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Nat Commun. 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.

van Setten J1, Brody JA2, Jamshidi Y3, Swenson BR2,4, Butler AM5, Campbell H6, Del Greco FM7, Evans DS8, Gibson Q9, Gudbjartsson DF10,11, Kerr KF12, Krijthe BP13, Lyytikäinen LP14,15, Müller C16,17, Müller-Nurasyid M18,19,20,21, Nolte IM21, Padmanabhan S22, Ritchie MD23, Robino A24, Smith AV25,26,27, Steri M28, Tanaka T29, Teumer A30,31, Trompet S32,33, Ulivi S24, Verweij N34, Yin X35, Arnar DO10,26,36, Asselbergs FW37,38,39,40, Bader JS41, Barnard J42, Bis J16,17, Blankenberg S17,18, Boerwinkle E43, Bradford Y23, Buckley BM44, Chung MK45,46, Crawford D47, den Hoed M48,49, Denny JC50, Dominiczak AF22, Ehret GB51, Eijgelsheim M13,52, Ellinor PT53,54,55, Felix SB31,56, Franco OH13, Franke L57, Harris TB58, Holm H10, Ilaria G59, Iorio A60, Kähönen M61,62, Kolcic I63, Kors JA64, Lakatta EG65, Launer LJ58, Lin H35, Lin HJ66, Loos RJF67,68, Lubitz SA53,54,55, Macfarlane PW69, Magnani JW70, Leach IM34, Meitinger T20,71,72, Mitchell BD73, Munzel T74,75,76, Papanicolaou GJ77, Peters A20,78,79, Pfeufer A80, Pramstaller PP7,81, Raitakari OT82,83, Rotter JI84, Rudan I6, Samani NJ85,86, Schlessinger D87, Silva Aldana CT88,89, Sinner MF19,20, Smith JD45,90, Snieder H21, Soliman EZ91, Spector TD92, Stott DJ22, Strauch K18,93, Tarasov KV65, Thorsteinsdottir U10,26, Uitterlinden AG94, Van Wagoner DR45,46, Völker U31,95, Völzke H30,31, Waldenberger M20,78,96, Jan Westra H57, Wild PS75,76,97,98, Zeller T16,17, Alonso A99, Avery CL100, Bandinelli S101, Benjamin EJ38, Cucca F28, Dörr M31,56, Ferrucci L29, Gasparini P24,59, Gudnason V25,26, Hayward C102, Heckbert SR103, Hicks AA7, Jukema JW32,104,105, Kääb S19,20, Lehtimäki T14,15, Liu Y106, Munroe PB107,108, Parsa A109, Polasek O63,110,111, Psaty BM112,113, Roden DM114, Schnabel RB16,17, Sinagra G60, Stefansson K10,26, Stricker BH13,94,115, van der Harst P34,116,117, van Duijn CM88, Wilson JF6,102, Gharib SA118, de Bakker PIW119,120, Isaacs A121,122,123, Arking DE124, Sotoodehnia N125.

Author information

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.

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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