Genome-wide interaction analyses of serum calcium on ventricular repolarization time in 125393 participants
Young, William J. ; van der Most, Peter J. ; Bartz, Traci M. ; Bos, Maxime M. ; Biino, Ginevra ; Duong, ThuyVy ; Foco, Luisa ; Lominchar, Jesus T. ; Müller-Nurasyid, Martina ; Nardone, Giuseppe Giovanni ; Pecori, Alessandro ; Ramirez, Julia (Universidad de Zaragoza) ; Repetto, Linda ; Schramm, Katharina ; Shen, Xia ; van Duijvenboden, Stefan ; van Heemst, Diana ; Weiss, Stefan ; Yao, Jie ; Benjamins, Jan-Walter ; Alonso, Alvaro ; Spedicati, Beatrice ; Biggs, Mary L. ; Brody, Jennifer A. ; Dörr, Marcus ; Fuchsberger, Christian ; Gögele, Martin ; Guo, Xiuqing ; Ikram, M. Arfan ; Jukema, J. Wouter ; Kääb, Stefan ; Kanters, Jørgen K. ; Lin, Henry J. ; Linneberg, Allan ; Nauck, Matthias ; Nolte, Ilja M. ; Pianigiani, Giulia ; Santin, Aurora ; Soliman, Elsayed Z. ; Tesolin, Paola ; Vaccargiu, Simona ; Waldenberger, Melanie ; van der Harst, Pim ; Verweij, Niek ; Arking, Dan E. ; Concas, Maria Pina ; De Grandi, Alessandro ; Girotto, Giorgia ; Grarup, Niels ; Kavousi, Maryam ; Mook-Kanamori, Dennis O. ; Navarro, Pau ; Orini, Michele ; Padmanabhan, Sandosh ; Pattaro, Cristian ; Peters, Annette ; Pirastu, Mario ; Pramstaller, Peter P. ; Heckbert, Susan R. ; Sinner, Mortiz ; Snieder, Harold ; Völker, Uwe ; Wilson, James F. ; Gauderman, W. James ; Lambiase, Pier D. ; Sotoodehnia, Nona ; Tinker, Andrew ; Warren, Helen R. ; Noordam, Raymond ; Munroe, Patricia B.
Resumen: Background
Ventricular repolarization time (ECG QT and JT intervals) is associated with malignant arrhythmia. Genome‐wide association studies have identified 230 independent loci for QT and JT; however, 50% of their heritability remains unexplained. Previous work supports a causal effect of lower serum calcium concentrations on longer ventricular repolarization time. We hypothesized calcium interactions with QT and JT variant associations could explain a proportion of the missing heritability.
Methods and Results
We performed genome‐wide calcium interaction analyses for QT and JT intervals. Participants were stratified by their calcium level relative to the study distribution (top or bottom 20%). We performed a 2‐stage analysis (genome‐wide discovery [N=62 532] and replication [N=59 861] of lead variants) and a single‐stage genome‐wide meta‐analysis (N=122 393, [European ancestry N=117 581, African ancestry N=4812]). We also calculated 2‐degrees of freedom joint main and interaction and 1‐degree of freedom interaction P values. In 2‐stage and single‐stage analyses, 50 and 98 independent loci, respectively, were associated with either QT or JT intervals (2‐degrees of freedom joint main and interaction P value <5×10−8). No lead variant had a significant interaction result after correcting for multiple testing and sensitivity analyses provided similar findings. Two loci in the single‐stage meta‐analysis were not reported previously (SPPL2B and RFX6).
Conclusions
We have found limited support for an interaction effect of serum calcium on QT and JT variant associations despite sample sizes with suitable power to detect relevant effects. Therefore, such effects are unlikely to explain a meaningful proportion of the heritability of QT and JT, and factors including rare variation and other environmental interactions need to be considered.
Idioma: Inglés
DOI: 10.1161/JAHA.123.034760
Año: 2024
Publicado en: Journal of the American Heart Association. Cardiovascular and cerebrovascular disease 13, 17 (2024), e034760. 16 pp.]
