Journal
HEART RHYTHM
Volume 9, Issue 10, Pages 1627-1634Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.hrthm.2012.06.008
Keywords
Early repolarization; Sudden cardiac death; Arrhythmia; GWAS; Meta-analysis; Electrocardiogram
Categories
Funding
- German Heart Foundation
- Finnish Foundation for Cardiovascular Research
- Orion-Farmos Research Foundation
- Max Schaldach Fellowship in Cardiac Pacing and Electrophysiology
- National Institutes of Health [RO1HL092577, 5R21DA027021, 1RO1HL104156, 1K24HL10578]
- German National Genome Research Network NGFN-Plus [01GS0838]
- German Federal Ministry for Education and Research (BMBF)/French Agence National de la Recherche (ANR) [SCD-Gene: 01KU0907]
- BMBF cluster of excellence personalized medicine M4
- National Institutes of Health
- Burroughs Wellcome Fund
- Academy of Finland [129494, 139635, 134309, 126925, 121584, 124282, 129378, 117787, 41071]
- Affymetrix, Inc [N02-HL-6-4278]
- Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine
- Boston Medical Center
- NHLBI Division of Intramural Research
- National Institute for Health and Welfare
- Finnish Centre for Pensions
- Social Insurance Institution of Finland
- Local Government Pensions Institution
- Wellcome Trust Sanger Institute
- BMBF
- state of Bavaria
- BMBF in the context of NGFN plus [01GS0838]
- LMU Excellence Initiative
- Munich Center of Health Sciences (MC Health) as part of LMUinnovativ
- Social Insurance Institution of Finland, Kuopio, Tampere
- Turku University Hospital Medical Funds [9M048, 9N035]
- Juho Vainio Foundation
- Paavo Nurmi Foundation
- Finnish Foundation of Cardiovascular Research
- Finnish Cultural Foundation
- Tampere Tuberculosis Foundation
- Emil Aaltonen Foundation
- project of Genetic Park of FVG
- Regione FVG [L.26.2008]
- Associazione Amici del Cuore
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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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