Meta-Analysis

. 2020 May 21;11(1):2542.

doi: 10.1038/s41467-020-15706-x.

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

Ioanna Ntalla^#¹, Lu-Chen Weng^#^{2

3}, James H Cartwright¹, Amelia Weber Hall^{2

3}, Gardar Sveinbjornsson⁴, Nathan R Tucker^{2

3}, Seung Hoan Choi³, Mark D Chaffin³, Carolina Roselli^{3

5}, Michael R Barnes^{1

6}, Borbala Mifsud^{1

7}, Helen R Warren^{1

6}, Caroline Hayward⁸, Jonathan Marten⁸, James J Cranley¹, Maria Pina Concas⁹, Paolo Gasparini^{9

10}, Thibaud Boutin⁸, Ivana Kolcic¹¹, Ozren Polasek^{11

12

13}, Igor Rudan¹⁴, Nathalia M Araujo¹⁵, Maria Fernanda Lima-Costa¹⁶, Antonio Luiz P Ribeiro¹⁷, Renan P Souza¹⁵, Eduardo Tarazona-Santos¹⁵, Vilmantas Giedraitis¹⁸, Erik Ingelsson^{19

20

21

22}, Anubha Mahajan²³, Andrew P Morris^{23

24

25}, Fabiola Del Greco M²⁶, Luisa Foco²⁶, Martin Gögele²⁶, Andrew A Hicks²⁶, James P Cook²⁴, Lars Lind²⁷, Cecilia M Lindgren^{28

29

30}, Johan Sundström³¹, Christopher P Nelson^{32

33}, Muhammad B Riaz^{32

33}, Nilesh J Samani^{32

33}, Gianfranco Sinagra³⁴, Sheila Ulivi⁹, Mika Kähönen^{35

36}, Pashupati P Mishra^{37

38}, Nina Mononen^{37

38}, Kjell Nikus^{39

40}, Mark J Caulfield^{1

6}, Anna Dominiczak⁴¹, Sandosh Padmanabhan^{41

42}, May E Montasser^{43

44}, Jeff R O'Connell^{43

44}, Kathleen Ryan^{43

44}, Alan R Shuldiner^{43

44}, Stefanie Aeschbacher⁴⁵, David Conen^{45

46}, Lorenz Risch^{47

48

49}, Sébastien Thériault^{46

50}, Nina Hutri-Kähönen^{51

52}, Terho Lehtimäki^{37

38}, Leo-Pekka Lyytikäinen^{37

38

39}, Olli T Raitakari^{53

54

55}, Catriona L K Barnes¹⁴, Harry Campbell¹⁴, Peter K Joshi¹⁴, James F Wilson^{8

14}, Aaron Isaacs⁵⁶, Jan A Kors⁵⁷, Cornelia M van Duijn⁵⁸, Paul L Huang², Vilmundur Gudnason^{59

60}, Tamara B Harris⁶¹, Lenore J Launer⁶¹, Albert V Smith^{59

62}, Erwin P Bottinger⁶³, Ruth J F Loos^{63

64}, Girish N Nadkarni⁶³, Michael H Preuss⁶³, Adolfo Correa⁶⁵, Hao Mei⁶⁶, James Wilson⁶⁷, Thomas Meitinger^{68

69

70}, Martina Müller-Nurasyid^{68

71

72

73}, Annette Peters^{68

74

75}, Melanie Waldenberger^{68

75

76}, Massimo Mangino^{77

78}, Timothy D Spector⁷⁷, Michiel Rienstra⁵, Yordi J van de Vegte⁵, Pim van der Harst⁵, Niek Verweij^{5

