Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk

Background- Rare genetic variants influence blood pressure (BP). Methods and Results- Whole-exome sequencing was performed on DNA samples from 17 956 individuals of European ancestry and African ancestry (14 497, first-stage discovery and 3459, second-stage discovery) to examine the effect of rare variants on hypertension and 4 BP traits: systolic BP, diastolic BP, pulse pressure, and mean arterial pressure. Tests of approximate to 170 000 common variants (minor allele frequency, >= 1%; statistical significance, P <= 2.9x10(-7)) and gene-based tests of rare variants (minor allele frequency, < 1%; approximate to 17 000 genes; statistical significance, P <= 1.5x10(-6)) were evaluated for each trait and ancestry, followed by multiethnic meta-analyses. In the first-stage discovery, rare coding variants (splicing, stop-gain, stop-loss, nonsynonymous variants, or indels) in CLCN6 were associated with lower diastolic BP (cumulative minor allele frequency, 1.3%; beta=-3.20; P=4.1x10(-6)) and were independent of a nearby common variant (rs17367504) previously associated with BP. CLCN6 rare variants were also associated with lower systolic BP (beta=-4.11; P=2.8x10(-4)), mean arterial pressure (beta=-3.50; P=8.9x10(-6)), and reduced hypertension risk (odds ratio, 0.72; P=0.017). Meta-analysis of the 2-stage discovery samples showed that CLCN6 was associated with lower diastolic BP at exome-wide significance (cumulative minor allele frequency, 1.1%; beta=-3.30; P=5.0x10(-7)). Conclusions- These findings implicate the effect of rare coding variants in CLCN6 in BP variation and offer new insights into BP regulation.