TY - JOUR
T1 - A meta-analysis of genome-wide association studies of the electrocardiographic early repolarization pattern
AU - Sinner, Moritz F.
AU - Porthan, Kimmo
AU - Noseworthy, Peter A.
AU - Havulinna, Aki S.
AU - Tikkanen, Jani T.
AU - Müller-Nurasyid, Martina
AU - Peloso, Gina
AU - Ulivi, Sheila
AU - Beckmann, Britt Maria
AU - Brockhaus, A. Catharina
AU - Cooper, Rebecca R.
AU - Gasparini, Paolo
AU - Hengstenberg, Christian
AU - Hwang, Shih Jen
AU - Iorio, Annamaria
AU - Junttila, M. Juhani
AU - Klopp, Norman
AU - Kähönen, Mika
AU - Laaksonen, Maarit A.
AU - Lehtimäki, Terho
AU - Lichtner, Peter
AU - Lyytikäinen, Leo Pekka
AU - Martens, Eimo
AU - Meisinger, Christa
AU - Meitinger, Thomas
AU - Merchant, Faisal M.
AU - Nieminen, Markku S.
AU - Peters, Annette
AU - Pietilä, Arto
AU - Perz, Siegfried
AU - Oikarinen, Lasse
AU - Raitakari, Olli
AU - Reinhard, Wibke
AU - Silander, Kaisa
AU - Thorand, Barbara
AU - Wichmann, H. Erich
AU - Sinagra, Gianfranco
AU - Viikari, Jorma
AU - O'Donnell, Christopher J.
AU - Ellinor, Patrick T.
AU - Huikuri, Heikki V.
AU - Kääb, Stefan
AU - Newton-Cheh, Christopher
AU - Salomaa, Veikko
PY - 2012/10
Y1 - 2012/10
N2 - 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.
AB - 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.
KW - Arrhythmia
KW - Early repolarization
KW - Electrocardiogram
KW - GWAS
KW - Meta-analysis
KW - Sudden cardiac death
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UR - http://www.scopus.com/inward/citedby.url?scp=84866740007&partnerID=8YFLogxK
U2 - 10.1016/j.hrthm.2012.06.008
DO - 10.1016/j.hrthm.2012.06.008
M3 - Article
C2 - 22683750
AN - SCOPUS:84866740007
SN - 1547-5271
VL - 9
SP - 1627
EP - 1634
JO - Heart rhythm
JF - Heart rhythm
IS - 10
ER -