79}, Stefan Kääb^{68

73}, Katharina Schramm^{68

71

73}, Moritz F Sinner^{68

73}, Konstantin Strauch^{71

72}, Michael J Cutler⁸⁰, Diane Fatkin^{81

82

83}, Barry London⁸⁴, Morten Olesen^{85

86}, Dan M Roden⁸⁷, M Benjamin Shoemaker⁸⁸, J Gustav Smith⁸⁹, Mary L Biggs^{90

91}, Joshua C Bis⁹⁰, Jennifer A Brody⁹⁰, Bruce M Psaty^{90

92

93}, Kenneth Rice⁹¹, Nona Sotoodehnia^{90

92

94}, Alessandro De Grandi²⁶, Christian Fuchsberger²⁶, Cristian Pattaro²⁶, Peter P Pramstaller²⁶, Ian Ford⁹⁵, J Wouter Jukema^{96

97}, Peter W Macfarlane⁹⁸, Stella Trompet⁹⁹, Marcus Dörr^{100

101}, Stephan B Felix^{100

101}, Uwe Völker^{100

102}, Stefan Weiss^{100

102}, Aki S Havulinna^{103

104}, Antti Jula¹⁰³, Katri Sääksjärvi¹⁰³, Veikko Salomaa¹⁰³, Xiuqing Guo¹⁰⁵, Susan R Heckbert¹⁰⁶, Henry J Lin¹⁰⁵, Jerome I Rotter¹⁰⁵, Kent D Taylor¹⁰⁵, Jie Yao¹⁰⁷, Renée de Mutsert¹⁰⁸, Arie C Maan⁹⁶, Dennis O Mook-Kanamori^{108

109}, Raymond Noordam⁹⁹, Francesco Cucca¹¹⁰, Jun Ding¹¹¹, Edward G Lakatta¹¹², Yong Qian¹¹¹, Kirill V Tarasov¹¹², Daniel Levy^{113

114}, Honghuang Lin^{114

115}, Christopher H Newton-Cheh^{3

116}, Kathryn L Lunetta^{114

117}, Alison D Murray¹¹⁸, David J Porteous^{119

120}, Blair H Smith¹²¹, Bruno H Stricker¹²², André Uitterlinden¹²³, Marten E van den Berg¹²², Jeffrey Haessler¹²⁴, Rebecca D Jackson¹²⁵, Charles Kooperberg¹²⁴, Ulrike Peters¹²⁴, Alexander P Reiner^{124

92}, Eric A Whitsel¹²⁶, Alvaro Alonso¹²⁷, Dan E Arking¹²⁸, Eric Boerwinkle¹²⁹, Georg B Ehret¹³⁰, Elsayed Z Soliman¹³¹, Christy L Avery^{132

133}, Stephanie M Gogarten⁹¹, Kathleen F Kerr⁹¹, Cathy C Laurie⁹¹, Amanda A Seyerle¹³⁴, Adrienne Stilp⁹¹, Solmaz Assa⁵, M Abdullah Said⁵, M Yldau van der Ende⁵, Pier D Lambiase^{135

136}, Michele Orini^{135

137}, Julia Ramirez^{1

136}, Stefan Van Duijvenboden^{1

136}, David O Arnar^{4

60

138}, Daniel F Gudbjartsson^{4

139}, Hilma Holm⁴, Patrick Sulem⁴, Gudmar Thorleifsson⁴, Rosa B Thorolfsdottir^{4

