Key result
Serum calcium concentrations showed no significant interaction with genetic variants for QT and JT intervals, suggesting these interactions do not explain the missing heritability of repolarization time.
Why the study?
Half of the heritability of ventricular repolarization time remains unexplained, and the authors hypothesized that serum calcium interactions with QT and JT variants could explain some of this missing heritability.
Does serum calcium interact with genetic variants to affect ventricular repolarization time (QT and JT intervals)?
Meta-Analysis (n=125,393)
Does serum calcium interact with genetic variants to affect ventricular repolarization time (QT and JT intervals)?
Serum calcium levels do not significantly interact with common genetic variants to explain the missing heritability of ventricular repolarization time (QT and JT intervals).
No evidence supports serum calcium–variant interactions on QT/JT; leaves open other contributors to repolarization heritability.
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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Young et al. (2024) conducted a meta-analysis in Ventricular repolarization time (QT and JT intervals) (n=125,393). Serum calcium concentration was evaluated on Interaction effect of serum calcium on QT and JT variant associations. Serum calcium concentrations showed no significant interaction with genetic variants for QT and JT intervals, suggesting these interactions do not explain the missing heritability of repolarization time.
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