title: 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.
  
  
  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.
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mesh_terms: D000368:Aged; D000818:Animals; D001281:Atrial Fibrillation / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D002874:Chromosome Mapping; D018031:Connexin 43 / Q000235:genetics* / Q000502:physiology; D005060:Europe; D005260:Female; D055785:Gene Knockdown Techniques; D056426:Genetic Loci / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000208:ethnology; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D040641:Quantitative Trait Loci; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000502:physiology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology; D000097577:Homeobox Protein PITX2
chemical_list: D018031:Connexin 43; D018398:Homeodomain Proteins; D009124:Muscle Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D029961:Zebrafish Proteins; D000097577:Homeobox Protein PITX2; C485649:CAND2 protein, human; C080632:CUX1 protein, human; C000596729:Cand2 protein, zebrafish; C500216:GJA1 protein, human; C103172:T-box transcription factor 5; C556508:NEURL1 protein, human; C000596730:neurl1aa protein, zebrafish
keywords: atrial fibrillation; epidemiology; gene expression; genetics; polymorphism; single nucleotide; zebrafish