60}, Unnur Thorsteinsdottir^{4

60}, Emelia J Benjamin^{114

140

141}, Andrew Tinker^{1

6}, Kari Stefansson^{4

60}, Patrick T Ellinor^{2

3

142}, Yalda Jamshidi¹⁴³, Steven A Lubitz^{144

145

146}, Patricia B Munroe^{147

148}

Affiliations

¹ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
² Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
³ Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ deCODE genetics/Amgen, Inc., Reykjavik, Iceland.
⁵ Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁶ National Institute for Health Research, Barts Cardiovascular Biomedical Research Centre, Queen Mary University of London, London, UK.
⁷ College of Health and Life Sciences, Hamad Bin Khalifa University, Education City, Doha, Qatar.
⁸ Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
⁹ Institute for Maternal and Child Health-IRCCS 'Burlo Garofolo', Trieste, Italy.
¹⁰ Department of Medicine, Surgery and Health Science, University of Trieste, Trieste, Italy.
¹¹ University of Split School of Medicine, Split, Croatia.
¹² Clinical Hospital Centre Split, Split, Croatia.
¹³ Psychiatric Hospital Sveti Ivan, Zagreb, Croatia.
¹⁴ Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
¹⁵ Departamento de Biologia Geral, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
¹⁶ Rene Rachou Reserch Institute, Oswaldo Cruz Foundation, Belo Horizonte, Minas Gerais, Brazil.
¹⁷ Hospital das Clínicas e Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
¹⁸ Department of Public Health, Geriatrics, Uppsala University, Uppsala, Sweden.
¹⁹ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
²⁰ Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
²¹ Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
²² Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
²³ Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
²⁴ Department of Biostatistics, University of Liverpool, Liverpool, UK.
²⁵ Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester, UK.
²⁶ Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy.
²⁷ Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
²⁸ Nuffield Department of Medicine, Li Ka Shing Centre for Health Information and Discovery, Big Data Institute, University of Oxford, Oxford, UK.
²⁹ Nuffield Department of Medicine, The Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
³⁰ The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³¹ Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
³² Department of Cardiovascular Sciences, Cardiovascular Research Centre, Glenfield Hospital, University of Leicester, Leicester, UK.
³³ NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Groby Road, Leicester, UK.
³⁴ Cardiovascular Department, Azienda Ospedaliera Universitaria Integrata of Trieste, Trieste, Italy.
³⁵ Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland.
³⁶ Department of Clinical Physiology, Faculty of Medicine and Health Technology, Finnish Cardiovascular Research Center Tampere University, Tampere, Finland.
³⁷ Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.
³⁸ Department of Clinical Chemistry, Faculty of Medicine and Health Technology, Finnish Cardiovascular Research Center, Tampere University, Tampere, Finland.
³⁹ Department of Cardiology, Heart Center, Tampere University Hospital, Tampere, Finland.
⁴⁰ Department of Cardiology, Finnish Cardiovascular Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
⁴¹ Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
⁴² Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
⁴³ Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA.
⁴⁴ Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
⁴⁵ Cardiology Division, University Hospital, Basel, Switzerland.
⁴⁶ Population Health Research Institute, McMaster University, Hamilton, ON, Canada.
⁴⁷ Institute of Clinical Chemistry, Inselspital Bern, University Hospital, University of Bern, Bern, Switzerland.
⁴⁸ Labormedizinisches Zentrum Dr. Risch, Vaduz, Liechtenstein.
⁴⁹ Private University of the Principality of Liechtenstein, Triesen, Liechtenstein.
⁵⁰ Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Quebec, QC, Canada.
⁵¹ Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
⁵² Department of Pediatrics, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
⁵³ Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
⁵⁴ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
⁵⁵ Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland.
⁵⁶ CARIM School for Cardiovascular Diseases, Maastricht Center for Systems Biology (MaCSBio), Department of Biochemistry, and Department of Physiology, Maastricht University, Maastricht, The Netherlands.
⁵⁷ Department of Medical Informatics Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁵⁸ Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁵⁹ Icelandic Heart Association, Kopavogur, Iceland.
⁶⁰ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁶¹ Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Baltimore, MD, USA.
⁶² School of Public Health, Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
⁶³ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶⁴ The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶⁵ Jackson Heart Study, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
⁶⁶ Department of Data Science, University of Mississippi Medical Center, Jackson, MS, USA.
⁶⁷ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
⁶⁸ DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany.
⁶⁹ Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
⁷⁰ Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
⁷¹ Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
⁷² IBE, Faculty of Medicine, LMU Munich, Munich, Germany.
⁷³ Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
⁷⁴ German Center for Diabetes Research, Neuherberg, Germany.
