Meta-Analysis

. 2017 Jun 14:8:15805.

doi: 10.1038/ncomms15805.

Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Ilja M Nolte¹, M Loretto Munoz¹, Vinicius Tragante², Azmeraw T Amare^{1

3

4}, Rick Jansen⁵, Ahmad Vaez^{1

6}, Benedikt von der Heyde^{7

8}, Christy L Avery⁹, Joshua C Bis¹⁰, Bram Dierckx^{11

12}, Jenny van Dongen¹³, Stephanie M Gogarten¹⁴, Philippe Goyette¹⁵, Jussi Hernesniemi^{16

17

18}, Ville Huikari¹⁹, Shih-Jen Hwang^{20

21}, Deepali Jaju²², Kathleen F Kerr¹⁴, Alexander Kluttig²³, Bouwe P Krijthe²⁴, Jitender Kumar^{7

8}, Sander W van der Laan²⁵, Leo-Pekka Lyytikäinen^{16

17}, Adam X Maihofer^{26

27}, Arpi Minassian^{26

27}, Peter J van der Most¹, Martina Müller-Nurasyid^{28

29

30}, Michel Nivard^{13

31}, Erika Salvi³², James D Stewart^{9

33}, Julian F Thayer³⁴, Niek Verweij³⁵, Andrew Wong³⁶, Delilah Zabaneh^{37

38}, Mohammad H Zafarmand^{39

40}, Abdel Abdellaoui^{13

31}, Sulayma Albarwani⁴¹, Christine Albert⁴², Alvaro Alonso⁴³, Foram Ashar⁴⁴, Juha Auvinen^{19

45}, Tomas Axelsson⁴⁶, Dewleen G Baker^{27

26}, Paul I W de Bakker^{47

48}, Matteo Barcella³², Riad Bayoumi⁴⁹, Rob J Bieringa¹, Dorret Boomsma^{13

31}, Gabrielle Boucher¹⁵, Annie R Britton⁵⁰, Ingrid Christophersen^{51

52

53}, Andrea Dietrich⁵⁴, George B Ehret^{55

56}, Patrick T Ellinor^{52

57}, Markku Eskola^{18

58}, Janine F Felix²⁴, John S Floras^{59

60}, Oscar H Franco²⁴, Peter Friberg⁶¹, Maaike G J Gademan³⁹, Mark A Geyer²⁶, Vilmantas Giedraitis⁶², Catharina A Hartman⁶³, Daiane Hemerich^{2

64}, Albert Hofman²⁴, Jouke-Jan Hottenga^{13

31}, Heikki Huikuri⁶⁵, Nina Hutri-Kähönen^{66

67}, Xavier Jouven⁶⁸, Juhani Junttila⁶⁵, Markus Juonala^{69

70}, Antti M Kiviniemi⁶⁵, Jan A Kors⁷¹, Meena Kumari^{50

72}, Tatiana Kuznetsova⁷³, Cathy C Laurie¹⁴, Joop D Lefrandt⁷⁴, Yong Li⁷⁵, Yun Li^{76

77

78}, Duanping Liao⁷⁹, Marian C Limacher⁸⁰, Henry J Lin^{81

82}, Cecilia M Lindgren^{83

84}, Steven A Lubitz^{52

57}, Anubha Mahajan⁸⁴, Barbara McKnight^{10

14

85}, Henriette Meyer Zu Schwabedissen⁸⁶, Yuri Milaneschi⁵, Nina Mononen^{16

17}, Andrew P Morris^{84

87}, Mike A Nalls⁸⁸, Gerjan Navis⁸⁹, Melanie Neijts^{13

31}, Kjell Nikus^{18

90}, Kari E North^{9

91}, Daniel T O'Connor⁹², Johan Ormel⁶³, Siegfried Perz⁹³, Annette Peters^{30

93

94}, Bruce M Psaty^{10

95

96}, Olli T Raitakari^{97

98}, Victoria B Risbrough^{26

27}, Moritz F Sinner^{29

30}, David Siscovick⁹⁹, Johannes H Smit⁵, Nicholas L Smith^{96

100

101}, Elsayed Z Soliman¹⁰², Nona Sotoodehnia¹⁰³, Jan A Staessen⁷³, Phyllis K Stein¹⁰⁴, Adrienne M Stilp¹⁴, Katarzyna Stolarz-Skrzypek¹⁰⁵, Konstantin Strauch^{28

