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.

Overview publication

TitleGenome-Wide Interaction Analyses of Serum Calcium on Ventricular Repolarization Time in 125 393 Participants.
DateAugust 29th, 2024
Issue nameJournal of the American Heart Association
Issue number:e034760
DOI10.1161/JAHA.123.034760
PubMed39206732
AuthorsYoung WJ, van der Most PJ, Bartz TM, Bos MM, Biino G, Duong T, Foco L, Lominchar JT, Müller-Nurasyid M, Nardone GG, Pecori A, Ramirez J, Repetto L, Schramm K, Shen X, van Duijvenboden S, van Heemst D, Weiss S, Yao J, Benjamins JW, Alonso A, Spedicati B, Biggs ML, Brody JA, Dörr M, Fuchsberger C, Gögele M, Guo X, Ikram MA, Jukema JW, Kääb S, Kanters JK, Lin HJ, Linneberg A, Nauck M, Nolte IM, Pianigiani G, Santin A, Soliman EZ, Tesolin P, Vaccargiu S, Waldenberger M, van der Harst P, Verweij N, Arking DE, Concas MP, De Grandi A, Girotto G, Grarup N, Kavousi M, Mook-Kanamori DO, Navarro P, Orini M, Padmanabhan S, Pattaro C, Peters A, Pirastu M, Pramstaller PP, Heckbert SR, Sinner M, Snieder H, Völker U, Wilson JF, Gauderman WJ, Lambiase PD, Sotoodehnia N, Tinker A, Warren HR, Noordam R & Munroe PB
KeywordsECG intervals, calcium, gene‐lifestyle interaction, genome‐wide association study, ventricular repolarization
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