Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease

doi:10.1038/s41467-023-36997-w

. 2023 Mar 14;14(1):1411.

doi: 10.1038/s41467-023-36997-w.

Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease

William J Young^{1

2}, Jeffrey Haessler³, Jan-Walter Benjamins⁴, Linda Repetto⁵, Jie Yao⁶, Aaron Isaacs^{7

8}, Andrew R Harper^{9

10}, Julia Ramirez^{1

11

12}, Sophie Garnier^{13

14}, Stefan van Duijvenboden^{1

11}, Antoine R Baldassari¹⁵, Maria Pina Concas¹⁶, ThuyVy Duong¹⁷, Luisa Foco¹⁸, Jonas L Isaksen¹⁹, Hao Mei²⁰, Raymond Noordam²¹, Casia Nursyifa²², Anne Richmond²³, Meddly L Santolalla^{24

25}, Colleen M Sitlani²⁶, Negin Soroush²⁷, Sébastien Thériault^{28

29}, Stella Trompet^{21

30}, Stefanie Aeschbacher³¹, Fariba Ahmadizar^{27

32}, Alvaro Alonso³³, Jennifer A Brody²⁶, Archie Campbell^{34

35

36}, Adolfo Correa³⁷, Dawood Darbar³⁸, Antonio De Luca³⁹, Jean-François Deleuze^{40

41

42}, Christina Ellervik^{43

44

45}, Christian Fuchsberger^{18

46

47}, Anuj Goel^{9

10}, Christopher Grace^{9

10}, Xiuqing Guo^{6

48

49}, Torben Hansen²², Susan R Heckbert^{26

50}, Rebecca D Jackson⁵¹, Jan A Kors⁵², Maria Fernanda Lima-Costa⁵³, Allan Linneberg^{54

55}, Peter W Macfarlane⁵⁶, Alanna C Morrison⁵⁷, Pau Navarro²³, David J Porteous^{36

58}, Peter P Pramstaller^{18

59}, Alexander P Reiner^{50

60}, Lorenz Risch^{61

62

63}, Ulrich Schotten⁷, Xia Shen^{5

64

65}, Gianfranco Sinagra³⁹, Elsayed Z Soliman⁶⁶, Monika Stoll^{8

67

68}, Eduardo Tarazona-Santos²⁴, Andrew Tinker^{1

69}, Katerina Trajanoska⁷⁰, Eric Villard^{13

14}, Helen R Warren^{1

69}, Eric A Whitsel^{15

71}, Kerri L Wiggins²⁶, Dan E Arking¹⁷, Christy L Avery¹⁵, David Conen²⁸, Giorgia Girotto^{16