106}, Johan Sundström¹⁰⁷, Cees A Swenne¹⁰⁸, Ann-Christine Syvänen⁴⁶, Jean-Claude Tardif^{15

109}, Kent D Taylor¹¹⁰, Alexander Teumer¹¹¹, Timothy A Thornton¹⁴, Lesley E Tinker⁸⁵, André G Uitterlinden^{24

112

113}, Jessica van Setten², Andreas Voss¹¹⁴, Melanie Waldenberger^{93

115}, Kirk C Wilhelmsen^{116

117}, Gonneke Willemsen^{13

31}, Quenna Wong¹⁴, Zhu-Ming Zhang^{102

118}, Alan B Zonderman¹¹⁹, Daniele Cusi^{120

121}, Michele K Evans¹¹⁹, Halina K Greiser¹²², Pim van der Harst³⁵, Mohammad Hassan⁴¹, Erik Ingelsson^{7

8

123}, Marjo-Riitta Järvelin^{19

45

124

125}, Stefan Kääb^{29

30}, Mika Kähönen^{126

127}, Mika Kivimaki⁵⁰, Charles Kooperberg⁸⁵, Diana Kuh³⁶, Terho Lehtimäki^{16

17}, Lars Lind¹⁰⁷, Caroline M Nievergelt^{26

27}, Chris J O'Donnell^{20

21

128}, Albertine J Oldehinkel⁶³, Brenda Penninx⁵, Alexander P Reiner^{85

100}, Harriëtte Riese⁶³, Arie M van Roon⁷⁴, John D Rioux^{15

109}, Jerome I Rotter¹¹⁰, Tamar Sofer¹⁴, Bruno H Stricker^{24

129}, Henning Tiemeier^{11

24}, Tanja G M Vrijkotte³⁹, Folkert W Asselbergs^{2

130

131}, Bianca J J M Brundel¹³², Susan R Heckbert^{10

100}, Eric A Whitsel^{9

133}, Marcel den Hoed^{7

8}, Harold Snieder¹, Eco J C de Geus^{13

31}

Affiliations

¹ Department of Epidemiology, University of Groningen, University Medical Center Groningen, PO Box 30001, Groningen 9700 RB, The Netherlands.
² Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584CX, The Netherlands.
³ Department of Epidemiology, School of Medicine, University of Adelaide, Adelaide, South Australia 5005, Australia.
⁴ College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar 6000, Ethiopia.
⁵ Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam 1081 BT, The Netherlands.
⁶ School of Medicine, Isfahan University of Medical Sciences, Isfahan 81746-73461, Iran.
⁷ Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala 75237, Sweden.
⁸ Science for Life Laboratory, Uppsala University, Uppsala 75237, Sweden.
⁹ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
¹⁰ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington 98104, USA.
¹¹ Department of Child and Adolescent Psychiatry/Psychology, Department of Child and Adolescent Psychiatry, PO Box 2060, Rotterdam 3000 CB, The Netherlands.
¹² The Generation R Study Group, Erasmus MC, PO Box 2060, Rotterdam 3000 CB, The Netherlands.
¹³ Department of Biological Psychology, Behavioral and Movement Sciences, VU University, Amsterdam 1081 BT, The Netherlands.
¹⁴ Department of Biostatistics, School of Public Health, University of Washington, Seattle, Washington 98195, USA.
¹⁵ Montreal Heart Institute, Montreal, Quebec, Canada H1T 1C8.
¹⁶ Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland.
¹⁷ Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere 33014, Finland.
¹⁸ Department of Cardiology, Heart Hospital, Tampere University Hospital, Tampere 33521, Finland.
¹⁹ Center for Life Course Health Research, University of Oulu, Oulu 90014, Finland.
²⁰ Framingham Heart Study, Framingham, Massachusetts 01702, USA.
²¹ Population Sciences Branch, National Heart, Lung and Blood Institute, Bethesda, Maryland 20892, USA.
²² Department of Clinical Physiology, Sultan Qaboos University Hospital, Muscat-Al Khoudh 123, Sultanate of Oman.
²³ Institute of Medical Epidemiology, Biostatistics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle (Saale) 06097, Germany.
²⁴ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, PO Box 2060, Rotterdam 3000 CB, The Netherlands.
²⁵ Laboratory of Experimental Cardiology, Department of Heart and Lung, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584 CX, The Netherlands.
²⁶ Department of Psychiatry, University of California, San Diego, San Diego, California 92093, USA.
²⁷ Center for Stress and Mental Health (CESAMH), VA San Diego Healthcare System, San Diego, California 92161, USA.
²⁸ Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg 85764, Germany.
²⁹ Department of Medicine, University Hospital Munich, Ludwig-Maximilians-University, Munich 80539, Germany.
³⁰ DZHK (German Centre for Cardiovascular Research), Partner site Munich Heart Alliance, Munich 80336, Germany.
³¹ EMGO+ Institute for Health and Care Research, VU University &VU University Medical Center, Amsterdam 1081 HV, The Netherlands.
³² Department of Health Sciences, University of Milano, Milano 20122, Italy.
³³ Carolina Population Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
³⁴ Department of Psychology, The Ohio State University, 1835 Neil Avenue, Columbus, Ohio 43210, USA.