⁷⁵ Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
⁷⁶ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
⁷⁷ Department of Twin Research and Genetic Epidemiology, Kings College London, London, UK.
⁷⁸ NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, UK.
⁷⁹ Genomics plc, Oxford, UK.
⁸⁰ Intermountain Heart Institute, Intermountain Medical Center, Murray, UT, USA.
⁸¹ Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.
⁸² Cardiology Department, St. Vincent's Hospital, Darlinghurst, NSW, Australia.
⁸³ St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Kensington, NSW, Australia.
⁸⁴ Department of Cardiovascular Medicine, University of Iowa, Iowa City, IA, USA.
⁸⁵ Laboratory for Molecular Cardiology, Department of Cardiology, The Heart Centre, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.
⁸⁶ Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁸⁷ Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸⁸ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸⁹ Department of Cardiology, Clinical Sciences, Wallenberg Center for Molecular Medicine, Lund University Diabetes Center, Lund University and Skane University Hospital, Lund, Sweden.
⁹⁰ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
⁹¹ Department of Biostatistics, University of Washington, Seattle, WA, USA.
⁹² Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁹³ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
⁹⁴ Cardiology Division, University of Washington, Seattle, WA, USA.
⁹⁵ Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK.
⁹⁶ Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
⁹⁷ Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
⁹⁸ Institute of Health and Wellbeing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
⁹⁹ Department of Internal Medicine, section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
¹⁰⁰ DZHK (German Centre for Cardiovascular Research), Greifswald, Germany.
¹⁰¹ Department of Internal Medicine B - Cardiology, Pneumology, Infectious Diseases, Intensive Care Medicine, University Medicine Greifswald, Greifswald, Germany.
¹⁰² Interfaculty Institute for Genetics and Functional Genomics; Department of Functional Genomics; University Medicine and University of Greifswald, Greifswald, Germany.
¹⁰³ Finnish Institute for Health and Welfare, Helsinki, Finland.
¹⁰⁴ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
¹⁰⁵ Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁰⁶ Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, WA, USA.
¹⁰⁷ Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁰⁸ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
¹⁰⁹ Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.
¹¹⁰ Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
¹¹¹ Laboratory of Genetics and Genomics, NIA/NIH, Baltimore, MD, USA.
¹¹² Laboratory of Cardiovascular Science, NIA/NIH, Baltimore, MD, USA.
¹¹³ Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
¹¹⁴ National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.
¹¹⁵ Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
¹¹⁶ Center for Human Genetic Research and Cardiovascular Research Center, Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA.
¹¹⁷ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹¹⁸ The Institute of Medical Sciences, Aberdeen Biomedical Imaging Centre, University of Aberdeen, Aberdeen, UK.
¹¹⁹ Centre for Genomic and Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
¹²⁰ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
¹²¹ Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
¹²² Department of Epidemiology Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹²³ Human Genotyping Facility Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹²⁴ Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, WA, USA.
¹²⁵ Division of Endocrinology, Diabetes and Metabolism, Ohio State University, Columbus, OH, USA.
¹²⁶ Departments of Epidemiology and Medicine, Gillings School of Global Public Health and School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
¹²⁷ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
¹²⁸ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹²⁹ Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA.
¹³⁰ Cardiology, Geneva University Hospitals, Geneva, Switzerland.
¹³¹ Epidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹³² Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
¹³³ Carolina Population Center, University of North Carolina, Chapel Hill, NC, USA.
¹³⁴ Division of Pharmaceutical Outcomes and Policy, University of North Carolina, Chapel Hill, NC, USA.
¹³⁵ Barts Heart Centre, St Bartholomews Hospital, London, UK.
¹³⁶ Institute of Cardiovascular Science, University College London, London, UK.
¹³⁷ Department of Mechanical Engineering, University College London, London, UK.
¹³⁸ Department of Medicine, Landspitali University Hospital, Reykjavik, Iceland.
¹³⁹ School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
¹⁴⁰ Section of Cardiovascular Medicine and Section of Preventive Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
¹⁴¹ Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
¹⁴² Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA.
¹⁴³ Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's, University of London, London, UK.
¹⁴⁴ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. slubitz@mgh.harvard.edu.
¹⁴⁵ Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA. slubitz@mgh.harvard.edu.
¹⁴⁶ Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA. slubitz@mgh.harvard.edu.
¹⁴⁷ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. p.b.munroe@qmul.ac.uk.
¹⁴⁸ National Institute for Health Research, Barts Cardiovascular Biomedical Research Centre, Queen Mary University of London, London, UK. p.b.munroe@qmul.ac.uk.