72}, Niels Grarup²², Caroline Hayward⁷³, J Wouter Jukema^{30

74

75}, Dennis O Mook-Kanamori^{76

77}, Morten Salling Olesen⁷⁸, Sandosh Padmanabhan⁷⁹, Bruce M Psaty^{26

50

80}, Cristian Pattaro¹⁸, Antonio Luiz P Ribeiro^{81

82}, Jerome I Rotter^{6

48

83}, Bruno H Stricker²⁷, Pim van der Harst^{4

84}, Cornelia M van Duijn^{85

86}, Niek Verweij⁴, James G Wilson^{87

88}, Michele Orini^{2

11}, Philippe Charron^{13

14

89

90}, Hugh Watkins^{9

10}, Charles Kooperberg³, Henry J Lin^{6

48

49}, James F Wilson^{5

23}, Jørgen K Kanters¹⁹, Nona Sotoodehnia⁹¹, Borbala Mifsud^{1

92}, Pier D Lambiase^{2

11}, Larisa G Tereshchenko^{93

94}, Patricia B Munroe^{95

96}

Affiliations

¹ William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London, UK.
² Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS trust, London, UK.
³ Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
⁴ University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, the Netherlands.
⁵ Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, Scotland.
⁶ Institute for Translational Genomics and Population Sciences/The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁷ Dept. of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.
⁸ Maastricht Center for Systems Biology (MaCSBio), Maastricht University, Maastricht, the Netherlands.
⁹ Radcliffe Department of Medicine, University of Oxford, Division of Cardiovascular Medicine, John Radcliffe Hospital, Oxford, UK.
¹⁰ Wellcome Centre for Human Genetics, Roosevelt Drive, Oxford, UK.
¹¹ Institute of Cardiovascular Sciences, University of College London, London, UK.
¹² Aragon Institute of Engineering Research, University of Zaragoza, Zaragoza, Spain and Center of Biomedical Research Network, Bioengineering, Biomaterials and Nanomedicine, Zaragoza, Spain.
¹³ Sorbonne Universite, INSERM, UMR-S1166, Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics & Pathophysiology of Cardiovascular Disease, Paris, 75013, France.
¹⁴ ICAN Institute for Cardiometabolism and Nutrition, Paris, 75013, France.
¹⁵ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁶ Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy.
¹⁷ McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁸ Eurac Research, Institute for Biomedicine (affiliated with the University of Lübeck), Bolzano, Italy.
¹⁹ Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
²⁰ Department of Data Science, University of Mississippi Medical Center, Jackson, MS, USA.
²¹ Department of Internal Medicine, section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
²² Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²³ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland.
²⁴ Department of Genetics, Ecology and Evolution, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
²⁵ Emerge, Emerging Diseases and Climate Change Research Unit, School of Public Health and Administration, Universidad Peruana Cayetano Heredia, Lima, 15152, Peru.
²⁶ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
²⁷ Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
²⁸ Population Health Research Institute, McMaster University, Hamilton, ON, Canada.
²⁹ Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Quebec, QC, Canada.
³⁰ Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
³¹ Cardiovascular Research Institute Basel, University Hospital Basel, University of Basel, Basel, Switzerland.
³² Julius Global Health, University Utrecht Medical Center, Utrecht, the Netherlands.
³³ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
³⁴ Usher Institute, University of Edinburgh, Nine, Edinburgh Bioquarter, 9 Little France Road, Edinburgh, UK.
³⁵ Health Data Research UK, University of Edinburgh, Nine, Edinburgh Bioquarter, 9 Little France Road, Edinburgh, UK.
³⁶ Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
³⁷ Departments of Medicine, Pediatrics and Population Health Science, University of Mississippi Medical Center, Jackson, MS, USA.
³⁸ Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
³⁹ Cardiothoracovascular Department, Division of Cardiology, Azienda Sanitaria Universitaria Giuliano Isontina and University of Trieste, Trieste, Italy.
⁴⁰ Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 91057, Evry, France.
⁴¹ Laboratory of Excellence GENMED (Medical Genomics), Paris, France.
