{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T02:53:01Z","timestamp":1792637581211,"version":"4.5.0"},"reference-count":57,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2020,7,28]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (\n                      <jats:italic>P<\/jats:italic>\n                      &lt;5\u00d710\n                      <jats:sup>\u22128<\/jats:sup>\n                      ) near\n                      <jats:italic>NOS1AP<\/jats:italic>\n                      ,\n                      <jats:italic>KCNQ1<\/jats:italic>\n                      , and\n                      <jats:italic>KLF12<\/jats:italic>\n                      , and 1 missense variant in\n                      <jats:italic>KCNE1<\/jats:italic>\n                      (p.Asp85Asn) at the suggestive threshold (\n                      <jats:italic>P<\/jats:italic>\n                      &lt;10\n                      <jats:sup>\u22126<\/jats:sup>\n                      ). Heritability analyses showed that \u224815% of variance in overall LQTS susceptibility was attributable to common genetic variation (\n                      <jats:italic>h2SNP<\/jats:italic>\n                      0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r\n                      <jats:sub>g<\/jats:sub>\n                      =0.40;\n                      <jats:italic>P<\/jats:italic>\n                      =3.2\u00d710\n                      <jats:sup>\u22123<\/jats:sup>\n                      ). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (\n                      <jats:italic>P<\/jats:italic>\n                      &lt;10\u221213), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.005).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.120.045956","type":"journal-article","created":{"date-parts":[[2020,5,20]],"date-time":"2020-05-20T05:00:36Z","timestamp":1589950836000},"page":"324-338","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":131,"title":["Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome"],"prefix":"10.1161","volume":"142","author":[{"given":"Najim","family":"Lahrouchi","sequence":"first","affiliation":[{"name":"Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (N.L., R.T., Y.M., P.G.P., L.B., R.W., N.H., H.L.T., A.A.W., C.R.B.)."},{"name":"Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafik","family":"Tadros","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (N.L., R.T., Y.M., P.G.P., L.B., R.W., N.H., H.L.T., A.A.W., C.R.B.)."},{"name":"Cardiovascular Genetics Center, Montreal Heart Institute and Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Canada (R.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lia","family":"Crotti","sequence":"additional","affiliation":[{"name":"Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)."},{"name":"Center for Cardiac Arrhythmias of Genetic Origin (L.C., F.D., P.J.S.), Istituto Auxologico Italiano, IRCCS, Milan, Italy."},{"name":"Laboratory of Cardiovascular Genetics (L.C., M.P., P.J.S.), Istituto Auxologico Italiano, IRCCS, Milan, Italy."},{"name":"Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital (L.C.), Istituto Auxologico Italiano, IRCCS, Milan, Italy."},{"name":"Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy (L.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Mizusawa","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (N.L., R.T., Y.M., P.G.P., L.B., R.W., N.H., H.L.T., A.A.W., C.R.B.)."},{"name":"Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter G.","family":"Postema","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (N.L., R.T., Y.M., P.G.P., L.B., R.W., N.H., H.L.T., A.A.W., C.R.B.)."},{"name":"Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leander","family":"Beekman","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (N.L., R.T., Y.M., P.G.P., L.B., R.W., N.H., H.L.T., A.A.W., C.R.B.)."},{"name":"Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roddy","family":"Walsh","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, The Netherlands (N.L., R.T., Y.M., P.G.P., L.B., R.W., N.H., H.L.T., A.A.W., C.R.B.)."},{"name":"Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanae","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan (K.H., S.O., H.I., M.H.)."},{"name":"Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui, Japan (K.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Barc","sequence":"additional","affiliation":[{"name":"Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)."},{"name":"L\u2019Institut du Thorax, INSERM, CNRS, UNIV Nantes, France (J.B., J.-J.S., J.-B.G., V.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marko","family":"Ernsting","sequence":"additional","affiliation":[{"name":"Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)."},{"name":"Institute for Genetics of Heart Diseases, Department of Cardiovascular Medicine, University Hospital Muenster, Germany (M.E., B.S., S.Z., E.S.