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Nat Genet. 2014 Aug;46(8):826-36. doi: 10.1038/ng.3014. Epub 2014 Jun 22.

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

Arking DE1, Pulit SL2, Crotti L3, van der Harst P4, Munroe PB5, Koopmann TT6, Sotoodehnia N7, Rossin EJ8, Morley M9, Wang X10, Johnson AD11, Lundby A12, Gudbjartsson DF13, Noseworthy PA14, Eijgelsheim M15, Bradford Y16, Tarasov KV17, Dörr M18, Müller-Nurasyid M19, Lahtinen AM20, Nolte IM21, Smith AV22, Bis JC23, Isaacs A24, Newhouse SJ25, Evans DS26, Post WS27, Waggott D28, Lyytikäinen LP29, Hicks AA30, Eisele L31, Ellinghaus D32, Hayward C33, Navarro P33, Ulivi S34, Tanaka T35, Tester DJ36, Chatel S37, Gustafsson S38, Kumari M39, Morris RW40, Naluai ÅT41, Padmanabhan S42, Kluttig A43, Strohmer B44, Panayiotou AG45, Torres M46, Knoflach M47, Hubacek JA48, Slowikowski K49, Raychaudhuri S50, Kumar RD51, Harris TB52, Launer LJ52, Shuldiner AR53, Alonso A54, Bader JS55, Ehret G56, Huang H8, Kao WH57, Strait JB58, Macfarlane PW59, Brown M60, Caulfield MJ25, Samani NJ61, Kronenberg F62, Willeit J47; CARe Consortium; COGENT Consortium, Smith JG63, Greiser KH64, Meyer Zu Schwabedissen H65, Werdan K66, Carella M67, Zelante L67, Heckbert SR68, Psaty BM69, Rotter JI70, Kolcic I71, Polašek O71, Wright AF33, Griffin M72, Daly MJ73; DCCT/EDIC, Arnar DO74, Hólm H13, Thorsteinsdottir U13; eMERGE Consortium, Denny JC75, Roden DM76, Zuvich RL16, Emilsson V77, Plump AS78, Larson MG79, O'Donnell CJ80, Yin X81, Bobbo M82, D'Adamo AP83, Iorio A82, Sinagra G82, Carracedo A84, Cummings SR26, Nalls MA85, Jula A86, Kontula KK87, Marjamaa A20, Oikarinen L88, Perola M89, Porthan K88, Erbel R90, Hoffmann P91, Jöckel KH31, Kälsch H90, Nöthen MM92; HRGEN Consortium, den Hoed M93, Loos RJ94, Thelle DS95, Gieger C96, Meitinger T97, Perz S98, Peters A99, Prucha H100, Sinner MF101, Waldenberger M102, de Boer RA103, Franke L104, van der Vleuten PA4, Beckmann BM101, Martens E105, Bardai A6, Hofman N106, Wilde AA107, Behr ER108, Dalageorgou C109, Giudicessi JR110, Medeiros-Domingo A110, Barc J111, Kyndt F37, Probst V37, Ghidoni A112, Insolia R112, Hamilton RM113, Scherer SW114, Brandimarto J9, Margulies K9, Moravec CE9, del Greco M F30, Fuchsberger C115, O'Connell JR116, Lee WK42, Watt GC117, Campbell H118, Wild SH118, El Mokhtari NE119, Frey N120, Asselbergs FW121, Mateo Leach I103, Navis G122, van den Berg MP103, van Veldhuisen DJ103, Kellis M123, Krijthe BP124, Franco OH124, Hofman A124, Kors JA125, Uitterlinden AG126, Witteman JC124, Kedenko L127, Lamina C62, Oostra BA15, Abecasis GR115, Lakatta EG17, Mulas A128, Orrú M128, Schlessinger D129, Uda M128, Markus MR130, Völker U131, Snieder H21, Spector TD132, Ärnlöv J133, Lind L134, Sundström J134, Syvänen AC135, Kivimaki M39, Kähönen M136, Mononen N29, Raitakari OT137, Viikari JS138, Adamkova V48, Kiechl S47, Brion M139, Nicolaides AN140, Paulweber B127, Haerting J43, Dominiczak AF42, Nyberg F141, Whincup PH142, Hingorani AD39, Schott JJ37, Bezzina CR6, Ingelsson E143, Ferrucci L35, Gasparini P83, Wilson JF118, Rudan I118, Franke A32, Mühleisen TW144, Pramstaller PP145, Lehtimäki TJ29, Paterson AD146, Parsa A116, Liu Y147, van Duijn CM15, Siscovick DS148, Gudnason V22, Jamshidi Y149, Salomaa V86, Felix SB18, Sanna S128, Ritchie MD150, Stricker BH151, Stefansson K152, Boyer LA153, Cappola TP9, Olsen JV154, Lage K155, Schwartz PJ156, Kääb S157, Chakravarti A56, Ackerman MJ158, Pfeufer A159, de Bakker PI160, Newton-Cheh C161.

