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

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. To study the association of genetic variants with AF at GWA...

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Veröffentlicht in:Heart rhythm Jg. 11; H. 3; S. 452
Hauptverfasser: Lin, Honghuang, Sinner, Moritz F, Brody, Jennifer A, Arking, Dan E, Lunetta, Kathryn L, Rienstra, Michiel, Lubitz, Steven A, Magnani, Jared W, Sotoodehnia, Nona, McKnight, Barbara, McManus, David D, Boerwinkle, Eric, Psaty, Bruce M, Rotter, Jerome I, Bis, Joshua C, Gibbs, Richard A, Muzny, Donna, Kovar, Christie L, Morrison, Alanna C, Gupta, Mayetri, Folsom, Aaron R, Kääb, Stefan, Heckbert, Susan R, Alonso, Alvaro, Ellinor, Patrick T, Benjamin, Emelia J
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.03.2014
Schlagworte:
Aged
Atrial Fibrillation - genetics
Female
Genetic Predisposition to Disease
Genetic Variation
Genome-Wide Association Study
Homeodomain Proteins - genetics
Humans
Linkage Disequilibrium
Male
Middle Aged
Polymorphism, Single Nucleotide
Receptors, Interleukin-6 - genetics
Genetics
Arrhythmia
Epidemiology
Atrial fibrillation
ISSN:1556-3871, 1556-3871
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Zusammenfassung: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. To study the association of genetic variants with AF at GWAS top loci. 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. 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). 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.
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ISSN:1556-3871
1556-3871
DOI:10.1016/j.hrthm.2013.11.012