³⁵ Department of Cardiology, University of Groningen, University Medical Center Groningen, PO Box 30001, Groningen 9700 RB, The Netherlands.
³⁶ MRC Unit for Lifelong Health and Ageing, University College London, 33 Bedford Place, London WC1B 5JU, UK.
³⁷ Institute of Psychiatry, Psychology &Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, UK.
³⁸ University College London Genetics Institute, University College London, London WC1E 6BT, UK.
³⁹ Department of Public Health, Academic Medical Center (AMC), University of Amsterdam, Amsterdam 1105 AZ, The Netherlands.
⁴⁰ Department of Obstetrics and Gynaecology, Academic Medical Centre, University of Amsterdam, Amsterdam 1105 AZ, The Netherlands.
⁴¹ Department of Physiology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat Al-Khoudh 123, Sultanate of Oman.
⁴² Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
⁴³ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, USA.
⁴⁴ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
⁴⁵ Unit of Primary Health Care, Oulu University Hospital, Oulu 90220, Finland.
⁴⁶ Department of Medical Sciences, Molecular Medicine, Uppsala University, Uppsala 75237, Sweden.
⁴⁷ Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
⁴⁸ Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
⁴⁹ College of Medicine, Mohammed Bin Rashid University, PO Box 505055, Dubai Healthcare City, United Arab Emirates.
⁵⁰ Department of Epidemiology and Public Health, University College London, London WC1E 6BT, UK.
⁵¹ Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
⁵² Program in Medical and Population Genetics, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02114, USA.
⁵³ Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Rud 1346, Norway.
⁵⁴ Department of Child- and Adolescent Psychiatry, University of Groningen, University Medical Center Groningen, PO Box 30001, Groningen 9700 RB, The Netherlands.
⁵⁵ Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
⁵⁶ Cardiology, Department of Specialties of Internal Medicine, Geneva University Hospital, Geneva 1211, Switzerland.
⁵⁷ Cardiac Arrhythmia Service &Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
⁵⁸ Department of Cardiology, University of Tampere School of Medicine, Tampere 33014, Finland.
⁵⁹ University Health Network and Mount Sinai Hospital Division of Cardiology, Department of Medicine, University of Toronto, Ontario, Canada M5S.
⁶⁰ Toronto General Research Institute, University Health Network, Toronto, Canada.
⁶¹ Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden.
⁶² Department of Public Health and Caring Sciences, Molecular Geriatrics, Uppsala University, Uppsala 75237, Sweden.
⁶³ Interdisciplinary Center Psychopathology and Emotion regulation, Department of Psychiatry, University of Groningen, University Medical Center Groningen, PO Box 30001, Groningen 9700 RB, The Netherlands.
⁶⁴ CAPES Foundation, Ministry of Education of Brazil, Brasília DF 70040-020, Brazil.
⁶⁵ Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu 90220, Finland.
⁶⁶ Department of Pediatrics, Tampere University Hospital, Tampere 33521, Finland.
⁶⁷ Department of Pediatrics, University of Tampere School of Medicine, Tampere 33014, Finland.
⁶⁸ INSERM U970, Paris Descartes University, Paris 75006, France.
⁶⁹ Department of Medicine, University of Turku, Turku 20520, Finland.
⁷⁰ Division of Medicine, Turku University Hospital, Turku 20521, Finland.
⁷¹ Department of Medical Informatics, Erasmus Medical Center, Rotterdam 3015 CE, The Netherlands.
⁷² ISER, Essex University, Colchester, Essex CO4 3SQ, UK.
⁷³ Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven 3000, Belgium.
⁷⁴ Department of Internal Medicine, Division of Vascular Medicine, University of Groningen, University Medical Center Groningen, PO Box 30001, Groningen 9700 RB, The Netherlands.
⁷⁵ Division of Genetic Epidemiology, Institute for Medical Biometry and Statistics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg 79110, Germany.
⁷⁶ Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
⁷⁷ Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
⁷⁸ Department of Computer Science, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
⁷⁹ Division of Epidemiology, Department of Public Health Sciences, Penn State University College of Medicine, Hershey, Pennsylvania 17033, USA.
⁸⁰ Division of Cardiovascular Medicine, University of Florida College of Medicine, Gainesville, Florida 32611, USA.
⁸¹ Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502, USA.
