In:
Circulation: Cardiovascular Genetics, Ovid Technologies (Wolters Kluwer Health), Vol. 9, No. 1 ( 2016-02), p. 64-70
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1942-325X
,
1942-3268
DOI:
10.1161/CIRCGENETICS.115.001215
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2016
detail.hit.zdb_id:
2927603-2
detail.hit.zdb_id:
2457085-0
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