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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)
Verlagsversion DOI PMC
Closed
Creative Commons Lizenzvertrag
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Ecg Intervals ; Calcium ; Gene‐lifestyle Interaction ; Genome‐wide Association Study ; Ventricular Repolarization; Aging Research; Association; Qt; Heart; Efficient; Intervals; Loci; Tool; Pharmacogenomics; Metaanalysis
Sprache englisch
Veröffentlichungsjahr 2024
HGF-Berichtsjahr 2024
e-ISSN 2047-9980
Zeitschrift Journal of the American Heart Association
Quellenangaben Band: 13, Heft: 17, Seiten: , Artikelnummer: e034760 Supplement: ,
Verlag Wiley
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Epidemiology (EPI)
Institute of Genetic Epidemiology (IGE)
POF Topic(s) 30202 - Environmental Health
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-504000-010
G-504100-001
G-504091-001
G-504090-001
Förderungen 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)
DOI 10.1161/JAHA.123.034760
WOS ID 001304211600046
Scopus ID 85216505655
PubMed ID 39206732
Erfassungsdatum 2024-10-14
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