title: Very early-onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation.
abstract: BACKGROUND
  Atrial fibrillation (AF) is the most common cardiac arrhythmia. Currently, 14 genes important for ion channel function, intercellular signaling, and homeostatic control have been associated with AF.
  
  
  OBJECTIVE
  We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early-onset lone AF patients than in the background population.
  
  
  METHODS
  Sequencing results of KCNQ1, KCNH2, SCN5A, KCNA5, KCND3, KCNE1, 2, 5, KCNJ2, SCN1-3B, NPPA, and GJA5 from 192 early-onset lone AF patients were compared with data from the National Heart, Lung, and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies.
  
  
  RESULTS
  Among the lone AF patients, 29 (7.6%) alleles harbored a novel or very rare variant (minor allele frequency <0.1 in the Exome Variant Server), a frequency that was significantly higher than what was found in the reference database (4.1%; with minor allele frequency <0.1; P = .0012). Previously published electrophysiological data showed that 96% (n = 23) of the rare variants that has been functionally investigated (n = 24) displayed significant functional changes.
  
  
  CONCLUSIONS
  We report a much higher prevalence of rare variants in genes associated with AF in early-onset lone AF patients than in the background population. By presenting these data, we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF.
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark; Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: morten.salling.olesen@rh.regionh.dk.
authors.forename: Morten S
authors.initials: MS
authors.lastname: Olesen
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark; Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Laura
authors.initials: L
authors.lastname: Andreasen
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark; Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Javad
authors.initials: J
authors.lastname: Jabbari
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark; Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lena
authors.initials: L
authors.lastname: Refsgaard
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark; Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Stig
authors.initials: S
authors.lastname: Haunsø
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Søren-Peter
authors.initials: SP
authors.lastname: Olesen
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark; Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jonas B
authors.initials: JB
authors.lastname: Nielsen
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schmitt
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark; Laboratory for Molecular Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jesper H
authors.initials: JH
authors.lastname: Svendsen
mesh_terms: D000328:Adult; D017668:Age of Onset; D000483:Alleles; D001281:Atrial Fibrillation / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D020641:Polymorphism, Single Nucleotide
keywords: AF; EVS; Exome Variant Server; Genetics; Lone AF; MAF; NGS; OR; Rare variants; Single nucleotide polymorphisms; atrial fibrillation; minor allele frequency; next generation sequencing; odds ratio