Meta-Analysis

. 2018 Jul 25;9(1):2904.

doi: 10.1038/s41467-018-04766-9.

PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Jessica van Setten¹, Jennifer A Brody², Yalda Jamshidi³, Brenton R Swenson^{2

4}, Anne M Butler⁵, Harry Campbell⁶, Fabiola M Del Greco⁷, Daniel S Evans⁸, Quince Gibson⁹, Daniel F Gudbjartsson^{10

11}, Kathleen F Kerr¹², Bouwe P Krijthe¹³, Leo-Pekka Lyytikäinen^{14

15}, Christian Müller^{16

17}, Martina Müller-Nurasyid^{18

19

20

21}, Ilja M Nolte²¹, Sandosh Padmanabhan²², Marylyn D Ritchie²³, Antonietta Robino²⁴, Albert V Smith^{25

26

27}, Maristella Steri²⁸, Toshiko Tanaka²⁹, Alexander Teumer^{30

31}, Stella Trompet^{32

33}, Sheila Ulivi²⁴, Niek Verweij³⁴, Xiaoyan Yin³⁵, David O Arnar^{10

26

36}, Folkert W Asselbergs^{37

38

39

40}, Joel S Bader⁴¹, John Barnard⁴², Josh Bis^{16

17}, Stefan Blankenberg^{17

18}, Eric Boerwinkle⁴³, Yuki Bradford²³, Brendan M Buckley⁴⁴, Mina K Chung^{45

46}, Dana Crawford⁴⁷, Marcel den Hoed^{48

49}, Josh C Denny⁵⁰, Anna F Dominiczak²², Georg B Ehret⁵¹, Mark Eijgelsheim^{13

52}, Patrick T Ellinor^{53

54

55}, Stephan B Felix^{31

56}, Oscar H Franco¹³, Lude Franke⁵⁷, Tamara B Harris⁵⁸, Hilma Holm¹⁰, Gandin Ilaria⁵⁹, Annamaria Iorio⁶⁰, Mika Kähönen^{61

62}, Ivana Kolcic⁶³, Jan A Kors⁶⁴, Edward G Lakatta⁶⁵, Lenore J Launer⁵⁸, Honghuang Lin³⁵, Henry J Lin⁶⁶, Ruth J F Loos^{67

68}, Steven A Lubitz^{53

54

55}, Peter W Macfarlane⁶⁹, Jared W Magnani⁷⁰, Irene Mateo Leach³⁴, Thomas Meitinger^{20

71

72}, Braxton D Mitchell⁷³, Thomas Munzel^{74

75

76}, George J Papanicolaou⁷⁷, Annette Peters^{20

78

79}, Arne Pfeufer⁸⁰, Peter P Pramstaller^{7

81}, Olli T Raitakari^{82

83}, Jerome I Rotter⁸⁴, Igor Rudan⁶, Nilesh J Samani^{85

86}, David Schlessinger⁸⁷, Claudia T Silva Aldana^{88

89}, Moritz F Sinner^{19

20}, Jonathan D Smith^{45

90}, Harold Snieder²¹, Elsayed Z Soliman⁹¹, Timothy D Spector⁹², David J Stott²², Konstantin Strauch^{18

93}, Kirill V Tarasov⁶⁵, Unnur Thorsteinsdottir^{10

26}, Andre G Uitterlinden⁹⁴, David R Van Wagoner^{45

46}, Uwe Völker^{31

95}, Henry Völzke^{30

31}, Melanie Waldenberger^{20

78

96}, Harm Jan Westra⁵⁷, Philipp S Wild^{75

76

97

98}, Tanja Zeller^{16

17}, Alvaro Alonso⁹⁹, Christy L Avery¹⁰⁰, Stefania Bandinelli¹⁰¹, Emelia J Benjamin³⁸, Francesco Cucca²⁸, Marcus Dörr^{31

56}, Luigi Ferrucci²⁹, Paolo Gasparini^{24

59}, Vilmundur Gudnason^{25

26}, Caroline Hayward¹⁰², Susan R Heckbert¹⁰³, Andrew A Hicks⁷, J Wouter Jukema^{32