ISSN: 2047-9980
Factor impacto JCR: 5.3 (2024)
Categ. JCR: CARDIAC & CARDIOVASCULAR SYSTEMS rank: 41 / 230 = 0.178 (2024) - Q1 - T1
Factor impacto CITESCORE: 8.5 - Cardiology and Cardiovascular Medicine (Q1)
Factor impacto SCIMAGO: 2.189 - Cardiology and Cardiovascular Medicine (Q1)
Financiación: info:eu-repo/grantAgreement/ES/AEI/PID2021-128972OA-I00
Financiación: info:eu-repo/grantAgreement/EC/H2020/786833/EU/GENetics and the Electrocardiogram for predicting Scd rISk/GENESIS
Tipo y forma: Artículo (Versión definitiva)
Área (Departamento): Área Teoría Señal y Comunicac. (Dpto. Ingeniería Electrón.Com.)
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Exportado de SIDERAL (2026-01-12-13:14:33)
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Ventricular repolarization time (ECG QT and JT intervals) is associated with malignant arrhythmia. Genome‐wide association studies have identified 230 independent loci for QT and JT; however, 50% of their heritability remains unexplained. Previous work supports a causal effect of lower serum calcium concentrations on longer ventricular repolarization time. We hypothesized calcium interactions with QT and JT variant associations could explain a proportion of the missing heritability.
Methods and Results
We performed genome‐wide calcium interaction analyses for QT and JT intervals. Participants were stratified by their calcium level relative to the study distribution (top or bottom 20%). We performed a 2‐stage analysis (genome‐wide discovery [N=62 532] and replication [N=59 861] of lead variants) and a single‐stage genome‐wide meta‐analysis (N=122 393, [European ancestry N=117 581, African ancestry N=4812]). We also calculated 2‐degrees of freedom joint main and interaction and 1‐degree of freedom interaction P values. In 2‐stage and single‐stage analyses, 50 and 98 independent loci, respectively, were associated with either QT or JT intervals (2‐degrees of freedom joint main and interaction P value <5×10−8). No lead variant had a significant interaction result after correcting for multiple testing and sensitivity analyses provided similar findings. Two loci in the single‐stage meta‐analysis were not reported previously (SPPL2B and RFX6).
Conclusions
We have found limited support for an interaction effect of serum calcium on QT and JT variant associations despite sample sizes with suitable power to detect relevant effects. Therefore, such effects are unlikely to explain a meaningful proportion of the heritability of QT and JT, and factors including rare variation and other environmental interactions need to be considered.
Idioma: Inglés
DOI: 10.1161/JAHA.123.034760
Año: 2024
Publicado en: Journal of the American Heart Association. Cardiovascular and cerebrovascular disease 13, 17 (2024), e034760. 16 pp.]
ISSN: 2047-9980
Factor impacto JCR: 5.3 (2024)
Categ. JCR: CARDIAC & CARDIOVASCULAR SYSTEMS rank: 41 / 230 = 0.178 (2024) - Q1 - T1
Factor impacto CITESCORE: 8.5 - Cardiology and Cardiovascular Medicine (Q1)
Factor impacto SCIMAGO: 2.189 - Cardiology and Cardiovascular Medicine (Q1)
Financiación: info:eu-repo/grantAgreement/ES/AEI/PID2021-128972OA-I00
Financiación: info:eu-repo/grantAgreement/EC/H2020/786833/EU/GENetics and the Electrocardiogram for predicting Scd rISk/GENESIS
Tipo y forma: Artículo (Versión definitiva)
Área (Departamento): Área Teoría Señal y Comunicac. (Dpto. Ingeniería Electrón.Com.)
Debe reconocer adecuadamente la autoría, proporcionar un enlace a la licencia e indicar si se han realizado cambios. Puede hacerlo de cualquier manera razonable, pero no de una manera que sugiera que tiene el apoyo del licenciador o lo recibe por el uso que hace. No puede utilizar el material para una finalidad comercial. Si remezcla, transforma o crea a partir del material, no puede difundir el material modificado.Exportado de SIDERAL (2026-01-12-13:14:33)
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Registro creado el 2024-09-26, última modificación el 2026-01-12