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Targeted sequencing in candidate genes for atrial fibrillation: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study.

Abstract：

BACKGROUND:Genome-wide association studies (GWAS) have identified common genetic variants that predispose to atrial fibrillation (AF). It is unclear whether rare and low-frequency variants in genes implicated by such GWAS confer additional risk of AF. OBJECTIVE:To study the association of genetic variants with AF at GWAS top loci. METHODS:In the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study, we selected and sequenced 77 target gene regions from GWAS loci of complex diseases or traits, including 4 genes hypothesized to be related to AF (PRRX1, CAV1, CAV2, and ZFHX3). Sequencing was performed in participants with (n = 948) and without (n = 3330) AF from the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Massachusetts General Hospital. RESULTS:One common variant (rs11265611; P = 1.70 × 10(-6)) intronic to IL6R (interleukin-6 receptor gene) was significantly associated with AF after Bonferroni correction (odds ratio 0.70; 95% confidence interval 0.58-0.85). The variant was not genotyped or imputed by prior GWAS, but it is in linkage disequilibrium (r(2) = .69) with the single-nucleotide polymorphism, with the strongest association with AF so far at this locus (rs4845625). In the rare variant joint analysis, damaging variants within the PRRX1 region showed significant association with AF after Bonferroni correction (P = .01). CONCLUSIONS:We identified 1 common single-nucleotide polymorphism and 1 gene region that were significantly associated with AF. Future sequencing efforts with larger sample sizes and more comprehensive genome coverage are anticipated to identify additional AF-related variants.

journal_name

Heart Rhythm

journal_title

Heart rhythm

authors

Lin H,Sinner MF,Brody JA,Arking DE,Lunetta KL,Rienstra M,Lubitz SA,Magnani JW,Sotoodehnia N,McKnight B,McManus DD,Boerwinkle E,Psaty BM,Rotter JI,Bis JC,Gibbs RA,Muzny D,Kovar CL,Morrison AC,Gupta M,Folsom AR,Kä

doi

10.1016/j.hrthm.2013.11.012

subject

Has Abstract

pub_date

2014-03-01 00:00:00

pages

452-7

issue

3

eissn

1547-5271

issn

1556-3871

pii

S1547-5271(13)01316-7

journal_volume

11

pub_type

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