Author information

1
1] Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2].
2
1] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [3] Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. [4].
3
1] Department of Molecular Medicine, Section of Cardiology, University of Pavia, Pavia, Italy. [2] Center for Cardiac Arrhythmias of Genetic Origin, Istituto di Ricerca e Cura a Carattere Scientifico Istituto Auxologico Italiano, Milan, Italy. [3] Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
4
1] Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. [2] Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
5
1] Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK. [2] Barts and the London Genome Centre, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK.
6
Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands.
7
1] Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA. [2] Cardiology Division, University of Washington, Seattle, Washington, USA.
8
1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Harvard Medical School, Boston, Massachusetts, USA.
9
Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
10
1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. [3] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
11
National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts, USA.
12
1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. [3] The Danish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Copenhagen, Denmark.
13
deCODE genetics, Reykjavik, Iceland.
14
1] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [3] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
15
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
16
Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
17
Laboratory of Cardiovascular Sciences, Human Cardiovascular Studies Unit, National Institute on Aging, US National Institutes of Health, Baltimore, Maryland, USA.
18
1] Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany. [2] DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.
19
1] Department of Medicine I, University Hospital Munich, Ludwig Maximilians Universität, Munich, Germany. [2] Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig Maximilians Universität, Munich, Germany. [3] Institute of Genetic Epidemiology, Helmholtz Zentrum Munich-German Research Center for Environmental Health, Neuherberg, Germany. [4] Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig Maximilians Universität, Munich, Germany. [5] DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
20
1] Research Programs Unit, Molecular Medicine, University of Helsinki, Helsinki, Finland. [2] Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
21
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
22
1] Icelandic Heart Association, Kopavogur, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
23
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
24
Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
25
Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK.
26
California Pacific Medical Center Research Institute, San Francisco, California, USA.
27
1] Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Department of Epidemiology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, USA.
28
Informatics and Biocomputing Platform, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
29
Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere, Finland.
30
Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy (affiliated institute of the University of Lübeck, Lübeck, Germany).
31
Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.
32
Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
33
Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
34
Institute for Maternal and Child Health, "Burlo Garofolo" Trieste, Trieste, Italy.
35
Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland, USA.
36
1] Department of Pediatrics, Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota, USA. [2] Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
37
1] Institut du Thorax, Centre Hospitalier Universitaire de Nantes, Université de Nantes, Nantes, France. [2] Institut du Thorax, INSERM UMR1087, CNRS UMR 6291, Université de Nantes, Nantes, France.
38
1] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. [2] Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
39
Institute of Cardiovascular Science, University College London, London, UK.
40
Department of Primary Care and Population Health, University College London, Royal Free Campus, London, UK.
41
1] Department of Medical and Clinical Genetics, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. [2] Biobanking and Molecular Resource Infrastructure of Sweden (BBMRI), Gothenburg, Sweden.
42
BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
43
Institute of Medical Epidemiology, Biostatistics and Informatics, Martin Luther University Halle-Wittenberg, Halle, Germany.
44
Second Department of Internal Medicine, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria.
45
1] Cyprus International Institute for Environmental and Public Health in association with the Harvard School of Public Health, Cyprus University of Technology, Limassol, Cyprus. [2] Cyprus Cardiovascular and Educational Research Trust, Nicosia, Cyprus.
46
Grupo de Medicina Xenómica, Centro Nacional de Genotipado, Centro de Investigación Biomédica en Red de Enfermedades Raras, Universidade de Santiago de Compostela, Santiago de Compostela, Spain.
47
Department of Neurology, Innsbruck Medical University, Innsbruck, Austria.
48
Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
49
1] Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [2] Harvard Bioinformatics and Integrative Genomics, Boston, Massachusetts, USA.
50
1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. [3] Partners HealthCare Center for Personalized Genetic Medicine, Boston, Massachusetts, USA. [4] Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA. [5] Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
51
1] Computational and Systems Biology Program, Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, Missouri, USA. [2] Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri, USA.
52
Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, Bethesda, Maryland, USA.
53
1] Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA. [2] Program for Personalized and Genomic Medicine, University of Maryland, Baltimore, Maryland, USA. [3] Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland, USA.
54
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.
55
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
56
Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
57
Department of Epidemiology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, USA.
58
1] Laboratory of Cardiovascular Sciences, Human Cardiovascular Studies Unit, National Institute on Aging, US National Institutes of Health, Baltimore, Maryland, USA. [2] Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland, USA.