⁸² Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California 90502, USA.
⁸³ Li Ka Shing Centre for Health Information and Discovery, The Big Data Institute, University of Oxford, Oxford OX3 7BN, UK.
⁸⁴ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
⁸⁵ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
⁸⁶ Biopharmacy, Department Pharmaceutical Sciences, University of Basel, Basel CH-4056, Switzerland.
⁸⁷ Department of Biostatistics, University of Liverpool, Liverpool L69 3GL, UK.
⁸⁸ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.
⁸⁹ Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, PO Box 30001, Groningen 9700 RB, The Netherlands.
⁹⁰ Department of Cardiology, University of Tampere, School of Medicine, Tampere 33014, Finland.
⁹¹ Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
⁹² Department of Medicine, University of California, San Diego, San Diego, California 92093, USA.
⁹³ Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg 85764, Germany.
⁹⁴ German Center for Diabetes Research, Neuherberg 85764, Germany.
⁹⁵ Departments of Epidemiology and Health Services, University of Washington, Seattle, Washington 98195, USA.
⁹⁶ Group Health Research Institute, Group Health Cooperative, Seattle, Washington 98101, USA.
⁹⁷ Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku 20521, Finland.
⁹⁸ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20520, Finland.
⁹⁹ The New York Academy of Medicine, New York, New York 10029, USA.
¹⁰⁰ Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington 98195, USA.
¹⁰¹ Seattle Epidemiologic Research and Information Center, Veterans Affairs Office of Research and Development, Seattle, Washington 98108, USA.
¹⁰² Epidemiological Cardiology Research Center (EPICARE), Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.
¹⁰³ Cardiovascular Health Research Unit, Division of Cardiology, Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington 98101, USA.
¹⁰⁴ Heart Rate Variability Lab, Washington University School of Medicine, St Louis, Missouri 63108, USA.
¹⁰⁵ First Department of Cardiology, Interventional Electrocardiology and Hypertension, Jagiellonian University Medical College, Cracow 31-008, Poland.
¹⁰⁶ Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich 81377, Germany.
¹⁰⁷ Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala 751 85, Sweden.
¹⁰⁸ Department of Cardiology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
¹⁰⁹ Université de Montréal, Montreal, Quebec, Canada H3T IJ4.
¹¹⁰ Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90509, USA.
¹¹¹ Institute for Community Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
¹¹² Department of Internal Medicine, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands.
¹¹³ Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging NCHA), Leiden 2300 RC, The Netherlands.
¹¹⁴ Institute of Innovative Health Technologies-IGHT Jena Ernst-Abbe-Hochschule Jena, Jena 07745, Germany.
¹¹⁵ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg 85764, Germany.
¹¹⁶ Departments of Genetics and Neurology University of North Carolina, Chapel Hill, North Carolina 27599, USA.
¹¹⁷ The Renaissance Computing Institute, Chapel Hill, North Carolina 27599, USA.
¹¹⁸ Department of Epidemiology &Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.
¹¹⁹ Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
¹²⁰ Institute of Biomedical Technologies, CNR-Italian National Research Council, Milan 20090, Italy.
¹²¹ KOS Genetic SRL, Bresso (Milano) 20091, Italy.
¹²² German Cancer Research Centre, Division of Cancer Epidemiology, Heidelberg 69210, Germany.
¹²³ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
¹²⁴ Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, St Mary's campus, Imperial College London, London W2 1PG, UK.
¹²⁵ Biocenter Oulu University of Oulu, Oulu 90014, Finland.
¹²⁶ Department of Clinical Physiology, Tampere University Hospital, Tampere 33521, Finland.
¹²⁷ Department of Clinical Physiology, University of Tampere, School of Medicine, Tampere 33014, Finland.
¹²⁸ Cardiology Section, Boston Veteran's Administration Healthcare, Boston, Maryland 02132, USA.
¹²⁹ Inspectorate for Health Care, The Hague 2511 VX, The Netherlands.
¹³⁰ Institute of Cardiovascular Science, University College London, 222 Euston Road, London NW1 2DA, UK.
¹³¹ Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht 3501 DG, The Netherlands.
¹³² Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, De Boelelaan 1118, Amsterdam 1081 HV, The Netherlands.
¹³³ Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