104

105}, Stefan Kääb^{19

20}, Terho Lehtimäki^{14

15}, Yongmei Liu¹⁰⁶, Patricia B Munroe^{107

108}, Afshin Parsa¹⁰⁹, Ozren Polasek^{63

110

111}, Bruce M Psaty^{112

113}, Dan M Roden¹¹⁴, Renate B Schnabel^{16

17}, Gianfranco Sinagra⁶⁰, Kari Stefansson^{10

26}, Bruno H Stricker^{13

94

115}, Pim van der Harst^{34

116

117}, Cornelia M van Duijn⁸⁸, James F Wilson^{6

102}, Sina A Gharib¹¹⁸, Paul I W de Bakker^{119

120}, Aaron Isaacs^{121

122

123}, Dan E Arking¹²⁴, Nona Sotoodehnia¹²⁵

Affiliations

¹ Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, 3584CX, The Netherlands. J.vanSetten@umcutrecht.nl.
² Department of Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, 98195, WA, USA.
³ Cardiogenetics Lab, Molecular and Clinical Sciences Research Institute, St George's University of London, London, SW17 0RE, UK.
⁴ Institute for Public Health Genetics, School of Public Health, University of Washington, Seattle, 98195, WA, USA.
⁵ Division of Infectious Diseases, Washington University School of Medicine, St. Louis, 63110, MO, USA.
⁶ Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, EH8 9YL, UK.
⁷ Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, 39100, Italy.
⁸ California Pacific Medical Center Research Institute, San Francisco, 94107, CA, USA.
⁹ Department of Surgery, University of Alabama Birmingham Hospital, Birmingham, 35233, AL, USA.
¹⁰ deCODE genetics/Amgen, Inc., Reykjavik, IS-101, Iceland.
¹¹ School of Engineering and Natural Sciences, University of Iceland, Reykjavik, 101, Iceland.
¹² Department of Biostatistics, School of Public Health, University of Washington, Seattle, 98195, WA, USA.
¹³ Department of Epidemiology, Erasmus Medical Center, Rotterdam, 3015GD, The Netherlands.
¹⁴ Department of Clinical Chemistry, Fimlab Laboratories, Tampere, 33520, Finland.
¹⁵ Department of Clinical Chemistry, Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, 33014, Finland.
¹⁶ Department of General and Interventional Cardiology, University Heart Center Hamburg-Eppendorf, Hamburg, 20251, Germany.
¹⁷ DZHK (German Center for Cardiovascular Research) Partner Site, Hamburg/Kiel/Lübeck, Germany.
¹⁸ Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, D-85764, Germany.
¹⁹ Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University (LMU) Munich, Munich, 81377, Germany.
²⁰ DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, 80802, Germany.
²¹ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, 9713GZ, The Netherlands.
²² Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, Scotland, UK.
²³ Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, PA, USA.
²⁴ Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste, 34137, Italy.
²⁵ Icelandic Heart Association, Kopavogur, IS-201, Iceland.
²⁶ Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland.
²⁷ Department of Biostatistics, University of Michigan, Ann Arbor, 48109, MI, USA.
²⁸ Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, 00185, Cagliari, Italy.
²⁹ Translational Gerontology Branch, NIA, Baltimore, 20892, MD, USA.
³⁰ Institute for Community Medicine, University Medicine Greifswald, Greifswald, 17489, Germany.
³¹ DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, 17475, Greifswald, Germany.
³² Department of Cardiology, Leiden University Medical Center, Leiden, 2300RC, The Netherlands.
³³ Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, 2300RC, The Netherlands.
³⁴ Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, 7913GZ, The Netherlands.
³⁵ Department of Medicine, Boston University School of Medicine, Boston, 02118, MA, USA.
³⁶ Department of Medicine, Landspitali University Hospital, Reykjavik, 101, Iceland.
³⁷ Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, 3584CX, The Netherlands.
³⁸ Durrer Center for Cardiogenetic Research, Netherlands Heart Institute, Utrecht, The Netherlands.
³⁹ Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, WC1E 6BT, UK.
