Hypertension (HTN) affects ~30% of adults in industrialized countries and is the major risk factor for cardiovascular disease.
We sought to study the genetic effect of coding and conserved non-coding variants in syndromic HTN genes on systolic (SBP) and diastolic (DBP) blood pressure to assess their overall impact on essential hypertension (EH).
Methods and Results
We resequenced 11 genes (AGT, CYP11B1, CYP17A1, HSD11B2, NR3C1, NR3C2, SCNN1A, SCNN1B, SCNN1G, WNK1 and WNK4) in 560 European (EA) and African (AA) ancestry GenNet participants with extreme SBP. We investigated genetic associations of 2,535 variants with BP in 19,997 EAs and 6,069 AAs in three types of analyses. First, we studied the combined effects of all variants in GenNet. Second, we studied 1000 Genomes imputed polymorphic variants in 9,747 EA and 3,207 AA ARIC subjects. Lastly, we genotyped 37 missense and common noncoding variants in 6,591 EAs and 6,521 individuals (3,659 EA/2,862 AA) from the CLUE and FBPP studies. None of the variants individually reached significant false-discovery rates (FDR≤0.05) for SBP and DBP. However, upon pooling all coding and non-coding variants we identified at least 5 loci (AGT, CYP11B1, NR3C2, SCNN1G and WNK1), with higher association at evolutionary conserved sites.
Both rare and common variants at these genes affect BP in the general population with modest effects sizes (<0.05 standard deviation units) and much larger sample sizes are required to assess the impact of individual genes. Collectively, conserved noncoding variants affect BP to a greater extent than missense mutations.