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