^# Contributed equally.

PMID: 32439900
PMCID: PMC7242331
DOI: 10.1038/s41467-020-15706-x

Meta-Analysis

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

Ioanna Ntalla et al. Nat Commun. 2020.

. 2020 May 21;11(1):2542.

doi: 10.1038/s41467-020-15706-x.

Authors

Affiliations

¹ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
² Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
³ Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ deCODE genetics/Amgen, Inc., Reykjavik, Iceland.
⁵ Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
⁶ National Institute for Health Research, Barts Cardiovascular Biomedical Research Centre, Queen Mary University of London, London, UK.
⁷ College of Health and Life Sciences, Hamad Bin Khalifa University, Education City, Doha, Qatar.
⁸ Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
⁹ Institute for Maternal and Child Health-IRCCS 'Burlo Garofolo', Trieste, Italy.
¹⁰ Department of Medicine, Surgery and Health Science, University of Trieste, Trieste, Italy.
¹¹ University of Split School of Medicine, Split, Croatia.
¹² Clinical Hospital Centre Split, Split, Croatia.
¹³ Psychiatric Hospital Sveti Ivan, Zagreb, Croatia.
¹⁴ Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
¹⁵ Departamento de Biologia Geral, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
¹⁶ Rene Rachou Reserch Institute, Oswaldo Cruz Foundation, Belo Horizonte, Minas Gerais, Brazil.
¹⁷ Hospital das Clínicas e Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
¹⁸ Department of Public Health, Geriatrics, Uppsala University, Uppsala, Sweden.
¹⁹ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
²⁰ Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
²¹ Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
²² Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
²³ Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
²⁴ Department of Biostatistics, University of Liverpool, Liverpool, UK.
²⁵ Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester, UK.
²⁶ Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy.
²⁷ Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
²⁸ Nuffield Department of Medicine, Li Ka Shing Centre for Health Information and Discovery, Big Data Institute, University of Oxford, Oxford, UK.
²⁹ Nuffield Department of Medicine, The Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
³⁰ The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³¹ Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
³² Department of Cardiovascular Sciences, Cardiovascular Research Centre, Glenfield Hospital, University of Leicester, Leicester, UK.
³³ NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Groby Road, Leicester, UK.
³⁴ Cardiovascular Department, Azienda Ospedaliera Universitaria Integrata of Trieste, Trieste, Italy.
³⁵ Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland.
³⁶ Department of Clinical Physiology, Faculty of Medicine and Health Technology, Finnish Cardiovascular Research Center Tampere University, Tampere, Finland.
³⁷ Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland.
³⁸ Department of Clinical Chemistry, Faculty of Medicine and Health Technology, Finnish Cardiovascular Research Center, Tampere University, Tampere, Finland.
³⁹ Department of Cardiology, Heart Center, Tampere University Hospital, Tampere, Finland.
⁴⁰ Department of Cardiology, Finnish Cardiovascular Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
⁴¹ Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
⁴² Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
⁴³ Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA.
⁴⁴ Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
⁴⁵ Cardiology Division, University Hospital, Basel, Switzerland.
⁴⁶ Population Health Research Institute, McMaster University, Hamilton, ON, Canada.
⁴⁷ Institute of Clinical Chemistry, Inselspital Bern, University Hospital, University of Bern, Bern, Switzerland.
⁴⁸ Labormedizinisches Zentrum Dr. Risch, Vaduz, Liechtenstein.
⁴⁹ Private University of the Principality of Liechtenstein, Triesen, Liechtenstein.
⁵⁰ Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Quebec, QC, Canada.
⁵¹ Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
⁵² Department of Pediatrics, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
⁵³ Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.
⁵⁴ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
⁵⁵ Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland.
⁵⁶ CARIM School for Cardiovascular Diseases, Maastricht Center for Systems Biology (MaCSBio), Department of Biochemistry, and Department of Physiology, Maastricht University, Maastricht, The Netherlands.
⁵⁷ Department of Medical Informatics Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁵⁸ Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
⁵⁹ Icelandic Heart Association, Kopavogur, Iceland.
⁶⁰ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁶¹ Laboratory of Epidemiology and Population Sciences, National Institute on Aging, NIH, Baltimore, MD, USA.
⁶² School of Public Health, Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
⁶³ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶⁴ The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁶⁵ Jackson Heart Study, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
⁶⁶ Department of Data Science, University of Mississippi Medical Center, Jackson, MS, USA.
⁶⁷ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
⁶⁸ DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany.
⁶⁹ Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
⁷⁰ Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
⁷¹ Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
⁷² IBE, Faculty of Medicine, LMU Munich, Munich, Germany.
⁷³ Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
⁷⁴ German Center for Diabetes Research, Neuherberg, Germany.