⁴² Centre d'Etude du Polymorphisme Humain, Fondation Jean Dausset, Paris, France.
⁴³ Department of Data and Data Support, Region Zealand, 4180, Sorø, Denmark.
⁴⁴ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark.
⁴⁵ Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA.
⁴⁶ Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁴⁷ Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁴⁸ Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA.
⁴⁹ Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
⁵⁰ Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁵¹ Center for Clinical and Translational Science, Ohio State Medical Center, Columbus, OH, USA.
⁵² Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁵³ Instituto René Rachou, fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.
⁵⁴ Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, København, Denmark.
⁵⁵ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵⁶ Institute of Health and Wellbeing, School of Health and Wellbeing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
⁵⁷ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁵⁸ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
⁵⁹ Department of Neurology, University of Lübeck, Lübeck, Germany.
⁶⁰ Fred Hutchinson Cancer Center, University of Washington, Seattle, WA, USA.
⁶¹ Labormedizinisches zentrum Dr. Risch, Vaduz, Liechtenstein.
⁶² Faculty of Medical Sciences, Private University in the Principality of Liechtenstein, Triesen, Liechtenstein.
⁶³ Center of Laboratory Medicine, University Institute of Clinical Chemistry, University of Bern, Inselspital, Bern, Switzerland.
⁶⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁶⁵ Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Nansha District, Guangzhou, China.
⁶⁶ Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston Salem, NC, USA.
⁶⁷ Dept. of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.
⁶⁸ Institute of Human Genetics, Genetic Epidemiology, University of Muenster, Muenster, Germany.
⁶⁹ NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁷⁰ Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
⁷¹ Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA.
⁷² Department of Medical, Surgery and Health Sciences, University of Trieste, Trieste, Italy.
⁷³ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
⁷⁴ Netherlands Heart Institute, Utrecht, the Netherlands.
⁷⁵ Durrer Center for Cardiovascular Research, Amsterdam, the Netherlands.
⁷⁶ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands, Leiden, the Netherlands.
⁷⁷ Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands, Leiden, the Netherlands.
⁷⁸ Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷⁹ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
⁸⁰ Department of Health Systems and Population Health, University of Washington, Seattte, WA, USA.
⁸¹ Department of Internal Medicine, Faculdade de Medicina, Universidade Federal de Minas Gerais, Brazil, Belo Horizonte, Minas Gerais, Brazil.
⁸² Cardiology Service and Telehealth Center, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil, Belo Horizonte, Minas Gerais, Brazil.
⁸³ Departments of Pediatrics and Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
⁸⁴ Department of Cardiology, Heart and Lung Division, University Medical Center Utrecht, Utrecht, the Netherlands.
⁸⁵ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁸⁶ Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
⁸⁷ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
⁸⁸ Department of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁸⁹ APHP, Cardiology Department, Pitié-Salpêtrière Hospital, Paris, 75013, France.
⁹⁰ APHP, Département de Génétique, Centre de Référence Maladies Cardiaques Héréditaires, Pitié-Salpêtrière Hospital, Paris, 75013, France.
⁹¹ Cardiovascular Health Research Unit, Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA, USA.
⁹² Genomics and Translational Biomedicine, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
⁹³ Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. tereshl@ccf.org.
⁹⁴ Department of Medicine, Cardiovascular Division, Johns Hopkins University, School of Medicine, Baltimore, MD, USA. tereshl@ccf.org.
⁹⁵ William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London, UK. p.b.munroe@qmul.ac.uk.
⁹⁶ NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. p.b.munroe@qmul.ac.uk.