⁴⁰ Farr Institute of Health Informatics Research and Institute of Health Informatics, University College London, London, WC1E 6BT, London, United Kingdom.
⁴¹ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, 21218, MD, USA.
⁴² Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, 44195, OH, USA.
⁴³ Human Genetics Center, University of Texas Health Science Center at Houston, Houston, 77030, TX, USA.
⁴⁴ Department of Pharmacology and Therapeutics, University College Cork, Cork, T12 K8AF, Ireland.
⁴⁵ Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, 44195, OH, USA.
⁴⁶ Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, 44195, OH, USA.
⁴⁷ Institute for Computational Biology, Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, 44106, OH, USA.
⁴⁸ Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SE-751 05, Sweden.
⁴⁹ Science for Life Laboratory, Uppsala University, Uppsala, SE-751 05, Sweden.
⁵⁰ Biomedical Informatics and Medicine, Vanderbilt University, Nashville, 37235, TN, USA.
⁵¹ Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, 21287, MD, USA.
⁵² Department of Nephrology, University Medical Center Groningen, Groningen, 7913GZ, The Netherlands.
⁵³ Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, 02142, MA, USA.
⁵⁴ Cardiovascular Research Center, Massachusetts General Hospital, Boston, 02114, MA, USA.
⁵⁵ Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, 02114, MA, USA.
⁵⁶ Department of Internal Medicine B, University Medicine Greifswald, Greifswald, 17489, Germany.
⁵⁷ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, 7913GZ, The Netherlands.
⁵⁸ Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, 20892, MD, USA.
⁵⁹ Department of Medical Sciences, University of Trieste, Trieste, 34127, Italy.
⁶⁰ Cardiovascular Department, "Ospedali Riuniti and University of Trieste", Trieste, 34124, Italy.
⁶¹ Department of Clinical Physiology, Tampere University Hospital, Tampere, 33521, Finland.
⁶² Department of Clinical Physiology, Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, 33014, Finland.
⁶³ Faculty of Medicine, University of Split, Split, 21000, Croatia.
⁶⁴ Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, 3015GD, The Netherlands.
⁶⁵ Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, 20892, MD, USA.
⁶⁶ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, 90502, CA, USA.
⁶⁷ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
⁶⁸ The Mindich Child health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
⁶⁹ Institute of Health and Wellbeing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
⁷⁰ Department of Medicine, Division of Cardiology, University of Pittsburgh Medical Center Heart and Vascular Institute, University of Pittsburgh, Pittsburgh, 15260, PA, USA.
⁷¹ Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, 85764, Germany.
⁷² Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, 81675, Germany.
⁷³ Department of Medicine, University of Maryland School of Medicine, Geriatrics Research and Education Clinical Center, Baltimore VA Medical Center, Baltimore, 21201, MD, USA.
⁷⁴ Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, 55131, Germany.
⁷⁵ DZHK (German Center for Cardiovascular Research), Partner Site Rhine-Main, Mainz, 55131, Germany.
⁷⁶ Center for Translational Vascular Biology (CTVB), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, 55131, Germany.
⁷⁷ Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, NIH, Bethesda, 20892, MD, USA.
⁷⁸ Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, 85764, Germany.
⁷⁹ German Center for Diabetes Research, Neuherberg, 85764, Germany.
⁸⁰ MVZ für Molekulardiagnostik, Munich, 81543, Germany.
⁸¹ Department of Neurology, Central Hospital, Bolzano, 39100, Italy.
⁸² Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, 20521, Finland.
⁸³ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, 20014, Finland.
⁸⁴ Departments of Medicine and Pediatrics, The Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, 90502, CA, USA.