⁷⁵ Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
⁷⁶ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
⁷⁷ Department of Twin Research and Genetic Epidemiology, Kings College London, London, UK.
⁷⁸ NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, UK.
⁷⁹ Genomics plc, Oxford, UK.
⁸⁰ Intermountain Heart Institute, Intermountain Medical Center, Murray, UT, USA.
⁸¹ Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.
⁸² Cardiology Department, St. Vincent's Hospital, Darlinghurst, NSW, Australia.
⁸³ St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Kensington, NSW, Australia.
⁸⁴ Department of Cardiovascular Medicine, University of Iowa, Iowa City, IA, USA.
⁸⁵ Laboratory for Molecular Cardiology, Department of Cardiology, The Heart Centre, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.
⁸⁶ Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁸⁷ Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸⁸ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸⁹ Department of Cardiology, Clinical Sciences, Wallenberg Center for Molecular Medicine, Lund University Diabetes Center, Lund University and Skane University Hospital, Lund, Sweden.
⁹⁰ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
⁹¹ Department of Biostatistics, University of Washington, Seattle, WA, USA.
⁹² Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁹³ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
⁹⁴ Cardiology Division, University of Washington, Seattle, WA, USA.
⁹⁵ Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK.
⁹⁶ Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
⁹⁷ Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
⁹⁸ Institute of Health and Wellbeing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
⁹⁹ Department of Internal Medicine, section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
¹⁰⁰ DZHK (German Centre for Cardiovascular Research), Greifswald, Germany.
¹⁰¹ Department of Internal Medicine B - Cardiology, Pneumology, Infectious Diseases, Intensive Care Medicine, University Medicine Greifswald, Greifswald, Germany.
¹⁰² Interfaculty Institute for Genetics and Functional Genomics; Department of Functional Genomics; University Medicine and University of Greifswald, Greifswald, Germany.
¹⁰³ Finnish Institute for Health and Welfare, Helsinki, Finland.
¹⁰⁴ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
¹⁰⁵ Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁰⁶ Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, WA, USA.
¹⁰⁷ Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁰⁸ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
¹⁰⁹ Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.
¹¹⁰ Department of Biomedical Sciences, University of Sassari, Sassari, Italy.
¹¹¹ Laboratory of Genetics and Genomics, NIA/NIH, Baltimore, MD, USA.
¹¹² Laboratory of Cardiovascular Science, NIA/NIH, Baltimore, MD, USA.
¹¹³ Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
¹¹⁴ National Heart Lung and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.
¹¹⁵ Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
¹¹⁶ Center for Human Genetic Research and Cardiovascular Research Center, Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA.
¹¹⁷ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹¹⁸ The Institute of Medical Sciences, Aberdeen Biomedical Imaging Centre, University of Aberdeen, Aberdeen, UK.
¹¹⁹ Centre for Genomic and Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.
¹²⁰ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
¹²¹ Division of Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
¹²² Department of Epidemiology Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹²³ Human Genotyping Facility Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
¹²⁴ Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, WA, USA.
¹²⁵ Division of Endocrinology, Diabetes and Metabolism, Ohio State University, Columbus, OH, USA.
¹²⁶ Departments of Epidemiology and Medicine, Gillings School of Global Public Health and School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
¹²⁷ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
¹²⁸ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹²⁹ Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA.
¹³⁰ Cardiology, Geneva University Hospitals, Geneva, Switzerland.
¹³¹ Epidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹³² Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA.
¹³³ Carolina Population Center, University of North Carolina, Chapel Hill, NC, USA.
¹³⁴ Division of Pharmaceutical Outcomes and Policy, University of North Carolina, Chapel Hill, NC, USA.
¹³⁵ Barts Heart Centre, St Bartholomews Hospital, London, UK.
¹³⁶ Institute of Cardiovascular Science, University College London, London, UK.
¹³⁷ Department of Mechanical Engineering, University College London, London, UK.
¹³⁸ Department of Medicine, Landspitali University Hospital, Reykjavik, Iceland.
¹³⁹ School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
¹⁴⁰ Section of Cardiovascular Medicine and Section of Preventive Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
¹⁴¹ Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
¹⁴² Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA.
¹⁴³ Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's, University of London, London, UK.
¹⁴⁴ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. slubitz@mgh.harvard.edu.
¹⁴⁵ Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA. slubitz@mgh.harvard.edu.
¹⁴⁶ Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA. slubitz@mgh.harvard.edu.
¹⁴⁷ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. p.b.munroe@qmul.ac.uk.
¹⁴⁸ National Institute for Health Research, Barts Cardiovascular Biomedical Research Centre, Queen Mary University of London, London, UK. p.b.munroe@qmul.ac.uk.

