Dataset Information

Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation.

ABSTRACT: BACKGROUND:Atrial fibrillation (AF) affects >30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood. METHODS AND RESULTS:To identify new AF-related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (expression quantitative trait loci) mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501; relative risk [RR]=1.18; 95% confidence interval [CI], 1.13-1.23; P=6.5×10(-16)), GJA1 (rs13216675; RR=1.10; 95% CI, 1.06-1.14; P=2.2×10(-8)), TBX5 (rs10507248; RR=1.12; 95% CI, 1.08-1.16; P=5.7×10(-11)), and CAND2 (rs4642101; RR=1.10; 95% CI, 1.06-1.14; P=9.8×10(-9)). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95% CI, 1.26-1.39; P=2.0×10(-25)) and CUX2 (rs6490029; RR=1.12; 95% CI, 1.08-1.16; P=3.9×10(-9)). The top single-nucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6×10(-19)), GJA1 (P=2.66×10(-6)), and TBX5 (P=1.36×10(-5)). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17% and 45%, respectively). CONCLUSIONS:We have identified 5 novel loci for AF. Our results expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.

SUBMITTER: Sinner MF

PROVIDER: S-EPMC4190011 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation.

Sinner Moritz F MF Tucker Nathan R NR Lunetta Kathryn L KL Ozaki Kouichi K Smith J Gustav JG Trompet Stella S Bis Joshua C JC Lin Honghuang H Chung Mina K MK Nielsen Jonas B JB Lubitz Steven A SA Krijthe Bouwe P BP Magnani Jared W JW Ye Jiangchuan J Gollob Michael H MH Tsunoda Tatsuhiko T Müller-Nurasyid Martina M Lichtner Peter P Peters Annette A Dolmatova Elena E Kubo Michiaki M Smith Jonathan D JD Psaty Bruce M BM Smith Nicholas L NL Jukema J Wouter JW Chasman Daniel I DI Albert Christine M CM Ebana Yusuke Y Furukawa Tetsushi T Macfarlane Peter W PW Harris Tamara B TB Darbar Dawood D Dörr Marcus M Holst Anders G AG Svendsen Jesper H JH Hofman Albert A Uitterlinden Andre G AG Gudnason Vilmundur V Isobe Mitsuaki M Malik Rainer R Dichgans Martin M Rosand Jonathan J Van Wagoner David R DR Benjamin Emelia J EJ Milan David J DJ Melander Olle O Heckbert Susan R SR Ford Ian I Liu Yongmei Y Barnard John J Olesen Morten S MS Stricker Bruno H C BH Tanaka Toshihiro T Kääb Stefan S Ellinor Patrick T PT

Circulation 20140814 15

<h4>Background</h4>Atrial fibrillation (AF) affects >30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood.<h4>Methods and results</h4>To identify new AF-related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (expression quantitative trait loci) mapping, and functional val ...[more]

PMID: 25124494

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Project description:BACKGROUND:Ablation is a widely used therapy for atrial fibrillation (AF); however, arrhythmia recurrence and repeat procedures are common. Studies examining surrogate markers of genetic susceptibility to AF, such as family history and individual AF susceptibility alleles, suggest these may be associated with recurrence outcomes. Accordingly, the aim of this study was to test the association between AF genetic susceptibility and recurrence after ablation using a comprehensive polygenic risk score for AF. METHODS:Ten centers from the AF Genetics Consortium identified patients who had undergone de novo AF ablation. AF genetic susceptibility was measured using a previously described polygenic risk score (N=929 single-nucleotide polymorphisms) and tested for an association with clinical characteristics and time-to-recurrence with a 3 month blanking period. Recurrence was defined as >30 seconds of AF, atrial flutter, or atrial tachycardia. Multivariable analysis adjusted for age, sex, height, body mass index, persistent AF, hypertension, coronary disease, left atrial size, left ventricular ejection fraction, and year of ablation. RESULTS:Four thousand two hundred seventy-six patients were eligible for analysis of baseline characteristics and 3259 for recurrence outcomes. The overall arrhythmia recurrence rate between 3 and 12 months was 44% (1443/3259). Patients with higher AF genetic susceptibility were younger (P<0.001) and had fewer clinical risk factors for AF (P=0.001). Persistent AF (hazard ratio [HR], 1.39 [95% CI, 1.22-1.58]; P<0.001), left atrial size (per cm: HR, 1.32 [95% CI, 1.19-1.46]; P<0.001), and left ventricular ejection fraction (per 10%: HR, 0.88 [95% CI, 0.80-0.97]; P=0.008) were associated with increased risk of recurrence. In univariate analysis, higher AF genetic susceptibility trended towards a higher risk of recurrence (HR, 1.08 [95% CI, 0.99-1.18]; P=0.07), which became less significant in multivariable analysis (HR, 1.06 [95% CI, 0.98-1.15]; P=0.13). CONCLUSIONS:Higher AF genetic susceptibility was associated with younger age and fewer clinical risk factors but not recurrence. Arrhythmia recurrence after AF ablation may represent a genetically different phenotype compared to AF susceptibility.

Dataset Information

Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation.

Publications

Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation.

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