⁸⁵ Department of Cardiovascular Sciences, University of Leicester, Leicester, LE1 7RH, UK.
⁸⁶ NIHR Leicester Biomedical Research Centre, Leicester, LE3 9QD, UK.
⁸⁷ Laboratory of Genetics and Genomics, National Institute on Aging, National Institute of Health, Baltimore, 20892, MD, USA.
⁸⁸ Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3015GD, The Netherlands.
⁸⁹ Institute of Translational Medicine-IMT, Center For Research in Genetics and Genomics-CIGGUR, GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Cl. 12c #6-25, Colombia.
⁹⁰ Department of Cellular and Molecular Medicine Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, 44195, OH, USA.
⁹¹ Epidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston-Salem, 27101, NC, USA.
⁹² Department of Twin Research and Genetic Epidemiology, St Thomas Hospital, King's College London, London, WC2R 2LS, UK.
⁹³ Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Munich, 81377, Germany.
⁹⁴ Department of Internal Medicine, Erasmus Medical Center, Rotterdam, 3015GD, The Netherlands.
⁹⁵ Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, 17489, Germany.
⁹⁶ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, 85764, Germany.
⁹⁷ Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, 55131, Germany.
⁹⁸ Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, 55131, Germany.
⁹⁹ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, 30322, GA, USA.
¹⁰⁰ Department of Epidemiology and Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA.
¹⁰¹ Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, 50122, Italy.
¹⁰² Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH8 9YL, UK.
¹⁰³ Cardiovascular Health Research Unit and the Department of Epidemiology, University of Washington, Seattle, 98195, WA, USA.
¹⁰⁴ Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, 2300RC, The Netherlands.
¹⁰⁵ Interuniversity Cardiology Institute of the Netherlands, Utrecht, 3511EP, The Netherlands.
¹⁰⁶ Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, 27101, NC, USA.
¹⁰⁷ Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, E1 4NS, UK.
¹⁰⁸ NIHR Biomedical Research Centre at Barts, Barts Health NHS Trust and Queen Mary University of London, London, E1 4NS, UK.
¹⁰⁹ Department of Medicine, University of Maryland School of Medicine and Baltimore VA Medical Center, Baltimore, 21201, MD, USA.
¹¹⁰ Psychiatric hospital "Sveti Ivan", Zagreb, 10000, Croatia.
¹¹¹ Gen-info Ltd., Zagreb, 10000, Croatia.
¹¹² Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, 98195, WA, USA.
¹¹³ Kaiser Permanente Washington Health Research Institute, Seattle, 98101, WA, USA.
¹¹⁴ Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University, Nashville, 37235, TN, USA.
¹¹⁵ Inspectorate for Health Care, The Hague, 2511VX, The Netherlands.
¹¹⁶ University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, 7913GZ, The Netherlands.
¹¹⁷ Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, 3511EP, The Netherlands.
¹¹⁸ Cardiovascular Health Research Unit, Division of Pulmonary Critical Care and Sleep Medicine, Computational Medicine Core at Center for Lung Biology, Department of Medicine, University of Washington, Seattle, 98195, WA, USA.
¹¹⁹ Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, 3584CX, The Netherlands.
¹²⁰ Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, 3584CX, The Netherlands.
¹²¹ CARIM School for Cardiovascular Diseases, Maastricht, 6229ER, The Netherlands.
¹²² Center for Systems Biology (MaCSBio), Maastricht University, Maastricht, 6229ER, The Netherlands.
¹²³ Department of Biochemistry, Maastricht University, Maastricht, 6229ER, The Netherlands.
¹²⁴ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, 21287, MD, USA.
¹²⁵ Departments of Medicine and Epidemiology, Cardiovascular Health Research Unit, Division of Cardiology, University of Washington, Seattle, 98101, WA, USA. nsotoo@u.washington.edu.

