title: Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk.
abstract: BACKGROUND
  Rare genetic variants influence blood pressure (BP).
  
  
  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.
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authors.lastname: Yu
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authors.forename: Aravinda
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authors.lastname: Chakravarti
authors.forename: Adolfo
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authors.lastname: Correa
authors.forename: Albert W
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authors.lastname: Dreisbach
authors.forename: Oscar H
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authors.lastname: Franceschini
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authors.lastname: Hofman
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authors.initials: DY
authors.lastname: Lin
authors.forename: Ginger A
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authors.lastname: Metcalf
authors.forename: Solomon K
authors.initials: SK
authors.lastname: Musani
authors.forename: Donna
authors.initials: D
authors.lastname: Muzny
authors.forename: Walter
authors.initials: W
authors.lastname: Palmas
authors.forename: Leslie
authors.initials: L
authors.lastname: Raffel
authors.forename: Alex
authors.initials: A
authors.lastname: Reiner
authors.forename: Ken
authors.initials: K
authors.lastname: Rice
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Narayanan
authors.initials: N
authors.lastname: Veeraraghavan
authors.forename: Ervin
authors.initials: E
authors.lastname: Fox
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Guo
authors.forename: Kari E
authors.initials: KE
authors.lastname: North
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.forename: Christopher
authors.initials: C
authors.lastname: Newton-Cheh
authors.forename: Alanna C
authors.initials: AC
authors.lastname: Morrison
mesh_terms: D000483:Alleles; D044383:Black People; D001794:Blood Pressure / Q000235:genetics*; D018118:Chloride Channels / Q000235:genetics*; D059472:Exome; D005260:Female; D005787:Gene Frequency; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D008297:Male; D012307:Risk Factors; D044465:White People
chemical_list: C097539:CLCN6 protein, human; D018118:Chloride Channels
keywords: blood pressure; exome; genetic variation; genome-wide association study; hypertension