Large scale replication and meta-analysis of variants on chromosome 4q25 associated with atrial fibrillation

Stefan Kääb, Dawood Darbar, Charlotte Van Noord, Josée Dupuis, Arne Pfeufer, Christopher Newton-Cheh, Renate Schnabel, Seiko Makino, Moritz F. Sinner, Prince J. Kannankeril, Britt M. Beckmann, Subbarao Choudry, Brian S. Donahue, Jan Heeringa, Siegfried Perz, Kathryn L. Lunetta, Martin G. Larson, Daniel Levy, Calum A. MacRae, Jeremy N. RuskinAnnette Wacker, Albert Schömig, H. Erich Wichmann, Gerhard Steinbeck, Thomas Meitinger, André G. Uitterlinden, Jacqueline C.M. Witteman, Dan M. Roden, Emelia J. Benjamin, Patrick T. Ellinor

Research output: Contribution to journalArticlepeer-review

176 Scopus citations


Aims: A recent genome-wide association study identified a haplotype block on chromosome 4q25 associated with atrial fibrillation (AF). We sought to replicate this association in four independent cohorts.Methods and resultsThe Framingham Heart Study and Rotterdam Study are community-based longitudinal studies. The Vanderbilt AF Registry and German AF Network (AFNet) are case-control studies. Participants with AF (n = 3508) were more likely to be male and were older than referent participants (n = 12 173; Framingham 82 ± 10 vs. 71 ± 13 years; Rotterdam 73 ± 8 vs. 69 ± 9 years; Vanderbilt 54 ± 14 vs. 57 ± 14 years; AFNet 62 ± 12 vs. 49 ± 14 years). Single nucleotide polymorphism (SNP) rs2200733 was associated with AF in all four cohorts, with odds ratios (ORs) ranging from 1.37 in Rotterdam [95 confidence interval (CI) 1.18-1.59; P = 3.1 × 10 -5] to 2.52 in AFNet (95 CI 2.22-2.8; P = 1.8 × 10 -49). There also was a significant association between AF and rs10033464 in Framingham (OR 1.34; 95 CI 1.03-1.75; P = 0.031) and AFNet (OR 1.30; 95 CI 1.13-1.51; P = 0.0002), but not Vanderbilt (OR 1.16; 95 CI 0.86-1.56; P = 0.33). A meta-analysis of the current and prior AF studies revealed an OR of 1.90 (95 CI 1.60-2.26; P = 3.3 × 10-13) for rs2200733 and of 1.36 (95 CI 1.26-1.47; P = 6.7 × 10-15) for rs10033464.ConclusionThe non-coding SNPs rs2200733 and rs10033464 are strongly associated with AF in four cohorts of European descent. These results confirm the significant relations between AF and intergenic variants on chromosome 4.

Original languageEnglish
Pages (from-to)813-819
Number of pages7
JournalEuropean Heart Journal
Issue number7
StatePublished - Apr 2009


  • Arrhythmia
  • Atrial fibrillation
  • Genetics
  • Meta-analysis
  • Polymorphism


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