A meta-analysis of genome-wide association studies of the electrocardiographic early repolarization pattern

Moritz F. Sinner, Kimmo Porthan, Peter A. Noseworthy, Aki S. Havulinna, Jani T. Tikkanen, Martina Müller-Nurasyid, Gina Peloso, Sheila Ulivi, Britt Maria Beckmann, A. Catharina Brockhaus, Rebecca R. Cooper, Paolo Gasparini, Christian Hengstenberg, Shih Jen Hwang, Annamaria Iorio, M. Juhani Junttila, Norman Klopp, Mika Kähönen, Maarit A. Laaksonen, Terho LehtimäkiPeter Lichtner, Leo Pekka Lyytikäinen, Eimo Martens, Christa Meisinger, Thomas Meitinger, Faisal M. Merchant, Markku S. Nieminen, Annette Peters, Arto Pietilä, Siegfried Perz, Lasse Oikarinen, Olli Raitakari, Wibke Reinhard, Kaisa Silander, Barbara Thorand, H. Erich Wichmann, Gianfranco Sinagra, Jorma Viikari, Christopher J. O'Donnell, Patrick T. Ellinor, Heikki V. Huikuri, Stefan Kääb, Christopher Newton-Cheh, Veikko Salomaa

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Background: The early repolarization pattern (ERP) is common and associated with risk of sudden cardiac death. ERP is heritable, and mutations have been described in syndromatic cases. Objective: To conduct a meta-analysis of genome-wide association studies to identify common genetic variants influencing ERP. Methods: We ascertained ERP on the basis of electrocardiograms in 3 large community-based cohorts from Europe and the United States: the Framingham Heart Study, the Health 2000 Study, and the KORA F4 Study. We analyzed genome-wide association studies in participants with and without ERP by logistic regression assuming an additive genetic model and meta-analyzed individual cohort results. We then sought to strengthen support for findings that reached P ≤ 1 × 10-5 in independent individuals by direct genotyping or in-silico analysis of genome-wide data. We meta-analyzed the results from both stages. Results: Of 7482 individuals in the discovery stage, 452 showed ERP (ERP positive: mean age 46.9 ± 8.9 years, 30.3% women; ERP negative: 47.5 ± 9.4 years, 54.2% women). After meta-analysis, 8 single nucleotide polymorphisms reached P ≤ 1 × 10-5: The most significant finding was intergenic rs11653989 (odds ratio 0.47; 95% confidence interval 0.36-0.61; P = 6.9 × 10-9). The most biologically relevant finding was intronic to KCND3: rs17029069 (odds ratio 1.46; 95% confidence interval 1.25-1.69; P = 8.5 × 10-7). In the replication step (7151 individuals), none of the 8 variants replicated, and combined meta-analysis results failed to reach genome-wide significance. Conclusions: In a genome-wide association study, we were not able to reliably identify genetic variants predisposing to ERP, presumably due to insufficient statistical power and phenotype heterogeneity. The reported heritability of ERP warrants continued investigation in larger well-phenotyped populations.

Original languageEnglish (US)
Pages (from-to)1627-1634
Number of pages8
JournalHeart rhythm
Volume9
Issue number10
DOIs
StatePublished - Oct 2012

Keywords

  • Arrhythmia
  • Early repolarization
  • Electrocardiogram
  • GWAS
  • Meta-analysis
  • Sudden cardiac death

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Fingerprint Dive into the research topics of 'A meta-analysis of genome-wide association studies of the electrocardiographic early repolarization pattern'. Together they form a unique fingerprint.

Cite this