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

William J. Young, Jeffrey Haessler, Jan-Walter Benjamins, Linda Repetto, Jie Yao, Aaron Isaacs, Andrew R. Harper, Julia Ramirez, Sophie Garnier, Stefan Duijvenboden, Antoine R. Baldassari, Maria Pina Concas, ThuyVy Duong, Luisa Foco, Jonas L. Isaksen, Hao Mei, Raymond Noordam, Casia Nursyifa, Anne Richmond, Meddly L. Santolalla, Colleen M. Sitlani, Negin Soroush, Sébastien Thériault, Stella Trompet, Stefanie Aeschbacher, Fariba Ahmadizar, Alvaro Alonso, Jennifer A. Brody, Archie Campbell, Adolfo Correa, Dawood Darbar, Antonio Luca, Jean-François Deleuze, Christina Ellervik, Christian Fuchsberger, Anuj Goel, Christopher Grace, Xiuqing Guo, Torben Hansen, Susan R. Heckbert, Rebecca D. Jackson, Jan A. Kors, Maria Fernanda Lima-Costa, Allan Linneberg, Peter W. Macfarlane, Alanna C. Morrison, Pau Navarro, David J. Porteous, Peter P. Pramstaller, Alexander P. Reiner, Lorenz Risch, Ulrich Schotten, Xia Shen, Gianfranco Sinagra, Elsayed Z. Soliman, Monika Stoll, Eduardo Tarazona-Santos, Andrew Tinker, Katerina Trajanoska, Eric Villard, Helen R. Warren, Eric A. Whitsel, Kerri L. Wiggins, Dan E. Arking, Christy L. Avery, David Conen, Giorgia Girotto, Niels Grarup, Caroline Hayward, J.Wouter Jukema, Dennis O. Mook-Kanamori, Morten Salling Olesen, Sandosh Padmanabhan, Bruce M. Psaty, Cristian Pattaro, Antonio Luiz P. Ribeiro, Jerome I. Rotter, Bruno H. Stricker, Pim Harst, Cornelia M. Duijn, Niek Verweij, James G. Wilson, Michele Orini, Philippe Charron, Hugh Watkins, Charles Kooperberg, Henry J. Lin, James F. Wilson, Jørgen K. Kanters, Nona Sotoodehnia, Borbala Mifsud, Pier D. Lambiase, Larisa G. Tereshchenko () and Patricia B. Munroe ()
Additional contact information
William J. Young: Queen Mary University of London
Jeffrey Haessler: Fred Hutchinson Cancer Center
Jan-Walter Benjamins: University of Groningen, University Medical Center Groningen, Department of Cardiology
Linda Repetto: Usher Institute, University of Edinburgh
Jie Yao: Institute for Translational Genomics and Population Sciences/The Lundquist Institute at Harbor-UCLA Medical Center
Aaron Isaacs: Cardiovascular Research Institute Maastricht (CARIM), Maastricht University
Andrew R. Harper: University of Oxford, Division of Cardiovascular Medicine, John Radcliffe Hospital
Julia Ramirez: Queen Mary University of London
Sophie Garnier: Sorbonne Universite, INSERM, UMR-S1166, Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics & Pathophysiology of Cardiovascular Disease
Stefan Duijvenboden: Queen Mary University of London
Antoine R. Baldassari: University of North Carolina at Chapel Hill
Maria Pina Concas: Institute for Maternal and Child Health – IRCCS “Burlo Garofolo”
ThuyVy Duong: Johns Hopkins University School of Medicine
Luisa Foco: Eurac Research, Institute for Biomedicine (affiliated with the University of Lübeck)
Jonas L. Isaksen: University of Copenhagen
Hao Mei: University of Mississippi Medical Center
Raymond Noordam: Leiden University Medical Center
Casia Nursyifa: University of Copenhagen
Anne Richmond: University of Edinburgh
Meddly L. Santolalla: Universidade Federal de Minas Gerais
Colleen M. Sitlani: University of Washington
Negin Soroush: Erasmus Medical Center
Sébastien Thériault: Population Health Research Institute, McMaster University
Stella Trompet: Leiden University Medical Center
Stefanie Aeschbacher: University Hospital Basel, University of Basel
Fariba Ahmadizar: Erasmus Medical Center
Alvaro Alonso: Rollins School of Public Health, Emory University
Jennifer A. Brody: University of Washington
Archie Campbell: Usher Institute, University of Edinburgh
Adolfo Correa: University of Mississippi Medical Center
Dawood Darbar: University of Illinois at Chicago
Antonio Luca: Azienda Sanitaria Universitaria Giuliano Isontina and University of Trieste
Jean-François Deleuze: Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH)
Christina Ellervik: Department of Data and Data Support, Region Zealand
Christian Fuchsberger: Eurac Research, Institute for Biomedicine (affiliated with the University of Lübeck)