^# Contributed equally.

PMID: 32439900
PMCID: PMC7242331
DOI: 10.1038/s41467-020-15706-x

Abstract

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

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Conflict of interest statement

I.N. became a full-time employee of Gilead Sciences Ltd following submission of the manuscript. S.A.L. receives sponsored research support from Bristol Myers Squibb/Pfizer, Bayer AG, and Boehringer Ingelheim, and has consulted for Bristol Myers Squibb/Pfizer and Bayer AG. P.T.E. is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases. P.T.E. has also served on advisory boards or consulted for Bayer AG, Quest Diagnostics, and Novartis. M.J.C. is Chief Scientist for Genomics England, a UK Government company. B.M.P. serves on the DSMB of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. V.S. has participated in a conference trip sponsored by Novo Nordisk and received a modest honorarium for participating in an advisory board meeting. K.S., H.H., P.S., G.S., G.T., R.B.T., U.T., D.O.A., D.F.G. are employed by deCODE genetics/Amgen Inc. E.I. is employed by GlaxoSmithKline. A.M. is employed by Genentech Inc.

Figures

**Fig. 1. Overview of the study design.**
An overview of contributing studies, single-stage discovery approach, and downstream bioinformatics and in silico annotations performed to link variants to genes, and polygenic risk score analysis to link variants to cardiovascular disease risk is illustrated. Asterisk (*) The multi-ancestry meta-analysis is our primary analysis. Previously not reported loci were identified from the multi-ancestry meta-analysis. Ancestry specific and chromosome X meta-analysis are secondary. Hash (^#) For bioinformatics and in silico annotations we also included loci that reached genome-wide significance in European only meta-analysis (N = 8) and were borderline genome-wide significant in the multi-ancestry meta-analysis.

