{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T01:51:23Z","timestamp":1769737883225,"version":"3.49.0"},"reference-count":57,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"17","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2024,9,3]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Ventricular repolarization time (ECG QT and JT intervals) is associated with malignant arrhythmia. Genome\u2010wide 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      We performed genome\u2010wide 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\u2010stage analysis (genome\u2010wide discovery [N=62\u2009532] and replication [N=59\u2009861] of lead variants) and a single\u2010stage genome\u2010wide meta\u2010analysis (N=122\u2009393, [European ancestry N=117\u2009581, African ancestry N=4812]). We also calculated 2\u2010degrees of freedom joint main and interaction and 1\u2010degree of freedom interaction\n                      <jats:italic toggle=\"no\">P<\/jats:italic>\n                      values. In 2\u2010stage and single\u2010stage analyses, 50 and 98 independent loci, respectively, were associated with either QT or JT intervals (2\u2010degrees of freedom joint main and interaction\n                      <jats:italic toggle=\"no\">P<\/jats:italic>\n                      value &lt;5\u00d710\n                      <jats:sup>\u22128<\/jats:sup>\n                      ). No lead variant had a significant interaction result after correcting for multiple testing and sensitivity analyses provided similar findings. Two loci in the single\u2010stage meta\u2010analysis were not reported previously (\n                      <jats:italic toggle=\"no\">SPPL2B<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"no\">RFX6<\/jats:italic>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">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\u00a0including rare variation and other environmental interactions need to be considered.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.123.034760","type":"journal-article","created":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T06:32:12Z","timestamp":1724913132000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Genome\u2010Wide Interaction Analyses of Serum Calcium on Ventricular Repolarization Time in 125\u2009393 Participants"],"prefix":"10.1161","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9831-6817","authenticated-orcid":false,"given":"William J.","family":"Young","sequence":"first","affiliation":[{"name":"William Harvey Research Institute, Queen Mary University of London","place":["United Kingdom"]},{"name":"St Bartholomew\u2019s Hospital, Barts Health NHS Trust","place":["London, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8450-3518","authenticated-orcid":false,"given":"Peter J.","family":"van der Most","sequence":"additional","affiliation":[{"name":"University of Groningen, University Medical Center Groningen","place":["Groningen, The Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3403-8763","authenticated-orcid":false,"given":"Traci M.","family":"Bartz","sequence":"additional","affiliation":[{"name":"University of Washington","place":["Seattle, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5028-4820","authenticated-orcid":false,"given":"Maxime M.","family":"Bos","sequence":"additional","affiliation":[{"name":"Erasmus MC University Medical Center","place":["Rotterdam, Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9936-946X","authenticated-orcid":false,"given":"Ginevra","family":"Biino","sequence":"additional","affiliation":[{"name":"Institute of Molecular Genetics, National Research Council of Italy","place":["Pavia, Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9733-440X","authenticated-orcid":false,"given":"ThuyVy","family":"Duong","sequence":"additional","affiliation":[{"name":"McKusick\u2010Nathans Institute, Johns Hopkins University School of Medicine","place":["Baltimore, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6694-3322","authenticated-orcid":false,"given":"Luisa","family":"Foco","sequence":"additional","affiliation":[{"name":"Institute for Biomedicine (Affiliated with the University of L\u00fcbeck)","place":["Bolzano, 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