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Meta-Analysis
. 2024 Sep 3;13(17):e034760.
doi: 10.1161/JAHA.123.034760. Epub 2024 Aug 29.

Genome-Wide Interaction Analyses of Serum Calcium on Ventricular Repolarization Time in 125 393 Participants

William J Young  1   2 , Peter J van der Most  3 , Traci M Bartz  4 , Maxime M Bos  5 , Ginevra Biino  6 , ThuyVy Duong  7 , Luisa Foco  8 , Jesus T Lominchar  9 , Martina Müller-Nurasyid  10   11   12 , Giuseppe Giovanni Nardone  13 , Alessandro Pecori  14 , Julia Ramirez  1   15   16 , Linda Repetto  17 , Katharina Schramm  10   11   12 , Xia Shen  17   18   19 , Stefan van Duijvenboden  1   20   21 , Diana van Heemst  22 , Stefan Weiss  23   24 , Jie Yao  25 , Jan-Walter Benjamins  26 , Alvaro Alonso  27 , Beatrice Spedicati  13 , Mary L Biggs  28   29 , Jennifer A Brody  28 , Marcus Dörr  23   30 , Christian Fuchsberger  8   31   32 , Martin Gögele  8 , Xiuqing Guo  33   34 , M Arfan Ikram  5 , J Wouter Jukema  35   36 , Stefan Kääb  37   38 , Jørgen K Kanters  39 ; Lifelines Cohort Study  40 ; Henry J Lin  25   34   41 , Allan Linneberg  42   43 , Matthias Nauck  23   44 , Ilja M Nolte  3 , Giulia Pianigiani  14 , Aurora Santin  13 , Elsayed Z Soliman  45 , Paola Tesolin  14 , Simona Vaccargiu  46 , Melanie Waldenberger  38   47 , Pim van der Harst  26   48 , Niek Verweij  26 , Dan E Arking  7 , Maria Pina Concas  14 , Alessandro De Grandi  8 , Giorgia Girotto  13 , Niels Grarup  9 , Maryam Kavousi  5 , Dennis O Mook-Kanamori  49   50 , Pau Navarro  51 , Michele Orini  2   20 , Sandosh Padmanabhan  52 , Cristian Pattaro  8 , Annette Peters  10   11   38 , Mario Pirastu  53 , Peter P Pramstaller  8   54 , Susan R Heckbert  28   55 , Mortiz Sinner  37   38 , Harold Snieder  3 , Uwe Völker  23   24 , James F Wilson  17   51 , W James Gauderman  56 , Pier D Lambiase  2   20 , Nona Sotoodehnia  57 , Andrew Tinker  1   58 , Helen R Warren  1   58 , Raymond Noordam  22 , Patricia B Munroe  1   58
Affiliations
Meta-Analysis

Genome-Wide Interaction Analyses of Serum Calcium on Ventricular Repolarization Time in 125 393 Participants

William J Young et al. J Am Heart Assoc. .

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.

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.

Keywords: ECG intervals; calcium; gene‐lifestyle interaction; genome‐wide association study; ventricular repolarization.

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Figures

Figure 1
Figure 1. Overview of the primary analysis performed in this study.
AF indicates allele frequency; df, degrees of freedom; GWAS, genome‐wide association study; MAC, minor allele count; MAF, minor allele frequency; N, number; P INT, interaction effect P value; P JOINT, joint (main and interaction effect) P value; and SNV, single nucleotide variant.
Figure 2
Figure 2. Overview of the single‐stage all cohorts interaction analysis and subsequent sensitivity analyses.
GWAS indicates genome‐wide association study; N, number; P INT, interaction effect P value; P JOINT, joint (main and interaction effect) P value; SNV, single nucleotide variant; and UKB, UK Biobank study.
Figure 3
Figure 3. Comparison of main effect beta estimates between exposed and unexposed groups in low or high calcium serum concentrations for QT and JT.
Correlation plots comparing replicated lead variant main effect estimates between “unexposed” (x‐axis) and “exposed” (y‐axis) groups using values from the combined discovery and replication meta‐analysis. Main effect estimates are plotted in milliseconds along with 95% CIs. Cor indicates Pearson correlation coefficient. Points in red indicate those with a 1‐degree of freedom interaction P value <0.05.
Figure 4
Figure 4. Manhattan plot for each single‐stage SNV‐by‐calcium interaction analysis 1‐df joint P values.
Joint 1‐degree of freedom P values from the single‐stage all cohorts genome‐wide high calcium‐SNV interaction meta‐analysis for the QT interval. (A) QT high calcium, (B) QT low calcium, (C) JT high calcium, (D) JT low calcium. Study‐level linear regression summary statistics for exposed (top or bottom 20% of serum calcium distribution) and unexposed (top or bottom 80% of serum calcium distribution) were meta‐analyzed separately before calculation of joint (main and interaction) effect P values. Variants within the boundaries of previously reported loci for QT and JT are highlighted in green. y axis: log P values, x axis: chromosome and base pair position (hg19). df indicates degrees of freedom; and SNV, single nucleotide variant.
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References

    1. Wong CX, Brown A, Lau DH, Chugh SS, Albert CM, Kalman JM, Sanders P. Epidemiology of sudden cardiac death: global and regional perspectives. Heart Lung Circ. 2019;28:6–14. doi: 10.1016/j.hlc.2018.08.026 - DOI - PubMed
    1. Srinivasan NT, Schilling RJ. Sudden cardiac death and arrhythmias. Arrhythmia Electrophysiol Rev. 2018;7:111–117. doi: 10.15420/aer.2018:15:2 - DOI - PMC - PubMed
    1. Zulqarnain MA, Qureshi WT, O'Neal WT, Shah AJ, Soliman EZ. Risk of mortality associated with QT and JT intervals at different levels of QRS duration (from the third National Health and nutrition examination survey). Am J Cardiol. 2015;116:74–78. doi: 10.1016/j.amjcard.2015.03.038 - DOI - PMC - PubMed
    1. Young WJ, Lahrouchi N, Isaacs A, Duong T, Foco L, Ahmed F, Brody JA, Salman R, Noordam R, Benjamins JW, et al. Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways. Nat Commun. 2022;13:5144. doi: 10.1038/s41467-022-32821-z - DOI - PMC - PubMed
    1. Noordam R, Young WJ, Salman R, Kanters JK, van den Berg ME, van Heemst D, Lin HJ, Barreto SM, Biggs ML, Biino G, et al. Effects of calcium, magnesium, and potassium concentrations on ventricular repolarization in unselected individuals. J Am Coll Cardiol. 2019;73:3118–3131. doi: 10.1016/j.jacc.2019.03.519 - DOI - PubMed

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