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

Circ Cardiovasc Genet. 2016 Feb;9(1):64-70. doi: 10.1161/CIRCGENETICS.115.001215. Epub 2015 Dec 11.


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 ≈170 000 common variants (minor allele frequency, ≥1%; statistical significance, P≤2.9×10(-7)) and gene-based tests of rare variants (minor allele frequency, <1%; ≈17 000 genes; statistical significance, P≤1.5×10(-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%; β=-3.20; P=4.1×10(-6)) and were independent of a nearby common variant (rs17367504) previously associated with BP. CLCN6 rare variants were also associated with lower systolic BP (β=-4.11; P=2.8×10(-4)), mean arterial pressure (β=-3.50; P=8.9×10(-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%; β=-3.30; P=5.0×10(-7)).

Conclusions: These findings implicate the effect of rare coding variants in CLCN6 in BP variation and offer new insights into BP regulation.

Keywords: blood pressure; exome; genetic variation; genome-wide association study; hypertension.

Publication types

  • Meta-Analysis
  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Black People
  • Blood Pressure / genetics*
  • Chloride Channels / genetics*
  • Exome*
  • Female
  • Gene Frequency*
  • Humans
  • Hypertension / genetics*
  • Male
  • Risk Factors
  • White People


  • CLCN6 protein, human
  • Chloride Channels

Grant support