PMID: 30046033
PMCID: PMC6060178
DOI: 10.1038/s41467-018-04766-9

Meta-Analysis

PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

Jessica van Setten et al. Nat Commun. 2018.

. 2018 Jul 25;9(1):2904.

doi: 10.1038/s41467-018-04766-9.

Authors

Affiliations

¹ Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, 3584CX, The Netherlands. J.vanSetten@umcutrecht.nl.
² Department of Medicine, Cardiovascular Health Research Unit, University of Washington, Seattle, 98195, WA, USA.
³ Cardiogenetics Lab, Molecular and Clinical Sciences Research Institute, St George's University of London, London, SW17 0RE, UK.
⁴ Institute for Public Health Genetics, School of Public Health, University of Washington, Seattle, 98195, WA, USA.
⁵ Division of Infectious Diseases, Washington University School of Medicine, St. Louis, 63110, MO, USA.
⁶ Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, EH8 9YL, UK.
⁷ Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, 39100, Italy.
⁸ California Pacific Medical Center Research Institute, San Francisco, 94107, CA, USA.
⁹ Department of Surgery, University of Alabama Birmingham Hospital, Birmingham, 35233, AL, USA.
¹⁰ deCODE genetics/Amgen, Inc., Reykjavik, IS-101, Iceland.
¹¹ School of Engineering and Natural Sciences, University of Iceland, Reykjavik, 101, Iceland.
¹² Department of Biostatistics, School of Public Health, University of Washington, Seattle, 98195, WA, USA.
¹³ Department of Epidemiology, Erasmus Medical Center, Rotterdam, 3015GD, The Netherlands.
¹⁴ Department of Clinical Chemistry, Fimlab Laboratories, Tampere, 33520, Finland.
¹⁵ Department of Clinical Chemistry, Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, 33014, Finland.
¹⁶ Department of General and Interventional Cardiology, University Heart Center Hamburg-Eppendorf, Hamburg, 20251, Germany.
¹⁷ DZHK (German Center for Cardiovascular Research) Partner Site, Hamburg/Kiel/Lübeck, Germany.
¹⁸ Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, D-85764, Germany.
¹⁹ Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University (LMU) Munich, Munich, 81377, Germany.
²⁰ DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, 80802, Germany.
²¹ Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, 9713GZ, The Netherlands.
²² Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, Scotland, UK.
²³ Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, PA, USA.
²⁴ Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste, 34137, Italy.
²⁵ Icelandic Heart Association, Kopavogur, IS-201, Iceland.
²⁶ Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland.
²⁷ Department of Biostatistics, University of Michigan, Ann Arbor, 48109, MI, USA.
²⁸ Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, 00185, Cagliari, Italy.
²⁹ Translational Gerontology Branch, NIA, Baltimore, 20892, MD, USA.
³⁰ Institute for Community Medicine, University Medicine Greifswald, Greifswald, 17489, Germany.
³¹ DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, 17475, Greifswald, Germany.
³² Department of Cardiology, Leiden University Medical Center, Leiden, 2300RC, The Netherlands.
³³ Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, 2300RC, The Netherlands.
³⁴ Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, 7913GZ, The Netherlands.
³⁵ Department of Medicine, Boston University School of Medicine, Boston, 02118, MA, USA.
³⁶ Department of Medicine, Landspitali University Hospital, Reykjavik, 101, Iceland.
³⁷ Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, 3584CX, The Netherlands.
³⁸ Durrer Center for Cardiogenetic Research, Netherlands Heart Institute, Utrecht, The Netherlands.
³⁹ Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, WC1E 6BT, UK.
⁴⁰ Farr Institute of Health Informatics Research and Institute of Health Informatics, University College London, London, WC1E 6BT, London, United Kingdom.
⁴¹ Department of Biomedical Engineering, Johns Hopkins University, Baltimore, 21218, MD, USA.
⁴² Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, 44195, OH, USA.
⁴³ Human Genetics Center, University of Texas Health Science Center at Houston, Houston, 77030, TX, USA.
⁴⁴ Department of Pharmacology and Therapeutics, University College Cork, Cork, T12 K8AF, Ireland.
⁴⁵ Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, 44195, OH, USA.
⁴⁶ Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, 44195, OH, USA.
⁴⁷ Institute for Computational Biology, Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, 44106, OH, USA.
⁴⁸ Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, SE-751 05, Sweden.
⁴⁹ Science for Life Laboratory, Uppsala University, Uppsala, SE-751 05, Sweden.
⁵⁰ Biomedical Informatics and Medicine, Vanderbilt University, Nashville, 37235, TN, USA.
⁵¹ Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, 21287, MD, USA.
⁵² Department of Nephrology, University Medical Center Groningen, Groningen, 7913GZ, The Netherlands.
⁵³ Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, 02142, MA, USA.
⁵⁴ Cardiovascular Research Center, Massachusetts General Hospital, Boston, 02114, MA, USA.
⁵⁵ Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, 02114, MA, USA.
⁵⁶ Department of Internal Medicine B, University Medicine Greifswald, Greifswald, 17489, Germany.
⁵⁷ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, 7913GZ, The Netherlands.
⁵⁸ Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, National Institutes of Health, Bethesda, 20892, MD, USA.
⁵⁹ Department of Medical Sciences, University of Trieste, Trieste, 34127, Italy.
⁶⁰ Cardiovascular Department, "Ospedali Riuniti and University of Trieste", Trieste, 34124, Italy.
⁶¹ Department of Clinical Physiology, Tampere University Hospital, Tampere, 33521, Finland.
⁶² Department of Clinical Physiology, Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, 33014, Finland.
