Abstract
ABSTRACTBackgroundHypertension, clinically defined by elevated blood pressure (BP), is an important cause of mortality and morbidity worldwide. Many risk factors for hypertension are known, including a positive family history, which suggests that genetics contribute to inter-individual BP variation. Genome-wide association studies (GWAS) have identified >1000 loci associated with BP, yet the identity of the genes responsible for these associations remains largely unknown.MethodsTo pinpoint genes that causally impact BP variation in humans, we analyzed predicted loss-of-function (pLoF) variants in the UK Biobank whole-exome sequencing dataset (n=454,709 participants, 6% non-European ancestry). We analyzed genetic associations between systolic or diastolic BP (SBP/DBP) and single pLoF variants (additive and recessive genetic models) as well as with the burden of very rare pLoF variants (minor allele frequency [MAF] <0.01%).ResultsSingle pLoF variants in ten genes associated with BP (ANKDD1B,ENPEP,PNCK, BTN3A2, C1orf145 [OBSCN-AS1],CASP9,DBH,KIAA1161 [MYORG],OR4X1, andTMC3). We also found a burden of rare pLoF variants in five additional genes associated with BP (TTN, NOS3, FES, SMAD6, COL21A1). Except forPNCK, which is located on the X-chromosome, these genes map near variants previously associated with BP by GWAS, validating the study of pLoF variants to prioritize causal genes at GWAS loci.ConclusionsOur study highlights 15 genes that likely modulate BP in humans, including five genes that harbor pLoF variants associated with lower BP.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献