-B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kari L.","family":"Turkowski","sequence":"additional","affiliation":[{"name":"Departments of Cardiovascular Medicine (Division of Heart Rhythm Services and the Windland Smith Rice Genetic Heart Rhythm Clinic), Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), and Molecular Pharmacology &amp; Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (K.L.T., D.J.T., J.M.B., M.J.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Mazzanti","sequence":"additional","affiliation":[{"name":"Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)."},{"name":"Molecular Cardiology, ICS Maugeri, IRCCS and Department of Molecular Medicine, University of Pavia, Italy (A.M., C.N., S.G.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britt M.","family":"Beckmann","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital of the Ludwig Maximilians University, Munich, Germany (B.M.B., M.M.-N., S.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Shimamoto","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan (K.S., W.S., T.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulla-Britt","family":"Diamant","sequence":"additional","affiliation":[{"name":"Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)."},{"name":"Department of Clinical Sciences, Unit of Paediatrics, Ume\u00e5 University, Sweden (U.-B.D., A.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanushi D.","family":"Wijeyeratne","sequence":"additional","affiliation":[{"name":"Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)."},{"name":"Molecular and Clinical Sciences Research Institute, St George\u2019s University of London and Cardiology Clinical Academic Group, St George\u2019s University Hospitals NHS Foundation Trust, United Kingdom (Y.D.W., A.A., E.R.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Kucho","sequence":"additional","affiliation":[{"name":"National Hospital Organization Kagoshima Medical Center, Japan (Y.K., M.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Robyns","sequence":"additional","affiliation":[{"name":"Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)."},{"name":"Department of Cardiovascular Diseases, University Hospitals Leuven, Belgium (T.R.)."},{"name":"Department of Cardiovascular Sciences, KU Leuven, Belgium (T.R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taisuke","family":"Ishikawa","sequence":"additional","affiliation":[{"name":"Omics Research Center, National Cerebral and Cardiovascular Center, Osaka, Japan (T.I.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Arbelo","sequence":"additional","affiliation":[{"name":"Cardiovascular Institute, Hospital Clinic de Barcelona, Universitat de Barcelona, Institut d\u2019Investigaci\u00f3 August Pi i Sunyer (IDIBAPS), and Centro de Investigacion Biomedica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain (E.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Christiansen","sequence":"additional","affiliation":[{"name":"Department of Congenital Disorders, Statens Serum Institute, Copenhagen, Denmark (M.C.)."},{"name":"The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Copenhagen, Denmark (M.C.)."},{"name":"Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, Denmark (M.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika","family":"Winbo","sequence":"additional","affiliation":[{"name":"Department of Physiology, The University of Auckland, New Zealand (A.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reza","family":"Jabbari","sequence":"additional","affiliation":[{"name":"Member of the European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart - ERN GUARD-Heart (N.L., L.C., Y.M., P.G.P., L.B., R.W., J.B., M.E., A.M., U.-B.D., Y.D.W., T.R., R.J., N.H., F.D., G.S.-B., I.D., A.L., C.N., J.-J.S., J.-B.G., J.T.-H., J.B., E.R.B., A.R., S.G.P., H.L.T., P.J.S., E.S.-B., V.P., A.A.W., C.R.B.)."},{"name":"The Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Denmark (R.J., P.E.W., J.T.-H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven A.","family":"Lubitz","sequence":"additional","affiliation":[{"name":"Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston (S.A.L., P.T.E.)."},{"name":"Cardiovascular Disease Initiative and Program in Medical and Population Genetics, Broad Institute, Cambridge, MA (S.A.L., P.T.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Steinfurt","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology I, Heart Center University of Freiburg, Medical Faculty, Germany (J.S., K.E.O.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boris","family":"Rudic","sequence":"additional","affiliation":[{"name":"Department of Medicine, University Medical Center Mannheim, and German Center for Cardiovascular Research (DZHK), Partner Site Heidelberg\/Mannheim, Germany (B.R., M.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart","family":"Loeys","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Antwerp University Hospital, Belgium (B.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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