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Young, W.J.* ; van der Most, P.J.* ; Bartz, T.M.* ; Bos, M.M.* ; Biino, G.* ; Duong, T.* ; Foco, L.* ; Lominchar, J.T.* ; Müller-Nurasyid, M. ; Nardone, G.G.* ; Pecori, A.* ; Ramirez, J.* ; Repetto, L.* ; Schramm, K. ; Shen, X.* ; Van Duijvenboden, S.* ; van Heemst, D.* ; Weiss, S.* ; Yao, J.* ; Benjamins, J.W.* ; Alonso, A.* ; Spedicati, B.* ; Biggs, M.L.* ; Brody, J.A.* ; Dörr, M.* ; Fuchsberger, C.* ; Gögele, M.* ; Guo, X.* ; Ikram, M.A.* ; Jukema, J.W.* ; Kääb, S.* ; Kanters, J.K.* ; Lin, H.J.* ; Linneberg, A.* ; Nauck, M.* ; Nolte, I.M.* ; Pianigiani, G.* ; Santin, A.* ; Soliman, E.Z.* ; Tesolin, P.* ; Vaccargiu, S.* ; Waldenberger, M. ; van der Harst, P.* ; Verweij, N.* ; Arking, D.E.* ; Concas, M.P.* ; de Grandi, A.* ; Girotto, G.* ; Grarup, N.* ; Kavousi, M.* ; Mook-Kanamori, D.O.* ; Navarro, P.* ; Orini, M.* ; Padmanabhan, S.* ; Pattaro, C.* ; Peters, A. ; Pirastu, M.* ; Pramstaller, P.P.* ; Heckbert, S.R.* ; Sinner, M.* ; Snieder, H.* ; Völker, U.* ; Wilson, J.F.* ; Gauderman, W.J.* ; Lambiase, P.D.* ; Sotoodehnia, N.* ; Tinker, A.* ; Warren, H.R.* ; Noordam, R.* ; Munroe, P.B.*

Genome-wide interaction analyses of serum calcium on ventricular repolarization time in 125 393 participants.

J. Am. Heart Assoc. 13:e034760 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Ecg Intervals ; Calcium ; Gene‐lifestyle Interaction ; Genome‐wide Association Study ; Ventricular Repolarization; Aging Research; Association; Qt; Heart; Efficient; Intervals; Loci; Tool; Pharmacogenomics; Metaanalysis
e-ISSN 2047-9980
Journal Journal of the American Heart Association
Quellenangaben Volume: 13, Issue: 17, Pages: , Article Number: e034760 Supplement: ,
Publisher Wiley
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology II (EPI2)
Institute of Genetic Epidemiology (IGE)
Grants National Institutes of Health CHARGE infrastructure grant
National Institute for Health and Care Research Integrated Academic Training program
Novo Nordisk Foundation
Dutch Science Organization (ZonMW-VENI)
Medical Research Council Human Genetics Unit program grant, "Quantitative traits in health and disease"
Swedish Research Council Starting Grant
National Natural Science Foundation of China
National Insititutes of Health
American Heart Association
John and Cookie Laughlin Family
University College London Hospital Biomedicine National Institute for Health and Care Research
National Institute for Health and Care Research (Barts Biomedical Research Centre)
European Union from the European Union "NextGenerationEU/PRTR"
MCIN/AEI
Medical Research Council (MRC)