59
Electrocardiology, University of Glasgow Institute of Cardiovascular and Medical Sciences, Royal Infirmary, Glasgow, UK.
60
Clinical Pharmacology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
61
Department of Cardiovascular Science, University of Leicester, Glenfield Hospital, Leicester, UK.
62
Division of Genetic Epidemiology, Innsbruck Medical University, Innsbruck, Austria.
63
1] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [3] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [4] Department of Cardiology, Lund University, Lund, Sweden.
64
1] Institute of Medical Epidemiology, Biostatistics and Informatics, Martin Luther University Halle-Wittenberg, Halle, Germany. [2] Division of Cancer Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
65
Department of Pharmacology, Ernst Moritz Arndt University of Greifswald, Greifswald, Germany.
66
Department of Medicine III, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle, Germany.
67
Medical Genetics Unit, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
68
1] Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA. [2] Department of Epidemiology, University of Washington, Seattle, Washington, USA.
69
1] Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA. [2] Department of Epidemiology, University of Washington, Seattle, Washington, USA. [3] Department of Health Services, University of Washington, Seattle, Washington, USA. [4] Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA. [5] Department of Medicine, University of Washington, Seattle, Washington, USA.
70
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles (UCLA) Medical Center, Torrance, California, USA.
71
Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia.
72
Vascular Screening and Diagnostic Centre, London, UK.
73
1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
74
Department of Medicine, Division of Cardiology, Landspitali University Hospital, Reykjavik, Iceland.
75
1] Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. [2] Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
76
1] Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. [2] Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA. [3] Office of Personalized Medicine, Vanderbilt University, Nashville, Tennessee, USA.
77
Icelandic Heart Association, Kopavogur, Iceland.
78
Sanofi Research and Development, Paris, France.
79
1] National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts, USA. [2] Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA. [3] Department of Mathematics and Statistics, Boston University, Boston, Massachusetts, USA.
80
1] National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts, USA. [2] Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, USA.
81
1] National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts, USA. [2] Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
82
Cardiovascular Department, Ospedali Riuniti and University of Trieste, Trieste, Italy.
83
1] Institute for Maternal and Child Health, "Burlo Garofolo" Trieste, Trieste, Italy. [2] Clinical Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
84
1] Grupo de Medicina Xenómica, Centro Nacional de Genotipado, Centro de Investigación Biomédica en Red de Enfermedades Raras, Universidade de Santiago de Compostela, Santiago de Compostela, Spain. [2] Fundación Publica Galega de Medicina Xenómica, Servicio Galego de Saude, Santiago de Compostela, Spain. [3] Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.
85
Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.
86
Chronic Disease Epidemiology and Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.
87
Department of Medicine, University of Helsinki, Helsinki, Finland.
88
Department of Medicine, Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
89
1] Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland. [2] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. [3] Estonian Genome Center, University of Tartu, Tartu, Estonia.
90
Department of Cardiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.
91
1] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany. [2] Institute of Human Genetics, University of Bonn, Bonn, Germany. [3] Division of Medical Genetics, University Hospital Basel, Basel, Switzerland. [4] Department of Biomedicine, University of Basel, Basel, Switzerland.
92
1] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany. [2] Institute of Human Genetics, University of Bonn, Bonn, Germany.
93
1] Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. [2] MRC Epidemiology Unit, University of Cambridge, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
94
1] MRC Epidemiology Unit, University of Cambridge, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK. [2] Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [3] Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
95
1] Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. [2] Department of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
96
Institute of Genetic Epidemiology, Helmholtz Zentrum Munich-German Research Center for Environmental Health, Neuherberg, Germany.
97
1] DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany. [2] Institute of Human Genetics, Technische Universität München, Munich, Germany. [3] Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
98
Institute for Biological and Medical Imaging, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
99
1] DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany. [2] Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
100
1] Christine Kühne-Center for Allergy and Education, Munich, Germany. [2] Department of Dermatology and Allergy, Technische Universität München, Munich, Germany.
101
Department of Medicine I, University Hospital Munich, Ludwig Maximilians Universität, Munich, Germany.
102
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
103
Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
104
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
105
1] Department of Medicine I, University Hospital Munich, Ludwig Maximilians Universität, Munich, Germany. [2] Department of Medicine, Hospital of Friedberg, Friedberg, Germany.
106
Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
107
1] Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands. [2] Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Saudi Arabia.
108
Cardiovascular and Cell Sciences Institute, St George's University of London, London, UK.
109
Biomedical Sciences, St George's University of London, London, UK.
110
Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
111
Institut du Thorax, INSERM UMR1087, CNRS UMR 6291, Université de Nantes, Nantes, France.
112
1] Department of Molecular Medicine, Section of Cardiology, University of Pavia, Pavia, Italy. [2] Center for Cardiac Arrhythmias of Genetic Origin, Istituto di Ricerca e Cura a Carattere Scientifico Istituto Auxologico Italiano, Milan, Italy.
113