PMID: 36918541
PMCID: PMC10015012
DOI: 10.1038/s41467-023-36997-w

Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease

William J Young et al. Nat Commun. 2023.

. 2023 Mar 14;14(1):1411.

doi: 10.1038/s41467-023-36997-w.

Authors

Affiliations

¹ William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London, UK.
² Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS trust, London, UK.
³ Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
⁴ University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, the Netherlands.
⁵ Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, Scotland.
⁶ Institute for Translational Genomics and Population Sciences/The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁷ Dept. of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.
⁸ Maastricht Center for Systems Biology (MaCSBio), Maastricht University, Maastricht, the Netherlands.
⁹ Radcliffe Department of Medicine, University of Oxford, Division of Cardiovascular Medicine, John Radcliffe Hospital, Oxford, UK.
¹⁰ Wellcome Centre for Human Genetics, Roosevelt Drive, Oxford, UK.
¹¹ Institute of Cardiovascular Sciences, University of College London, London, UK.
¹² Aragon Institute of Engineering Research, University of Zaragoza, Zaragoza, Spain and Center of Biomedical Research Network, Bioengineering, Biomaterials and Nanomedicine, Zaragoza, Spain.
¹³ Sorbonne Universite, INSERM, UMR-S1166, Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics & Pathophysiology of Cardiovascular Disease, Paris, 75013, France.
¹⁴ ICAN Institute for Cardiometabolism and Nutrition, Paris, 75013, France.
¹⁵ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁶ Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy.
¹⁷ McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁸ Eurac Research, Institute for Biomedicine (affiliated with the University of Lübeck), Bolzano, Italy.
¹⁹ Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
²⁰ Department of Data Science, University of Mississippi Medical Center, Jackson, MS, USA.
²¹ Department of Internal Medicine, section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
²² Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²³ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, Scotland.
²⁴ Department of Genetics, Ecology and Evolution, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
²⁵ Emerge, Emerging Diseases and Climate Change Research Unit, School of Public Health and Administration, Universidad Peruana Cayetano Heredia, Lima, 15152, Peru.
²⁶ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
²⁷ Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
²⁸ Population Health Research Institute, McMaster University, Hamilton, ON, Canada.
²⁹ Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Quebec, QC, Canada.
³⁰ Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands.
³¹ Cardiovascular Research Institute Basel, University Hospital Basel, University of Basel, Basel, Switzerland.
³² Julius Global Health, University Utrecht Medical Center, Utrecht, the Netherlands.
³³ Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
³⁴ Usher Institute, University of Edinburgh, Nine, Edinburgh Bioquarter, 9 Little France Road, Edinburgh, UK.
³⁵ Health Data Research UK, University of Edinburgh, Nine, Edinburgh Bioquarter, 9 Little France Road, Edinburgh, UK.
³⁶ Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
³⁷ Departments of Medicine, Pediatrics and Population Health Science, University of Mississippi Medical Center, Jackson, MS, USA.
³⁸ Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
³⁹ Cardiothoracovascular Department, Division of Cardiology, Azienda Sanitaria Universitaria Giuliano Isontina and University of Trieste, Trieste, Italy.
⁴⁰ Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), 91057, Evry, France.
⁴¹ Laboratory of Excellence GENMED (Medical Genomics), Paris, France.
⁴² Centre d'Etude du Polymorphisme Humain, Fondation Jean Dausset, Paris, France.
⁴³ Department of Data and Data Support, Region Zealand, 4180, Sorø, Denmark.
⁴⁴ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2100, Copenhagen, Denmark.
⁴⁵ Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA.
⁴⁶ Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁴⁷ Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁴⁸ Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA.
⁴⁹ Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
⁵⁰ Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁵¹ Center for Clinical and Translational Science, Ohio State Medical Center, Columbus, OH, USA.
⁵² Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁵³ Instituto René Rachou, fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.
⁵⁴ Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, København, Denmark.
⁵⁵ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁵⁶ Institute of Health and Wellbeing, School of Health and Wellbeing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
⁵⁷ Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁵⁸ Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
⁵⁹ Department of Neurology, University of Lübeck, Lübeck, Germany.
⁶⁰ Fred Hutchinson Cancer Center, University of Washington, Seattle, WA, USA.
⁶¹ Labormedizinisches zentrum Dr. Risch, Vaduz, Liechtenstein.
⁶² Faculty of Medical Sciences, Private University in the Principality of Liechtenstein, Triesen, Liechtenstein.
⁶³ Center of Laboratory Medicine, University Institute of Clinical Chemistry, University of Bern, Inselspital, Bern, Switzerland.
⁶⁴ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁶⁵ Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Nansha District, Guangzhou, China.
⁶⁶ Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston Salem, NC, USA.
⁶⁷ Dept. of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.
⁶⁸ Institute of Human Genetics, Genetic Epidemiology, University of Muenster, Muenster, Germany.
⁶⁹ NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁷⁰ Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
⁷¹ Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA.
⁷² Department of Medical, Surgery and Health Sciences, University of Trieste, Trieste, Italy.
⁷³ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
⁷⁴ Netherlands Heart Institute, Utrecht, the Netherlands.
⁷⁵ Durrer Center for Cardiovascular Research, Amsterdam, the Netherlands.
⁷⁶ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands, Leiden, the Netherlands.
⁷⁷ Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands, Leiden, the Netherlands.
⁷⁸ Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁷⁹ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
⁸⁰ Department of Health Systems and Population Health, University of Washington, Seattte, WA, USA.
⁸¹ Department of Internal Medicine, Faculdade de Medicina, Universidade Federal de Minas Gerais, Brazil, Belo Horizonte, Minas Gerais, Brazil.
⁸² Cardiology Service and Telehealth Center, Hospital das Clínicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil, Belo Horizonte, Minas Gerais, Brazil.
⁸³ Departments of Pediatrics and Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
⁸⁴ Department of Cardiology, Heart and Lung Division, University Medical Center Utrecht, Utrecht, the Netherlands.
⁸⁵ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁸⁶ Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
⁸⁷ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
⁸⁸ Department of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
⁸⁹ APHP, Cardiology Department, Pitié-Salpêtrière Hospital, Paris, 75013, France.
⁹⁰ APHP, Département de Génétique, Centre de Référence Maladies Cardiaques Héréditaires, Pitié-Salpêtrière Hospital, Paris, 75013, France.
⁹¹ Cardiovascular Health Research Unit, Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA, USA.
⁹² Genomics and Translational Biomedicine, College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
⁹³ Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. tereshl@ccf.org.
⁹⁴ Department of Medicine, Cardiovascular Division, Johns Hopkins University, School of Medicine, Baltimore, MD, USA. tereshl@ccf.org.
⁹⁵ William Harvey Research Institute, Clinical Pharmacology, Queen Mary University of London, London, UK. p.b.munroe@qmul.ac.uk.
⁹⁶ NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. p.b.munroe@qmul.ac.uk.