PMID: 28613276
PMCID: PMC5474732
DOI: 10.1038/ncomms15805

Meta-Analysis

Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Ilja M Nolte et al. Nat Commun. 2017.

. 2017 Jun 14:8:15805.

doi: 10.1038/ncomms15805.

Authors

Affiliations

¹ Department of Epidemiology, University of Groningen, University Medical Center Groningen, PO Box 30001, Groningen 9700 RB, The Netherlands.
² Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584CX, The Netherlands.
³ Department of Epidemiology, School of Medicine, University of Adelaide, Adelaide, South Australia 5005, Australia.
⁴ College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar 6000, Ethiopia.
⁵ Department of Psychiatry, EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam 1081 BT, The Netherlands.
⁶ School of Medicine, Isfahan University of Medical Sciences, Isfahan 81746-73461, Iran.
⁷ Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Uppsala 75237, Sweden.
⁸ Science for Life Laboratory, Uppsala University, Uppsala 75237, Sweden.
⁹ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
¹⁰ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington 98104, USA.
¹¹ Department of Child and Adolescent Psychiatry/Psychology, Department of Child and Adolescent Psychiatry, PO Box 2060, Rotterdam 3000 CB, The Netherlands.
¹² The Generation R Study Group, Erasmus MC, PO Box 2060, Rotterdam 3000 CB, The Netherlands.
¹³ Department of Biological Psychology, Behavioral and Movement Sciences, VU University, Amsterdam 1081 BT, The Netherlands.
¹⁴ Department of Biostatistics, School of Public Health, University of Washington, Seattle, Washington 98195, USA.
¹⁵ Montreal Heart Institute, Montreal, Quebec, Canada H1T 1C8.
¹⁶ Department of Clinical Chemistry, Fimlab Laboratories, Tampere 33520, Finland.
¹⁷ Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere 33014, Finland.
¹⁸ Department of Cardiology, Heart Hospital, Tampere University Hospital, Tampere 33521, Finland.
¹⁹ Center for Life Course Health Research, University of Oulu, Oulu 90014, Finland.
²⁰ Framingham Heart Study, Framingham, Massachusetts 01702, USA.
²¹ Population Sciences Branch, National Heart, Lung and Blood Institute, Bethesda, Maryland 20892, USA.
²² Department of Clinical Physiology, Sultan Qaboos University Hospital, Muscat-Al Khoudh 123, Sultanate of Oman.
²³ Institute of Medical Epidemiology, Biostatistics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle (Saale) 06097, Germany.
²⁴ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, PO Box 2060, Rotterdam 3000 CB, The Netherlands.
²⁵ Laboratory of Experimental Cardiology, Department of Heart and Lung, University Medical Center Utrecht, Heidelberglaan 100, Utrecht 3584 CX, The Netherlands.
²⁶ Department of Psychiatry, University of California, San Diego, San Diego, California 92093, USA.
²⁷ Center for Stress and Mental Health (CESAMH), VA San Diego Healthcare System, San Diego, California 92161, USA.
²⁸ Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg 85764, Germany.
²⁹ Department of Medicine, University Hospital Munich, Ludwig-Maximilians-University, Munich 80539, Germany.
³⁰ DZHK (German Centre for Cardiovascular Research), Partner site Munich Heart Alliance, Munich 80336, Germany.
³¹ EMGO+ Institute for Health and Care Research, VU University &VU University Medical Center, Amsterdam 1081 HV, The Netherlands.
³² Department of Health Sciences, University of Milano, Milano 20122, Italy.
³³ Carolina Population Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
³⁴ Department of Psychology, The Ohio State University, 1835 Neil Avenue, Columbus, Ohio 43210, USA.
³⁵ Department of Cardiology, University of Groningen, University Medical Center Groningen, PO Box 30001, Groningen 9700 RB, The Netherlands.
³⁶ MRC Unit for Lifelong Health and Ageing, University College London, 33 Bedford Place, London WC1B 5JU, UK.
³⁷ Institute of Psychiatry, Psychology &Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, UK.
³⁸ University College London Genetics Institute, University College London, London WC1E 6BT, UK.
³⁹ Department of Public Health, Academic Medical Center (AMC), University of Amsterdam, Amsterdam 1105 AZ, The Netherlands.
⁴⁰ Department of Obstetrics and Gynaecology, Academic Medical Centre, University of Amsterdam, Amsterdam 1105 AZ, The Netherlands.
