title: Weighted gene coexpression network analysis of human left atrial tissue identifies gene modules associated with atrial fibrillation.
abstract: BACKGROUND
  Genetic mechanisms of atrial fibrillation (AF) remain incompletely understood. Previous differential expression studies in AF were limited by small sample size and provided limited understanding of global gene networks, prompting the need for larger-scale, network-based analyses.
  
  
  RESULTS
  Left atrial tissues from Cleveland Clinic patients who underwent cardiac surgery were assayed using Illumina Human HT-12 mRNA microarrays. The data set included 3 groups based on cardiovascular comorbidities: mitral valve (MV) disease without coronary artery disease (n=64), coronary artery disease without MV disease (n=57), and lone AF (n=35). Weighted gene coexpression network analysis was performed in the MV group to detect modules of correlated genes. Module preservation was assessed in the other 2 groups. Module eigengenes were regressed on AF severity or atrial rhythm at surgery. Modules whose eigengenes correlated with either AF phenotype were analyzed for gene content. A total of 14 modules were detected in the MV group; all were preserved in the other 2 groups. One module (124 genes) was associated with AF severity and atrial rhythm across all groups. Its top hub gene, RCAN1, is implicated in calcineurin-dependent signaling and cardiac hypertrophy. Another module (679 genes) was associated with atrial rhythm in the MV and coronary artery disease groups. It was enriched with cell signaling genes and contained cardiovascular developmental genes including TBX5.
  
  
  CONCLUSIONS
  Our network-based approach found 2 modules strongly associated with AF. Further analysis of these modules may yield insight into AF pathogenesis by providing novel targets for functional studies.
authors.affiliation: Cleveland Clinic Lerner College of Medicine, Cleveland, OH 44195, USA. tann@ccf.org
authors.forename: Nicholas
authors.initials: N
authors.lastname: Tan
authors.forename: Mina K
authors.initials: MK
authors.lastname: Chung
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Smith
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hsu
authors.forename: David
authors.initials: D
authors.lastname: Serre
authors.forename: David W
authors.initials: DW
authors.lastname: Newton
authors.forename: Laurie
authors.initials: L
authors.lastname: Castel
authors.forename: Edward
authors.initials: E
authors.lastname: Soltesz
authors.forename: Gosta
authors.initials: G
authors.lastname: Pettersson
authors.forename: A Marc
authors.initials: AM
authors.lastname: Gillinov
authors.forename: David R
authors.initials: DR
authors.lastname: Van Wagoner
authors.forename: John
authors.initials: J
authors.lastname: Barnard
mesh_terms: D000368:Aged; D001281:Atrial Fibrillation / Q000235:genetics* / Q000473:pathology; D019703:Calcineurin / Q000378:metabolism; D016000:Cluster Analysis; D003324:Coronary Artery Disease / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D053263:Gene Regulatory Networks; D006325:Heart Atria / Q000503:physiopathology / Q000601:surgery*; D006349:Heart Valve Diseases / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008943:Mitral Valve / Q000503:physiopathology; D009124:Muscle Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D012044:Regression Analysis; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics; D020825:T-Box Domain Proteins / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C108612:RCAN1 protein, human; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D019703:Calcineurin
keywords: arrhythmias, cardiac; atrial fibrillation; bioinformatics; gene coexpression; gene regulatory networks; genetics; microarrays