PMID: 36918541
PMCID: PMC10015012
DOI: 10.1038/s41467-023-36997-w

Abstract

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.

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Conflict of interest statement

B.M.P serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. D.C has received speaker fees from BMS/Pfizer and Servier, and consultation fees from Roche Diagnostics and Trimedics. U.S received consultancy fees or honoraria from Università della Svizzera Italiana (USI, Switzerland), Roche Diagnostics (Switzerland), EP Solutions Inc. (Switzerland), Johnson & Johnson Medical Limited, (United Kingdom), Bayer Healthcare (Germany). D.O.M.-K is a part time research consultant at Metabolon, Inc. U.S is co-founder and shareholder of YourRhythmics BV, a spin-off company of the University Maastricht. The remaining authors declare no competing interests.

Figures

**Fig. 1. Graphical representation of the spQRSTa and fQRSTa alongside a single electrocardiogram lead signal.**
a Single lead electrocardiogram (ECG) signal with classical measures QRS duration and the QT interval labelled. The dark orange (estimates ventricular depolarization time) and blue (ventricular repolarization time) shaded sections of the signal represent the regions used to calculate the QRS and T-wave axes respectively with multiple ECG leads. b The spatial QRS-T angle (spQRSTa) mean is the angle between the mean amplitude of QRS and T-wave spatial loops. These spatial loops can be constructed from the resting 12-lead ECG using a standardised transformation, to produce representative X, Y and Z vectors that can be plotted over time. c The frontal QRS-T angle (fQRSTa) is the absolute difference between QRS and T-wave axes in the frontal plane only.

**Fig. 2. Manhattan plot for the spQRSTa multi-ancestry meta-analysis.**
Manahattan plot for the spatial QRS-T angle (spQRSTa) meta-analysis. Two-sided P-values are plotted on the -log₁₀ scale (Y-axis). The red horizontal line indicates genome-wide significance (P < 5 × 10⁻⁸). Variants within the boundaries of loci previously reported for the spatial QRS-T angle are labelled with the candidate gene and colored blue. Variants at previously unreported loci are green.

**Fig. 3. Manhattan plot for the fQRSTa multi-ancestry meta-analysis.**
Manahattan plot for the frontal QRS-T angle (fQRSTA) meta-analysis. Two-sided P-values are plotted on the -log₁₀ scale (Y-axis). The red horizontal line indicates genome-wide significance (P < 5 × 10⁻⁸). Variants within the boundaries of loci previously reported for the spatial QRS-T angle are labelled with the candidate gene and colored blue. Variants at previously unreported loci are green.

**Fig. 4. Significant GO biological processes from spQRSTa DEPICT multi-ancestry findings.**
All significant (false discovery rate <0.01) multi-ancestry spatial QRS-T angle (spQRSTa) gene-ontology (GO) biological processes from Data-driven Expression-Prioritization Integration for Complex Traits (DEPICT) software were analyzed using the Reduce and Visualize Gene Ontology (REVIGO) web application to remove redundant terms and cluster related nodes. Highly similar GO terms are linked by edges where the line width indicates the degree of similarity. Within each cluster, the colour gradient represents differences in the DEPICT gene-set enrichment two-sided P-values, with lighter gradients reflecting smaller enrichment P-values (therefore more significant) compared with other nodes in the same cluster.

