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

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

Research output: Contribution to journalArticle

37 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)1627-1634
Number of pages8
JournalHeart Rhythm
Volume9
Issue number10
DOIs
Publication statusPublished - Oct 2012

Fingerprint

Genome-Wide Association Study
Meta-Analysis
Odds Ratio
Genome
Confidence Intervals
Genetic Models
Sudden Cardiac Death
Computer Simulation
Single Nucleotide Polymorphism
Electrocardiography
Logistic Models
Phenotype
Mutation
Health
Population

Keywords

  • Arrhythmia
  • Early repolarization
  • Electrocardiogram
  • GWAS
  • Meta-analysis
  • Sudden cardiac death

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Sinner, M. F., Porthan, K., Noseworthy, P. A., Havulinna, A. S., Tikkanen, J. T., Müller-Nurasyid, M., ... Salomaa, V. (2012). A meta-analysis of genome-wide association studies of the electrocardiographic early repolarization pattern. Heart Rhythm, 9(10), 1627-1634. https://doi.org/10.1016/j.hrthm.2012.06.008

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

In: Heart Rhythm, Vol. 9, No. 10, 10.2012, p. 1627-1634.

Research output: Contribution to journalArticle

Sinner, MF, Porthan, K, Noseworthy, PA, Havulinna, AS, Tikkanen, JT, Müller-Nurasyid, M, Peloso, G, Ulivi, S, Beckmann, BM, Brockhaus, AC, Cooper, RR, Gasparini, P, Hengstenberg, C, Hwang, SJ, Iorio, A, Junttila, MJ, Klopp, N, Kähönen, M, Laaksonen, MA, Lehtimäki, T, Lichtner, P, Lyytikäinen, LP, Martens, E, Meisinger, C, Meitinger, T, Merchant, FM, Nieminen, MS, Peters, A, Pietilä, A, Perz, S, Oikarinen, L, Raitakari, O, Reinhard, W, Silander, K, Thorand, B, Wichmann, HE, Sinagra, G, Viikari, J, O'Donnell, CJ, Ellinor, PT, Huikuri, HV, Kääb, S, Newton-Cheh, C & Salomaa, V 2012, 'A meta-analysis of genome-wide association studies of the electrocardiographic early repolarization pattern', Heart Rhythm, vol. 9, no. 10, pp. 1627-1634. https://doi.org/10.1016/j.hrthm.2012.06.008
Sinner MF, Porthan K, Noseworthy PA, Havulinna AS, Tikkanen JT, Müller-Nurasyid M et al. A meta-analysis of genome-wide association studies of the electrocardiographic early repolarization pattern. Heart Rhythm. 2012 Oct;9(10):1627-1634. https://doi.org/10.1016/j.hrthm.2012.06.008
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. / A meta-analysis of genome-wide association studies of the electrocardiographic early repolarization pattern. In: Heart Rhythm. 2012 ; Vol. 9, No. 10. pp. 1627-1634.
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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 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.",
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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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