Analysis of rare variants in 470,000 exome-sequenced UK Biobank participants implicates novel genes affecting risk of hypertension

Abstract

AbstractBackgroundA previous study of 200,000 exome-sequenced UK Biobank participants to test for association of rare coding variants with hypertension implicated two genes at exome-wide significance,DNMT3AandFES. A total of 42 genes had an uncorrected p value < 0.001. These results were followed up in a larger sample of 470,000 exome-sequenced participants.Methods and ResultsWeighted burden analysis of rare coding variants in a new sample of 97,050 cases and 172,263 controls was carried out for these 42 genes. Those showing evidence for association were then analysed in the combined sample of 167,127 cases and 302,691 controls. The association ofDNMT3AandFESwith hypertension was replicated in the new sample and they and the previously implicated geneNPR1were all exome-wide significant in the combined sample. Also exome-wide significant as risk genes for hypertension wereGUCY1A1,ASXL1andSMAD6, whileGUCY1B1had a nominal p value of < 0.0001. For two genes,INPPL1andDBH, rare coding variants predicted to impair gene function were protective against hypertension, again with exome-wide significance.ConclusionsThe findings offer new insights into biological risk factors for hypertension which could be the subject of further investigation. In particular, genetic variants predicted to impair the function of either membrane-bound guanylate cyclase, activated by natriuretic peptides, or soluble guanylate cyclase, activated by nitric oxide, increase risk of hypertension. Conversely, variants impairing the function of dopamine beta hydroxylase, responsible for the synthesis of norepinephrine, reduce hypertension risk.This research has been conducted using the UK Biobank Resource.