1] The Labatt Family Heart Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
114
The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
115
Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
116
1] Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA. [2] Program for Personalized and Genomic Medicine, University of Maryland, Baltimore, Maryland, USA.
117
General Practice and Primary Care, University of Glasgow, Glasgow, UK.
118
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
119
Biobank PopGen, Institute of Experimental Medicine, Christian Albrechts University of Kiel, Kiel, Germany.
120
Department of Internal Medicine III, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.
121
1] Durrer Center for Cardiogenetic Research, Interuniversity Cardiology Institute of The Netherlands-Netherlands Heart Institute, Utrecht, The Netherlands. [2] Department of Cardiology, Division of Heart and Lungs, University Medical Centre Utrecht, Utrecht, The Netherlands. [3] Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK.
122
Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
123
1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
124
1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. [2] Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands.
125
Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands.
126
1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. [2] Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands. [3] Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
127
First Department of Internal Medicine, Paracelsus Medical University/Salzburger Landeskliniken, Salzburg, Austria.
128
Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, Cagliari, Italy.
129
Laboratory of Genetics, Intramural Research Program, National Institute on Aging, US National Institutes of Health, Baltimore, Maryland, USA.
130
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
131
1] DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany. [2] Interfaculty Institute for Genetics and Functional Genomics, Ernst Moritz Arndt University Greifswald, Greifswald, Germany.
132
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
133
1] Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. [2] School of Health and Social Sciences, Dalarna University, Falun, Sweden.
134
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
135
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
136
Department of Clinical Physiology, Tampere University Hospital and University of Tampere School of Medicine, Tampere, Finland.
137
1] Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland. [2] Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
138
Department of Medicine, Turku University Hospital and University of Turku, Turku, Finland.
139
1] Grupo de Medicina Xenómica, Centro Nacional de Genotipado, Centro de Investigación Biomédica en Red de Enfermedades Raras, Universidade de Santiago de Compostela, Santiago de Compostela, Spain. [2] Xenética de Enfermidades Cardiovasculares e Oftalmolóxicas, Complexo Hospitalario Universitario de Santiago de Compostela, Servicio Galego de Saude, Santiago de Compostela, Spain.
140
1] Cyprus Cardiovascular and Educational Research Trust, Nicosia, Cyprus. [2] Vascular Screening and Diagnostic Centre, London, UK.
141
1] Department of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. [2] Global Epidemiology, AstraZeneca Research and Development, Mölndal, Sweden.
142
Division of Population Health Sciences and Education, St George's University of London, London, UK.
143
1] Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. [2] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
144
1] Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany. [2] Institute of Human Genetics, University of Bonn, Bonn, Germany. [3] Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organization of the Brain, Genomic Imaging, Research Centre Juelich, Juelich, Germany.
145
1] Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy (affiliated institute of the University of Lübeck, Lübeck, Germany). [2] Department of Neurology, University of Lübeck, Lübeck, Germany. [3] Department of Neurology, General Central Hospital, Bolzano, Italy.
146
Genetics and Genome Biology Program, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
147
Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, North Carolina, USA.
148
1] Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA. [2] Department of Epidemiology, University of Washington, Seattle, Washington, USA. [3] Department of Medicine, University of Washington, Seattle, Washington, USA.
149
Human Genetics Research Centre, St George's University of London, London, UK.
150
Center for Systems Genomics, Pennsylvania State University, University Park, Pennsylvania, USA.
151
1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. [2] Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands. [3] Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands. [4] Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. [5] Inspectorate of Health Care, The Hague, The Netherlands.
152
1] deCODE genetics, Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
153
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
154
Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
155
1] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. [3] Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. [4] Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark. [5] Pediatric Surgical Research Laboratories, MassGeneral Hospital for Children, Massachusetts General Hospital, Boston, Massachusetts, USA.
156
Center for Cardiac Arrhythmias of Genetic Origin, Istituto di Ricerca e Cura a Carattere Scientifico Istituto Auxologico Italiano, Milan, Italy.
157
1] Department of Medicine I, University Hospital Munich, Ludwig Maximilians Universität, Munich, Germany. [2] DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
158
1] Department of Pediatrics, Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota, USA. [2] Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA. [3] Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA. [4].
159
1] Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy (affiliated institute of the University of Lübeck, Lübeck, Germany). [2] Institute of Human Genetics, Technische Universität München, Munich, Germany. [3] Institute for Bioinformatics and Systems Biology, Helmholtz Zentrum, Munich, Germany. [4].
160
1] Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands. [2] Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. [3].
161
1] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [3] Harvard Medical School, Boston, Massachusetts, USA. [4] Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA. [5].

Abstract

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

PMID:
24952745
PMCID:
PMC4124521
DOI:
10.1038/ng.3014
[Indexed for MEDLINE]
Free PMC Article

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