⁶³ Faculty of Medicine, University of Split, Split, 21000, Croatia.
⁶⁴ Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, 3015GD, The Netherlands.
⁶⁵ Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, 20892, MD, USA.
⁶⁶ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, 90502, CA, USA.
⁶⁷ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
⁶⁸ The Mindich Child health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
⁶⁹ Institute of Health and Wellbeing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
⁷⁰ Department of Medicine, Division of Cardiology, University of Pittsburgh Medical Center Heart and Vascular Institute, University of Pittsburgh, Pittsburgh, 15260, PA, USA.
⁷¹ Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, 85764, Germany.
⁷² Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, 81675, Germany.
⁷³ Department of Medicine, University of Maryland School of Medicine, Geriatrics Research and Education Clinical Center, Baltimore VA Medical Center, Baltimore, 21201, MD, USA.
⁷⁴ Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, 55131, Germany.
⁷⁵ DZHK (German Center for Cardiovascular Research), Partner Site Rhine-Main, Mainz, 55131, Germany.
⁷⁶ Center for Translational Vascular Biology (CTVB), University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, 55131, Germany.
⁷⁷ Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, NIH, Bethesda, 20892, MD, USA.
⁷⁸ Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, 85764, Germany.
⁷⁹ German Center for Diabetes Research, Neuherberg, 85764, Germany.
⁸⁰ MVZ für Molekulardiagnostik, Munich, 81543, Germany.
⁸¹ Department of Neurology, Central Hospital, Bolzano, 39100, Italy.
⁸² Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, 20521, Finland.
⁸³ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, 20014, Finland.
⁸⁴ Departments of Medicine and Pediatrics, The Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, 90502, CA, USA.
⁸⁵ Department of Cardiovascular Sciences, University of Leicester, Leicester, LE1 7RH, UK.
⁸⁶ NIHR Leicester Biomedical Research Centre, Leicester, LE3 9QD, UK.
⁸⁷ Laboratory of Genetics and Genomics, National Institute on Aging, National Institute of Health, Baltimore, 20892, MD, USA.
⁸⁸ Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, 3015GD, The Netherlands.
⁸⁹ Institute of Translational Medicine-IMT, Center For Research in Genetics and Genomics-CIGGUR, GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Cl. 12c #6-25, Colombia.
⁹⁰ Department of Cellular and Molecular Medicine Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, 44195, OH, USA.
⁹¹ Epidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston-Salem, 27101, NC, USA.
⁹² Department of Twin Research and Genetic Epidemiology, St Thomas Hospital, King's College London, London, WC2R 2LS, UK.
⁹³ Chair of Genetic Epidemiology, IBE, Faculty of Medicine, LMU Munich, Munich, 81377, Germany.
⁹⁴ Department of Internal Medicine, Erasmus Medical Center, Rotterdam, 3015GD, The Netherlands.
⁹⁵ Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, 17489, Germany.
⁹⁶ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, 85764, Germany.
⁹⁷ Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, 55131, Germany.
⁹⁸ Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, 55131, Germany.
⁹⁹ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, 30322, GA, USA.
¹⁰⁰ Department of Epidemiology and Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA.
¹⁰¹ Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, 50122, Italy.
¹⁰² Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH8 9YL, UK.
¹⁰³ Cardiovascular Health Research Unit and the Department of Epidemiology, University of Washington, Seattle, 98195, WA, USA.
¹⁰⁴ Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, 2300RC, The Netherlands.
¹⁰⁵ Interuniversity Cardiology Institute of the Netherlands, Utrecht, 3511EP, The Netherlands.
¹⁰⁶ Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, 27101, NC, USA.
¹⁰⁷ Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, E1 4NS, UK.
¹⁰⁸ NIHR Biomedical Research Centre at Barts, Barts Health NHS Trust and Queen Mary University of London, London, E1 4NS, UK.
¹⁰⁹ Department of Medicine, University of Maryland School of Medicine and Baltimore VA Medical Center, Baltimore, 21201, MD, USA.
¹¹⁰ Psychiatric hospital "Sveti Ivan", Zagreb, 10000, Croatia.
¹¹¹ Gen-info Ltd., Zagreb, 10000, Croatia.
¹¹² Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, 98195, WA, USA.
¹¹³ Kaiser Permanente Washington Health Research Institute, Seattle, 98101, WA, USA.
¹¹⁴ Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University, Nashville, 37235, TN, USA.
¹¹⁵ Inspectorate for Health Care, The Hague, 2511VX, The Netherlands.
¹¹⁶ University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, 7913GZ, The Netherlands.
¹¹⁷ Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, 3511EP, The Netherlands.
¹¹⁸ Cardiovascular Health Research Unit, Division of Pulmonary Critical Care and Sleep Medicine, Computational Medicine Core at Center for Lung Biology, Department of Medicine, University of Washington, Seattle, 98195, WA, USA.
¹¹⁹ Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, 3584CX, The Netherlands.
¹²⁰ Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, 3584CX, The Netherlands.
¹²¹ CARIM School for Cardiovascular Diseases, Maastricht, 6229ER, The Netherlands.
¹²² Center for Systems Biology (MaCSBio), Maastricht University, Maastricht, 6229ER, The Netherlands.
¹²³ Department of Biochemistry, Maastricht University, Maastricht, 6229ER, The Netherlands.
¹²⁴ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, 21287, MD, USA.
¹²⁵ Departments of Medicine and Epidemiology, Cardiovascular Health Research Unit, Division of Cardiology, University of Washington, Seattle, 98101, WA, USA. nsotoo@u.washington.edu.

