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 van Duijvenboden; Antoine R. Baldassari; Maria Pina Concas; Thuy Vy 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 De 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 van der Harst; Cornelia M. van 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; Patricia B. Munroe

doi:10.1038/s41467-023-36997-w

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 van Duijvenboden
, Antoine R. Baldassari
, Maria Pina Concas
, Thuy Vy 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 De 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 van der Harst, Cornelia M. van 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^*, Patricia B. Munroe^*

^*Corresponding author for this work

Genomics and Translational Biomedicine

Queen Mary University of London
Barts Health NHS Trust
Fred Hutchinson Cancer Research Center
University of Groningen
University of Edinburgh
University of California at Los Angeles
Maastricht University
University of Oxford
University College London
University of Zaragoza
Sorbonne Université
ICAN Institute for Cardiometabolism and Nutrition
University of North Carolina at Chapel Hill
IRCCS Ospedale Infantile Burlo Garofolo - Trieste
Johns Hopkins University
EURAC Research
University of Copenhagen
University of Mississippi
Leiden University
Universidade Federal de Minas Gerais
Universidad Peruana Cayetano Heredia
University of Washington
Erasmus University Rotterdam
Population Health Research Institute, Ontario
Université Laval
University of Basel
Utrecht University
Emory University
University of Illinois at Chicago
University of Trieste
Centre National de Recherche en Génomique Humaine
Laboratory of Excellence GENMED (Medical Genomics)
Fondation Jean Dausset
Region Zealand
Harvard University
University of Michigan, Ann Arbor
Ohio State University
Fundação Oswaldo Cruz
University of Glasgow
University of Texas Health Science Center at Houston
University of Lübeck
Labormedizinisches Zentrum Dr. Risch
Private University in the Principality of Liechtenstein
University of Bern
Karolinska Institutet
Fudan University
Wake Forest University
University of Münster
Interuniversity Cardiology Institute of the Netherlands
Durrer Center for Cardiovascular Research
Beth Israel Deaconess Medical Center
Cleveland Clinic Foundation

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

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.

Original language	English
Article number	1411
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-36997-w
Publication status	Published - Dec 2023

Keywords

Atlas
Database
Genome-wide association
Heart
Hypertrophic cardiomyopathy
Model
Protein
Qrs-t angle
Retinoic acid synthesis
Variants

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10.1038/s41467-023-36997-w

Cite this

Young, W. J., Haessler, J., Benjamins, J. W., Repetto, L., Yao, J., Isaacs, A., Harper, A. R., Ramirez, J., Garnier, S., van Duijvenboden, S., Baldassari, A. R., Concas, M. P., Duong, T. V., Foco, L., Isaksen, J. L., Mei, H., Noordam, R., Nursyifa, C., Richmond, A., ... Munroe, P. B. (2023). Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease. Nature Communications, 14(1), Article 1411. https://doi.org/10.1038/s41467-023-36997-w

@article{e0c4d7a28a1b48a5b1c63b4c8de8a83e,

title = "Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease",

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.",

keywords = "Atlas, Database, Genome-wide association, Heart, Hypertrophic cardiomyopathy, Model, Protein, Qrs-t angle, Retinoic acid synthesis, Variants",

author = "Young, \{William J.\} and Jeffrey Haessler and Benjamins, \{Jan Walter\} and Linda Repetto and Jie Yao and Aaron Isaacs and Harper, \{Andrew R.\} and Julia Ramirez and Sophie Garnier and \{van Duijvenboden\}, Stefan and Baldassari, \{Antoine R.\} and Concas, \{Maria Pina\} and Duong, \{Thuy Vy\} and Luisa Foco and Isaksen, \{Jonas L.\} and Hao Mei and Raymond Noordam and Casia Nursyifa and Anne Richmond and Santolalla, \{Meddly L.\} and Sitlani, \{Colleen M.\} and Negin Soroush and S{\'e}bastien Th{\'e}riault and Stella Trompet and Stefanie Aeschbacher and Fariba Ahmadizar and Alvaro Alonso and Brody, \{Jennifer A.\} and Archie Campbell and Adolfo Correa and Dawood Darbar and \{De Luca\}, Antonio and Deleuze, \{Jean Fran{\c c}ois\} and Christina Ellervik and Christian Fuchsberger and Anuj Goel and Christopher Grace and Xiuqing Guo and Torben Hansen and Heckbert, \{Susan R.\} and Jackson, \{Rebecca D.\} and Kors, \{Jan A.\} and Lima-Costa, \{Maria Fernanda\} and Allan Linneberg and Macfarlane, \{Peter W.\} and Morrison, \{Alanna C.\} and Pau Navarro and Porteous, \{David J.\} and Pramstaller, \{Peter P.\} and Reiner, \{Alexander P.\} and Lorenz Risch and Ulrich Schotten and Xia Shen and Gianfranco Sinagra and Soliman, \{Elsayed Z.\} and Monika Stoll and Eduardo Tarazona-Santos and Andrew Tinker and Katerina Trajanoska and Eric Villard and Warren, \{Helen R.\} and Whitsel, \{Eric A.\} and Wiggins, \{Kerri L.\} and Arking, \{Dan E.\} and Avery, \{Christy L.\} and David Conen and Giorgia Girotto and Niels Grarup and Caroline Hayward and Jukema, \{J. Wouter\} and Mook-Kanamori, \{Dennis O.\} and Olesen, \{Morten Salling\} and Sandosh Padmanabhan and Psaty, \{Bruce M.\} and Cristian Pattaro and Ribeiro, \{Antonio Luiz P.\} and Rotter, \{Jerome I.\} and Stricker, \{Bruno H.\} and \{van der Harst\}, Pim and \{van Duijn\}, \{Cornelia M.\} and Niek Verweij and Wilson, \{James G.\} and Michele Orini and Philippe Charron and Hugh Watkins and Charles Kooperberg and Lin, \{Henry J.\} and Wilson, \{James F.\} and Kanters, \{J{\o}rgen K.\} and Nona Sotoodehnia and Borbala Mifsud and Lambiase, \{Pier D.\} and Tereshchenko, \{Larisa G.\} and Munroe, \{Patricia B.\}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-36997-w",