⁴¹ Department of Physiology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat Al-Khoudh 123, Sultanate of Oman.
⁴² Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
⁴³ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, USA.
⁴⁴ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
⁴⁵ Unit of Primary Health Care, Oulu University Hospital, Oulu 90220, Finland.
⁴⁶ Department of Medical Sciences, Molecular Medicine, Uppsala University, Uppsala 75237, Sweden.
⁴⁷ Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
⁴⁸ Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
⁴⁹ College of Medicine, Mohammed Bin Rashid University, PO Box 505055, Dubai Healthcare City, United Arab Emirates.
⁵⁰ Department of Epidemiology and Public Health, University College London, London WC1E 6BT, UK.
⁵¹ Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
⁵² Program in Medical and Population Genetics, The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02114, USA.
⁵³ Department of Medical Research, Bærum Hospital, Vestre Viken Hospital Trust, Rud 1346, Norway.
⁵⁴ Department of Child- and Adolescent Psychiatry, University of Groningen, University Medical Center Groningen, PO Box 30001, Groningen 9700 RB, The Netherlands.
⁵⁵ Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
⁵⁶ Cardiology, Department of Specialties of Internal Medicine, Geneva University Hospital, Geneva 1211, Switzerland.
⁵⁷ Cardiac Arrhythmia Service &Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
⁵⁸ Department of Cardiology, University of Tampere School of Medicine, Tampere 33014, Finland.
⁵⁹ University Health Network and Mount Sinai Hospital Division of Cardiology, Department of Medicine, University of Toronto, Ontario, Canada M5S.
⁶⁰ Toronto General Research Institute, University Health Network, Toronto, Canada.
⁶¹ Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden.
⁶² Department of Public Health and Caring Sciences, Molecular Geriatrics, Uppsala University, Uppsala 75237, Sweden.
⁶³ Interdisciplinary Center Psychopathology and Emotion regulation, Department of Psychiatry, University of Groningen, University Medical Center Groningen, PO Box 30001, Groningen 9700 RB, The Netherlands.
⁶⁴ CAPES Foundation, Ministry of Education of Brazil, Brasília DF 70040-020, Brazil.
⁶⁵ Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu 90220, Finland.
⁶⁶ Department of Pediatrics, Tampere University Hospital, Tampere 33521, Finland.
⁶⁷ Department of Pediatrics, University of Tampere School of Medicine, Tampere 33014, Finland.
⁶⁸ INSERM U970, Paris Descartes University, Paris 75006, France.
⁶⁹ Department of Medicine, University of Turku, Turku 20520, Finland.
⁷⁰ Division of Medicine, Turku University Hospital, Turku 20521, Finland.
⁷¹ Department of Medical Informatics, Erasmus Medical Center, Rotterdam 3015 CE, The Netherlands.
⁷² ISER, Essex University, Colchester, Essex CO4 3SQ, UK.
⁷³ Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven 3000, Belgium.
⁷⁴ Department of Internal Medicine, Division of Vascular Medicine, University of Groningen, University Medical Center Groningen, PO Box 30001, Groningen 9700 RB, The Netherlands.
⁷⁵ Division of Genetic Epidemiology, Institute for Medical Biometry and Statistics, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg 79110, Germany.
⁷⁶ Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
⁷⁷ Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
⁷⁸ Department of Computer Science, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
⁷⁹ Division of Epidemiology, Department of Public Health Sciences, Penn State University College of Medicine, Hershey, Pennsylvania 17033, USA.
⁸⁰ Division of Cardiovascular Medicine, University of Florida College of Medicine, Gainesville, Florida 32611, USA.
⁸¹ Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502, USA.
⁸² Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California 90502, USA.
⁸³ Li Ka Shing Centre for Health Information and Discovery, The Big Data Institute, University of Oxford, Oxford OX3 7BN, UK.
⁸⁴ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
⁸⁵ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
