Background: Hypertension, 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. Methods: To 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%). Results: Single pLoF variants in ten genes associated with BP (ANKDD1B, ENPEP, PNCK, BTN3A2, C1orf145 [OBSCN-AS1], CASP9, DBH, KIAA1161 [MYORG], OR4X1, and TMC3). We also found a burden of rare pLoF variants in five additional genes associated with BP (TTN, NOS3, FES, SMAD6, COL21A1). Except for PNCK, 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. Conclusions: Our study highlights 15 genes that likely modulate BP in humans, including five genes that harbor pLoF variants associated with lower BP.

The authors have declared no competing interest.

This work was funded by the Canadian Institutes of Health Research (MOP #136979), the Canada Research Chair Program, the Foundation Joseph C. Edwards and the Montreal Heart Institute Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Montreal Heart Institute Ethics Committee gave ethical approval for this work (protocol #2017-2247).

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