| Title: | Genome-Wide Interaction Analyses of Serum Calcium on Ventricular Repolarization Time in 125 393 Participants |
| Journal: | Journal of the American Heart Association |
| Published: | 29 Aug 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39206732/ |
| DOI: | https://doi.org/10.1161/jaha.123.034760 |
| URL: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646519 |
Publication 13650
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Abstract
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.</p>
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).</p>
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.</p>
11 Keywords
- Action Potentials
- Arrhythmias, Cardiac
- Calcium
- Electrocardiography
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Heart Rate
- Humans
- Polymorphism, Single Nucleotide
- Risk Factors
- Time Factors
71 Authors
- William J. Young
- Peter J. van der Most
- Traci M. Bartz
- Maxime M. Bos
- Ginevra Biino
- ThuyVy Duong
- Luisa Foco
- Jesus T. Lominchar
- Martina Müller-Nurasyid
- Giuseppe Giovanni Nardone
- Alessandro Pecori
- Julia Ramirez
- Linda Repetto
- Katharina Schramm
- Xia Shen
- Stefan van Duijvenboden
- Diana van Heemst
- Stefan Weiss
- Jie Yao
- Jan-Walter Benjamins
- Alvaro Alonso
- Beatrice Spedicati
- Mary L. Biggs
- Jennifer A. Brody
- Marcus Dörr
- Christian Fuchsberger
- Martin Gögele
- Xiuqing Guo
- M. Arfan Ikram
- J. Wouter Jukema
- Stefan Kääb
- Jørgen K. Kanters
- Lifelines Cohort Study
- Henry J. Lin
- Allan Linneberg
- Matthias Nauck
- Ilja M. Nolte
- Giulia Pianigiani
- Aurora Santin
- Elsayed Z. Soliman
- Paola Tesolin
- Simona Vaccargiu
- Melanie Waldenberger
- Pim van der Harst
- Niek Verweij
- Dan E. Arking
- Maria Pina Concas
- Alessandro De Grandi
- Giorgia Girotto
- Niels Grarup
- Maryam Kavousi
- Dennis O. Mook-Kanamori
- Pau Navarro
- Michele Orini
- Sandosh Padmanabhan
- Cristian Pattaro
- Annette Peters
- Mario Pirastu
- Peter P. Pramstaller
- Susan R. Heckbert
- Mortiz Sinner
- Harold Snieder
- Uwe Völker
- James F. Wilson
- W. James Gauderman
- Pier D. Lambiase
- Nona Sotoodehnia
- Andrew Tinker
- Helen R. Warren
- Raymond Noordam
- Patricia B. Munroe
1 Application
| Application ID | Title |
|---|---|
| 8256 | Understanding genetic influences in the response of the cardiac electrical system to exercise |
Enabling scientific discoveries that improve human health