⁸⁶ Biopharmacy, Department Pharmaceutical Sciences, University of Basel, Basel CH-4056, Switzerland.
⁸⁷ Department of Biostatistics, University of Liverpool, Liverpool L69 3GL, UK.
⁸⁸ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.
⁸⁹ Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, PO Box 30001, Groningen 9700 RB, The Netherlands.
⁹⁰ Department of Cardiology, University of Tampere, School of Medicine, Tampere 33014, Finland.
⁹¹ Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
⁹² Department of Medicine, University of California, San Diego, San Diego, California 92093, USA.
⁹³ Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg 85764, Germany.
⁹⁴ German Center for Diabetes Research, Neuherberg 85764, Germany.
⁹⁵ Departments of Epidemiology and Health Services, University of Washington, Seattle, Washington 98195, USA.
⁹⁶ Group Health Research Institute, Group Health Cooperative, Seattle, Washington 98101, USA.
⁹⁷ Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku 20521, Finland.
⁹⁸ Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20520, Finland.
⁹⁹ The New York Academy of Medicine, New York, New York 10029, USA.
¹⁰⁰ Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington 98195, USA.
¹⁰¹ Seattle Epidemiologic Research and Information Center, Veterans Affairs Office of Research and Development, Seattle, Washington 98108, USA.
¹⁰² Epidemiological Cardiology Research Center (EPICARE), Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.
¹⁰³ Cardiovascular Health Research Unit, Division of Cardiology, Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington 98101, USA.
¹⁰⁴ Heart Rate Variability Lab, Washington University School of Medicine, St Louis, Missouri 63108, USA.
¹⁰⁵ First Department of Cardiology, Interventional Electrocardiology and Hypertension, Jagiellonian University Medical College, Cracow 31-008, Poland.
¹⁰⁶ Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich 81377, Germany.
¹⁰⁷ Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala 751 85, Sweden.
¹⁰⁸ Department of Cardiology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands.
¹⁰⁹ Université de Montréal, Montreal, Quebec, Canada H3T IJ4.
¹¹⁰ Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90509, USA.
¹¹¹ Institute for Community Medicine, University Medicine Greifswald, Greifswald 17475, Germany.
¹¹² Department of Internal Medicine, Erasmus University Medical Center, Rotterdam 3015 CE, The Netherlands.
¹¹³ Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging NCHA), Leiden 2300 RC, The Netherlands.
¹¹⁴ Institute of Innovative Health Technologies-IGHT Jena Ernst-Abbe-Hochschule Jena, Jena 07745, Germany.
¹¹⁵ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg 85764, Germany.
¹¹⁶ Departments of Genetics and Neurology University of North Carolina, Chapel Hill, North Carolina 27599, USA.
¹¹⁷ The Renaissance Computing Institute, Chapel Hill, North Carolina 27599, USA.
¹¹⁸ Department of Epidemiology &Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157, USA.
¹¹⁹ Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
¹²⁰ Institute of Biomedical Technologies, CNR-Italian National Research Council, Milan 20090, Italy.
¹²¹ KOS Genetic SRL, Bresso (Milano) 20091, Italy.
¹²² German Cancer Research Centre, Division of Cancer Epidemiology, Heidelberg 69210, Germany.
¹²³ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
¹²⁴ Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, St Mary's campus, Imperial College London, London W2 1PG, UK.
¹²⁵ Biocenter Oulu University of Oulu, Oulu 90014, Finland.
¹²⁶ Department of Clinical Physiology, Tampere University Hospital, Tampere 33521, Finland.
¹²⁷ Department of Clinical Physiology, University of Tampere, School of Medicine, Tampere 33014, Finland.
¹²⁸ Cardiology Section, Boston Veteran's Administration Healthcare, Boston, Maryland 02132, USA.
¹²⁹ Inspectorate for Health Care, The Hague 2511 VX, The Netherlands.
¹³⁰ Institute of Cardiovascular Science, University College London, 222 Euston Road, London NW1 2DA, UK.
¹³¹ Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht 3501 DG, The Netherlands.
¹³² Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, De Boelelaan 1118, Amsterdam 1081 HV, The Netherlands.
¹³³ Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