Anuj Goel: University of Oxford, Division of Cardiovascular Medicine, John Radcliffe Hospital
Christopher Grace: University of Oxford, Division of Cardiovascular Medicine, John Radcliffe Hospital
Xiuqing Guo: Institute for Translational Genomics and Population Sciences/The Lundquist Institute at Harbor-UCLA Medical Center
Torben Hansen: University of Copenhagen
Susan R. Heckbert: University of Washington
Rebecca D. Jackson: Ohio State Medical Center
Jan A. Kors: Erasmus University Medical Center
Maria Fernanda Lima-Costa: Instituto René Rachou, fundação Oswaldo Cruz
Allan Linneberg: Bispebjerg and Frederiksberg Hospital
Peter W. Macfarlane: University of Glasgow
Alanna C. Morrison: The University of Texas Health Science Center at Houston
Pau Navarro: University of Edinburgh
David J. Porteous: Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital
Peter P. Pramstaller: Eurac Research, Institute for Biomedicine (affiliated with the University of Lübeck)
Alexander P. Reiner: University of Washington
Lorenz Risch: Labormedizinisches zentrum Dr. Risch
Ulrich Schotten: Cardiovascular Research Institute Maastricht (CARIM), Maastricht University
Xia Shen: Usher Institute, University of Edinburgh
Gianfranco Sinagra: Azienda Sanitaria Universitaria Giuliano Isontina and University of Trieste
Elsayed Z. Soliman: Wake Forest School of Medicine
Monika Stoll: Maastricht University
Eduardo Tarazona-Santos: Universidade Federal de Minas Gerais
Andrew Tinker: Queen Mary University of London
Katerina Trajanoska: Erasmus Medical Center
Eric Villard: Sorbonne Universite, INSERM, UMR-S1166, Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics & Pathophysiology of Cardiovascular Disease
Helen R. Warren: Queen Mary University of London
Eric A. Whitsel: University of North Carolina at Chapel Hill
Kerri L. Wiggins: University of Washington
Dan E. Arking: Johns Hopkins University School of Medicine
Christy L. Avery: University of North Carolina at Chapel Hill
David Conen: Population Health Research Institute, McMaster University
Giorgia Girotto: Institute for Maternal and Child Health – IRCCS “Burlo Garofolo”
Niels Grarup: University of Copenhagen
Caroline Hayward: University of Edinburgh, Western General Hospital
J.Wouter Jukema: Leiden University Medical Center
Dennis O. Mook-Kanamori: Leiden University Medical Center, Leiden, the Netherlands
Morten Salling Olesen: University of Copenhagen
Sandosh Padmanabhan: University of Glasgow
Bruce M. Psaty: University of Washington
Cristian Pattaro: Eurac Research, Institute for Biomedicine (affiliated with the University of Lübeck)
Antonio Luiz P. Ribeiro: Universidade Federal de Minas Gerais, Brazil
Jerome I. Rotter: Institute for Translational Genomics and Population Sciences/The Lundquist Institute at Harbor-UCLA Medical Center
Bruno H. Stricker: Erasmus Medical Center
Pim Harst: University of Groningen, University Medical Center Groningen, Department of Cardiology
Cornelia M. Duijn: University of Oxford
Niek Verweij: University of Groningen, University Medical Center Groningen, Department of Cardiology
James G. Wilson: University of Mississippi Medical Center
Michele Orini: St Bartholomew’s Hospital, Barts Health NHS trust
Philippe Charron: Sorbonne Universite, INSERM, UMR-S1166, Research Unit on Cardiovascular Disorders, Metabolism and Nutrition, Team Genomics & Pathophysiology of Cardiovascular Disease
Hugh Watkins: University of Oxford, Division of Cardiovascular Medicine, John Radcliffe Hospital
Charles Kooperberg: Fred Hutchinson Cancer Center
Henry J. Lin: Institute for Translational Genomics and Population Sciences/The Lundquist Institute at Harbor-UCLA Medical Center
James F. Wilson: Usher Institute, University of Edinburgh
Jørgen K. Kanters: University of Copenhagen
Nona Sotoodehnia: University of Washington
Borbala Mifsud: Queen Mary University of London
Pier D. Lambiase: St Bartholomew’s Hospital, Barts Health NHS trust
Larisa G. Tereshchenko: Lerner Research Institute, Cleveland Clinic
Patricia B. Munroe: Queen Mary University of London

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36997-w

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