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 (GWAS) to identify common genetic variants influencing ERP. METHODS:: We ascertained ERP based on electrocardiograms in three large community-based cohorts from Europe and the US: the Framingham Heart Study, the Health 2000 Study, and the KORA F4 Study. We analyzed GWAS 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=1x10(-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, eight single nucleotide polymorphisms reached p=1x10(-5): The most significant finding was intergenic rs11653989 (odds ratio 0.47; 95\% confidence interval 0.36-0.61; p=6.9x10(-9)). The most biologically relevant finding was intronic to KCND3: rs17029069 (odds ratio 1.46; 95\% confidence interval 1.25-1.69; p=8.5x10(-7)). In the replication step (7151 individuals), none of the eight variants replicated, and combined meta-analysis results failed to reach genome-wide significance. CONCLUSIONS:: In a GWAS, 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.
A Meta-Analysis of Genome-Wide Association Studies of the Electrocardiographic Early Repolarization Pattern.
GASPARINI, PAOLO;SINAGRA, GIANFRANCO;
2012-01-01
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 (GWAS) to identify common genetic variants influencing ERP. METHODS:: We ascertained ERP based on electrocardiograms in three large community-based cohorts from Europe and the US: the Framingham Heart Study, the Health 2000 Study, and the KORA F4 Study. We analyzed GWAS 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=1x10(-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, eight single nucleotide polymorphisms reached p=1x10(-5): The most significant finding was intergenic rs11653989 (odds ratio 0.47; 95\% confidence interval 0.36-0.61; p=6.9x10(-9)). The most biologically relevant finding was intronic to KCND3: rs17029069 (odds ratio 1.46; 95\% confidence interval 1.25-1.69; p=8.5x10(-7)). In the replication step (7151 individuals), none of the eight variants replicated, and combined meta-analysis results failed to reach genome-wide significance. CONCLUSIONS:: In a GWAS, 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.Pubblicazioni consigliate
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