PMID: 28613276
PMCID: PMC5474732
DOI: 10.1038/ncomms15805

Erratum in

Erratum: Genetic loci associated with heart rate variability and their effects on cardiac disease risk.
Nolte IM, Munoz ML, Tragante V, Amare AT, Jansen R, Vaez A, von der Heyde B, Avery CL, Bis JC, Dierckx B, van Dongen J, Gogarten SM, Goyette P, Hernesniemi J, Huikari V, Hwang SJ, Jaju D, Kerr KF, Kluttig A, Krijthe BP, Kumar J, van der Laan SW, Lyytikäinen LP, Maihofer AX, Minassian A, van der Most PJ, Müller-Nurasyid M, Nivard M, Salvi E, Stewart JD, Thayer JF, Verweij N, Wong A, Zabaneh D, Zafarmand MH, Abdellaoui A, Albarwani S, Albert C, Alonso A, Ashar F, Auvinen J, Axelsson T, Baker DG, de Bakker PIW, Barcella M, Bayoumi R, Bieringa RJ, Boomsma D, Boucher G, Britton AR, Christophersen I, Dietrich A, Ehret GB, Ellinor PT, Eskola M, Felix JF, Floras JS, Franco OH, Friberg P, Gademan MGJ, Geyer MA, Giedraitis V, Hartman CA, Hemerich D, Hofman A, Hottenga JJ, Huikuri H, Hutri-Kähönen N, Jouven X, Junttila J, Juonala M, Kiviniemi AM, Kors JA, Kumari M, Kuznetsova T, Laurie CC, Lefrandt JD, Li Y, Li Y, Liao D, Limacher MC, Lin HJ, Lindgren CM, Lubitz SA, Mahajan A, McKnight B, Zu Schwabedissen HM, Milaneschi Y, Mononen N, Morris AP, Nalls MA, Navis G, Neijts M, Nikus K, North KE, O'Connor DT, Ormel J, Perz S, Peters A, Psaty BM, Raitakari OT, Risbrough VB, Sinner MF, Siscovick D,… See abstract for full author list ➔ Nolte IM, et al. Nat Commun. 2017 Aug 2;8:16140. doi: 10.1038/ncomms16140. Nat Commun. 2017. PMID: 28767105 Free PMC article.

Abstract

Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (-0.74<r_g<-0.55) and blood pressure (-0.35<r_g<-0.20). These findings provide clinically relevant biological insight into heritable variation in vagal heart rhythm regulation, with a key role for genetic variants (GNG11, RGS6) that influence G-protein heterotrimer action in GIRK-channel induced pacemaker membrane hyperpolarization.

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Conflict of interest statement

M.A.G. has an equity interest in San Diego Instruments. B.M.P. serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. The remaining authors declare no competing financial interests.

Figures

**Figure 1. Manhattan plots of the meta-analyses of stage 1 GWAS results.**
(a) SDNN, (b) RMSSD and (c) pvRSA/HF in up to 28,700 individuals of European ancestry. Only SNPs with a minor allele frequency >1% and that were present in at least 1/3 of the sample are plotted. Significant loci are shown in blue, suggestive ones in red. The blue horizontal line represents the genome-wide significance threshold. Genes closest to the lead SNPs are indicated for the loci that were genome-wide significantly associated with the trait after the stage 1+2 combined meta-analysis.

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References

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Genetic loci associated with heart rate variability and their effects on cardiac disease risk

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Genetic loci associated with heart rate variability and their effects on cardiac disease risk

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Erratum in

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