PMID: 30046033
PMCID: PMC6060178
DOI: 10.1038/s41467-018-04766-9

Abstract

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

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Conflict of interest statement

The authors declare no competing non-financial interests, but the following competing financial interests: Dr. de Bakker is currently an employee of and owns equity in Vertex Pharmaceuticals. Dr. Lubitz receives sponsored research support from Bristol Myers Squibb, Bayer HealthCare, Biotronik, and Boehringer Ingelheim, and has consulted for Abbott, Quest Diagnostics, Bristol Myers Squibb.Dr. Ellinor is the PI on a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics for cardiovascular diseases. Dr. Ellinor has served as a consultant to Novartis and Quest Diagnostics.Dr. Butler has received investigator-initiated grant support from Amgen and AstraZeneca for unrelated projects.All authors affiliated with deCODE genetics/Amgen, Inc. are employed by the company.

Figures

**Fig. 1**
Genome-wide results of PR interval in 92,340 individuals of European descent. 2.8 million SNPs were tested for association with PR interval in 31 cohorts. The Manhattan plot shows the meta-analysis association results: 44 independent loci (labeled) are associated at the genome-wide significance level of P ≤ 5 × 10⁻⁸, as marked by the dashed line

**Fig. 2**
Regional association plots of specific loci associated with PR interval. Each SNP is plotted with respect to its chromosomal location (x axis) and its P value (y axis on the left). The blue line indicates the recombination rate (y axis on the right) at that region of the chromosome. Blue outlined squares mark non-synonymous SNPs. Green triangles depict association results of the African Americans meta-analysis, only SNPs with P < 0.1 are shown. a Locus 2 and 3 (*SCN10A*–*SCN5A*) on chromosome 3. The index SNPs for the two genes are named with their rs-numbers and highlighted with two different colors (blue and red). Other SNPs in linkage disequilibrium with the index SNP are denoted in the same color; color saturation indicates the degree of correlation with the index SNP. b Locus 19 (*TTN*) on chromosome 2; and c Locus 9 and 10 (*TBX5*–*TBX3*) on chromosome 12

**Fig. 3**
Heatmap showing overlapping loci between four traits. For each locus associated with PR interval, we tested the strength of the association and direction of effect for three related traits: QRS duration, atrial fibrillation, and heart rate. While the genetic bases of these three traits show a distinct overlap with that of PR interval, we observe for each trait overlapping loci with both concordant and discordant associations, with some variants that prolong PR interval prolonging QRS duration or increasing heart rate (concordant associations), whereas others shorten QRS duration or decrease heart rate. Similarly, some variants that prolong PR interval increase AF risk (concordant association) while others decrease AF risk (discordant). Red color indicates concordant association with increasing PR associated with increasing QRS, or higher risk of AF, or higher HR. Blue color indicates discordant association of shortened QRS, or lower risk of AF, or lower HR. Intensity of color indicates significance of association: GWA (GWAS significant association), Bonf (Bonferroni corrected significance), Nom (nominal significance), NS (not significant)

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References

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PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

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PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity

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