**Fig. 2. Manhattan plot of the multi-ancestry meta-analysis for PR interval.**
P values are plotted on the -log₁₀ scale for all variants present in at least 60% of the maximum sample size from the fixed-effects meta-analysis of 293,051 individuals from multiple ancestries (multi-ancestry meta-analysis). Associations of genome-wide significant (P < 5 × 10⁻⁸) variants at previously not reported (N = 141) and previously reported loci (N = 61) are plotted in dark and light blue colors respectively.

**Fig. 3. Plausible candidate genes of PR interval from S-PrediXcan.**
Diagram of standard electrocardiographic intervals and the heart. The electrocardiographic features are illustratively aligned with the corresponding cardiac conduction system structures (orange) reflected on the tracing. The PR interval (labeled) indicates conduction through the atria, atrioventricular node, His bundle, and Purkinje fibers. Right: Supplementary Data 14 shows 113 genes whose expression in the left ventricle (N = 233) or right atrial appendage (N = 231) was associated with PR interval duration in a transcriptome-wide analysis using S-PrediXcan and GTEx v7. Displayed genes include those with significant associations after Bonferroni correction for all tested genes (P < 3.1 × 10⁻⁶). Longer PR intervals were associated with increased predicted expression of 56 genes (blue) and reduced expression of 57 genes (orange).

**Fig. 4. Bubble plot of phenome-wide association analysis of European ancestry PR interval polygenic risk score.**
The polygenic risk score was derived from the European ancestry meta-analysis. Orange circles indicate that polygenic predisposition to longer PR interval is associated with an increased risk of the condition, whereas blue circles indicate that polygenic predisposition to longer PR interval is associated with lower risk of the condition. The darkness of the color reflects the effect size (odds ratio, OR) per 1 standard deviation (s.d.) increment of the polygenic risk score from logistic regression. Sample size (N) in each regression model is provided under X-axis. Given correlation between traits, we set significance threshold at P < 3.13 × 10⁻³ after Bonferroni correction (P < 0.05/16; dotted line) for the analysis and also report nominal associations (P < 0.05; dashed line).

**Fig. 5. Candidate genes in PR interval loci encoding proteins involved in cardiac muscle cytoskeleton.**
Candidate genes or encoded proteins are indicated by a star symbol in the figure and are listed in Supplementary Data 3. More information about the genes is provided in Supplementary Data 18 and 19. This figure was created with BioRender. *Previously not reported locus, # genome-wide significant locus in transformed trait meta-analysis. ¹Missense variant; ²Nearest gene to the lead variant; ³Gene within the region (r² > 0.5); ⁴Variant(s) in the locus are associated with gene expression in left ventricle and/or right atrial appendage; ⁵Left ventricle best HiC locus interactor (RegulomeDB score ≤ 2); ⁶Animal model; ⁷Monogenic disease with a cardiovascular phenotype.

See this image and copyright information in PMC

References

1. Cheng S, et al. Long-term outcomes in individuals with prolonged PR interval or first-degree atrioventricular block. JAMA. 2009;301:2571–7. - PMC - PubMed
1. Alonso A, et al. Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium. J. Am. Heart Assoc. 2013;2:e000102. - PMC - PubMed
1. Rasmussen PV, et al. Electrocardiographic PR Interval Duration and Cardiovascular Risk: Results From the Copenhagen ECG Study. Can. J. Cardiol. 2017;33:674–681. - PubMed
1. Butler AM, et al. Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts. Circ. Cardiovasc. Genet. 2012;5:639–46. - PMC - PubMed
1. Chambers JC, et al. Genetic variation in SCN10A influences cardiac conduction. Nat. Genet. 2010;42:149–52. - PubMed

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Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

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Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

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