**Fig. 5. Overlap of multi-ancestry spQRSTa loci with ECG measures.**
Venn diagram showing spatial QRS-T angle (spQRSTa) multi-ancestry loci where a lead variant reported for another electrocardiographic ECG measure maps within the locus boundaries. For this figure, ECG measures shown are PR interval (cardiac conduction), QRS duration (ventricular depolarization), QT and JT intervals (ventricular repolarization) and heart rate (HR). Overlap was declared if a lead variant for these ECG measures mapped to within ±500 kb or r² > 0.1 of a lead variant at a spQRSTa locus. Some loci overlap with other ECG traits (not visualised here but presented in Supplementary Data 15). At seven spQRSTa loci, no overlap was observed with any ECG trait (blue circle bottom right).

**Fig. 6. Significant associations observed in phenome-wide association study of lead and conditionally independent spQRSTa variants.**
X-axis: Lead variant (RsID [Chromosome: Position (hg19): Allele1: Allele2]) or conditionally independent variant from the spatial QRS-T angle (spQRSTa) European ancestry meta-analysis that had a significant association with a clinical phenotype in UK Biobank. Y-axis: Phenotype derived from hospital episode statistics, with colour coding for each major group (circulatory system; red, digestive system; green, neoplasms; yellow, respiratory; blue). Odds ratios (OR) are color coded according to decreasing (blue) or increasing (green) odds. 3:38587306:A:G was a conditionally independent variant at the *SCN5A* locus.

**Fig. 7. Illustration of candidate genes at spQRSTa multi-ancestry loci and their potential function.**
Candidate genes at spatial QRS-T angle (spQRSTa) loci are grouped according to potential roles in embryonic development, cardiac structure and function. *RYR2* and *ACTN2* are candidate genes from the same locus. A summary of the bioinformatic evidence for each gene is presented in Supplementary Data 14. Created using BioRender.com.

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References

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[1] Fishman GI, et al. Sudden cardiac death prediction and prevention: report from a national heart, lung, and blood institute and heart rhythm society workshop. Circulation. 2010;122:2335–2348. doi: 10.1161/CIRCULATIONAHA.110.976092. - DOI - PMC - PubMed

[2] Fishman GI, et al. Sudden cardiac death prediction and prevention: report from a national heart, lung, and blood institute and heart rhythm society workshop. Circulation. 2010;122:2335–2348. doi: 10.1161/CIRCULATIONAHA.110.976092. - DOI - PMC - PubMed

[3] Joukar S. A comparative review on heart ion channels, action potentials and electrocardiogram in rodents and human: extrapolation of experimental insights to clinic. Lab. Anim. Res. 2021;37:25. doi: 10.1186/s42826-021-00102-3. - DOI - PMC - PubMed

[4] Joukar S. A comparative review on heart ion channels, action potentials and electrocardiogram in rodents and human: extrapolation of experimental insights to clinic. Lab. Anim. Res. 2021;37:25. doi: 10.1186/s42826-021-00102-3. - DOI - PMC - PubMed

[5] Oehler A, Feldman T, Henrikson CA, Tereshchenko LG. QRS-T angle: a review. Ann. Noninvasive Electrocardiol. 2014;19:534–542. doi: 10.1111/anec.12206. - DOI - PMC - PubMed

[6] Oehler A, Feldman T, Henrikson CA, Tereshchenko LG. QRS-T angle: a review. Ann. Noninvasive Electrocardiol. 2014;19:534–542. doi: 10.1111/anec.12206. - DOI - PMC - PubMed

[7] Plonsey R. A contemporary view of the ventricular gradient of Wilson. J. Electrocardiol. 1979;12:337–341. doi: 10.1016/S0022-0736(79)80001-1. - DOI - PubMed

[8] Plonsey R. A contemporary view of the ventricular gradient of Wilson. J. Electrocardiol. 1979;12:337–341. doi: 10.1016/S0022-0736(79)80001-1. - DOI - PubMed

[9] Young, W. et al. Comparisons of the spatial QRS-T angle with intra-cardiac markers of depolarization and repolarization. Comput. Cardiol. 2020 Computing in Cardiology, Rimini, Italy, pp. 1–4 (2020).

[10] Young, W. et al. Comparisons of the spatial QRS-T angle with intra-cardiac markers of depolarization and repolarization. Comput. Cardiol. 2020 Computing in Cardiology, Rimini, Italy, pp. 1–4 (2020).

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Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease

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Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease

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