based on biological functions similar to that reported by Curtis 35 , 47 . Details of these variants and their weights are shown in the Supplementary Table 1 .…”

“…Genetic variants with P < 1 × 10 −8 were declared ExWAS significant 46 . In addition to using European participants, recent ExWAS studies advocate to include participants of all ancestries 47,48 . Hence, we performed both white only and pan-ancestry analyses (added an additional covariate for four major ancestral groups, i.e., European, South Asian, East Asian, and African, identified by the K-Means clustering algorithm based on the first 10 PCs of genetic ancestry).…”

Kidney omics in hypertension: from statistical associations to biological mechanisms and clinical applications

“…40 Interestingly, FES was 1 of 2 genes showing exome-wide significant association with hypertension in gene-wise weighted burden analysis conducted in UK Biobank. 76 This convergence of evidence makes FES one of the most interesting novel genes of relevance to BP and hypertension. Further studies will be warranted to elucidate the biological pathways linking FES to BP regulation.…”

Exploration of weighting schemes based on allele frequency and annotation for weighted burden association analysis of complex phenotypes

“…These genes and phenotypes are listed in Table 2. The BMI phenotype was calculated directly from the fields for height and weight whereas the case definitions for hyperlipidaemia, hypertension and type 2 diabetes were derived from a mixture of self-report, recorded diagnoses and medication reports (Curtis, 2021a(Curtis, , 2021b(Curtis, , 2021c(Curtis, , 2020. In the case of PCSK9 and ANGPTL3 the original SLPs obtained were negative, indicating that variants impairing the function of these genes were protective and were associated with lower risk of developing hyperlipidaemia.…”