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Sinner, M.F.* ; Porthan, K.* ; Noseworthy, P.A.* ; Havulinna, A.S.* ; Tikkanen, J.T.* ; Müller-Nurasyid, M. ; Peloso, G.* ; Ulivi, S.* ; Beckmann, B.M.* ; Brockhaus, A.C. ; Cooper, R.R.* ; Gasparini, P.* ; Hengstenberg, C.* ; Hwang, S.-J.* ; Iorio, A.* ; Junttila, M.J.* ; Klopp, N. ; Kähönen, M.* ; Laaksonen, M.A.* ; Lehtimäki, T.* ; Lichtner, P. ; Lyytikäinen, L.-P.* ; Martens, E.* ; Meisinger, C. ; Meitinger, T. ; Merchant, F.M.* ; Nieminen, M.S.* ; Peters, A. ; Pietila, A.* ; Perz, S. ; Oikarinen, L.* ; Raitakari, O.* ; Reinhard, W.* ; Silander, K.* ; Thorand, B. ; Wichmann, H.-E. ; Sinagra, G.* ; Viikari, J.* ; O'Donnell, C.J.* ; Ellinor, P.T.* ; Huikuri, H.V.* ; Kääb, S.* ; Newton-Cheh, C.* ; Salomaa, V.*

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

Heart Rhythm 9, 1627-1634 (2012)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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 x 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 x 10(-5): The most significant finding was intergenic rs11653989 (odds ratio 0.47; 95% confidence interval 0.36-0.61; P = 6.9 x 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 x 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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Early Repolarization ; Sudden Cardiac Death ; Arrhythmia ; Gwas ; Meta-analysis ; Electrocardiogram; Transient Outward Current; QT Interval Duration; J-Point Elevation; J-Wave Syndromes; Atrial-Fibrillation; Common Variants; Ventricular-Fibrillation; Channel; Kv4.3; Mutations
ISSN (print) / ISBN 1547-5271
e-ISSN 1556-3871
Journal Heart Rhythm
Quellenangaben Volume: 9, Issue: 10, Pages: 1627-1634 Article Number: , Supplement: ,
Publisher Elsevier
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)
Institute of Epidemiology (EPI)
Institute of Biological and Medical Imaging (IBMI)
Institute of Human Genetics (IHG)
Institute of Genetic Epidemiology (IGE)
Research Unit Molecular Epidemiology (AME)