Genome‐Wide Interaction Analyses of Serum Calcium on Ventricular Repolarization Time in 125 393 Participants
Authors: Young William J. , van der Most Peter J. , Bartz Traci M. , Bos Maxime M. , Biino Ginevra , Duong ThuyVy , Foco Luisa , Lominchar Jesus T. , Müller‐Nurasyid Martina , Nardone Giuseppe Giovanni , Pecori Alessandro , Ramirez Julia , Repetto Linda , Schramm Katharina , Shen Xia , van Duijvenboden Stefan , van Heemst Diana , Weiss Stefan , Yao Jie , Benjamins Jan‐Walter , Alonso Alvaro , Spedicati Beatrice , Biggs Mary L. , Brody Jennifer A. , Dörr Marcus , Fuchsberger Christian , Gögele Martin , Guo Xiuqing , Ikram M. Arfan , Jukema J. Wouter , Kääb Stefan , Kanters Jørgen K. ,   Lifelines Cohort Study, Lin Henry J. , Linneberg Allan , Nauck Matthias , Nolte Ilja M. , Pianigiani Giulia , Santin Aurora , Soliman Elsayed Z. , Tesolin Paola , Vaccargiu Simona , Waldenberger Melanie , van der Harst Pim , Verweij Niek , Arking Dan E. , Concas Maria Pina , De Grandi Alessandro , Girotto Giorgia , Grarup Niels , Kavousi Maryam , Mook‐Kanamori Dennis O. , Navarro Pau , Orini Michele , Padmanabhan Sandosh , Pattaro Cristian , Peters Annette , Pirastu Mario , Pramstaller Peter P. , Heckbert Susan R. , Sinner Mortiz , Snieder Harold , Völker Uwe , Wilson James F. , Gauderman W. James , Lambiase Pier D. , Sotoodehnia Nona , Tinker Andrew , Warren Helen R. , Noordam Raymond , Munroe Patricia B. 
Published: August 2024

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.