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Young, WJ, Haessler, J, Benjamins, JW, Repetto, L, Yao, J, Isaacs, A, Harper, AR, Ramirez, J, Garnier, S, van Duijvenboden, S, Baldassari, AR, Concas, MP, Duong, TV, Foco, L, Isaksen, JL, Mei, H, Noordam, R, Nursyifa, C, Richmond, A, Santolalla, ML, Sitlani, CM, Soroush, N, Thériault, S, Trompet, S, Aeschbacher, S, Ahmadizar, F, Alonso, A, Brody, JA, Campbell, A, Correa, A, Darbar, D, De Luca, A, Deleuze, JF, Ellervik, C, Fuchsberger, C, Goel, A, Grace, C, Guo, X, Hansen, T, Heckbert, SR, Jackson, RD, Kors, JA, Lima-Costa, MF, Linneberg, A, Macfarlane, PW, Morrison, AC, Navarro, P, Porteous, DJ, Pramstaller, PP, Reiner, AP, Risch, L, Schotten, U, Shen, X, Sinagra, G, Soliman, EZ, Stoll, M, Tarazona-Santos, E, Tinker, A, Trajanoska, K, Villard, E, Warren, HR, Whitsel, EA, Wiggins, KL, Arking, DE, Avery, CL, Conen, D, Girotto, G, Grarup, N, Hayward, C, Jukema, JW, Mook-Kanamori, DO, Olesen, MS, Padmanabhan, S, Psaty, BM, Pattaro, C, Ribeiro, ALP, Rotter, JI, Stricker, BH, van der Harst, P, van Duijn, CM, Verweij, N, Wilson, JG, Orini, M, Charron, P, Watkins, H, Kooperberg, C, Lin, HJ, Wilson, JF, Kanters, JK, Sotoodehnia, N, Mifsud, B, Lambiase, PD, Tereshchenko, LG & Munroe, PB 2023, 'Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease', Nature Communications, vol. 14, no. 1, 1411. https://doi.org/10.1038/s41467-023-36997-w

TY - JOUR

T1 - Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease

AU - Young, William J.

AU - Haessler, Jeffrey

AU - Benjamins, Jan Walter

AU - Repetto, Linda

AU - Yao, Jie

AU - Isaacs, Aaron

AU - Harper, Andrew R.

AU - Ramirez, Julia

AU - Garnier, Sophie

AU - van Duijvenboden, Stefan

AU - Baldassari, Antoine R.

AU - Concas, Maria Pina

AU - Duong, Thuy Vy

AU - Foco, Luisa

AU - Isaksen, Jonas L.

AU - Mei, Hao

AU - Noordam, Raymond

AU - Nursyifa, Casia

AU - Richmond, Anne

AU - Santolalla, Meddly L.

AU - Sitlani, Colleen M.

AU - Soroush, Negin

AU - Thériault, Sébastien

AU - Trompet, Stella

AU - Aeschbacher, Stefanie

AU - Ahmadizar, Fariba

AU - Alonso, Alvaro

AU - Brody, Jennifer A.

AU - Campbell, Archie

AU - Correa, Adolfo

AU - Darbar, Dawood

AU - De Luca, Antonio

AU - Deleuze, Jean François

AU - Ellervik, Christina

AU - Fuchsberger, Christian

AU - Goel, Anuj

AU - Grace, Christopher

AU - Guo, Xiuqing

AU - Hansen, Torben

AU - Heckbert, Susan R.

AU - Jackson, Rebecca D.

AU - Kors, Jan A.

AU - Lima-Costa, Maria Fernanda

AU - Linneberg, Allan

AU - Macfarlane, Peter W.

AU - Morrison, Alanna C.

AU - Navarro, Pau

AU - Porteous, David J.

AU - Pramstaller, Peter P.

AU - Reiner, Alexander P.

AU - Risch, Lorenz

AU - Schotten, Ulrich

AU - Shen, Xia

AU - Sinagra, Gianfranco

AU - Soliman, Elsayed Z.

AU - Stoll, Monika

AU - Tarazona-Santos, Eduardo

AU - Tinker, Andrew

AU - Trajanoska, Katerina

AU - Villard, Eric

AU - Warren, Helen R.

AU - Whitsel, Eric A.

AU - Wiggins, Kerri L.

AU - Arking, Dan E.

AU - Avery, Christy L.

AU - Conen, David

AU - Girotto, Giorgia

AU - Grarup, Niels

AU - Hayward, Caroline

AU - Jukema, J. Wouter

AU - Mook-Kanamori, Dennis O.

AU - Olesen, Morten Salling

AU - Padmanabhan, Sandosh

AU - Psaty, Bruce M.

AU - Pattaro, Cristian

AU - Ribeiro, Antonio Luiz P.

AU - Rotter, Jerome I.

AU - Stricker, Bruno H.

AU - van der Harst, Pim

AU - van Duijn, Cornelia M.

AU - Verweij, Niek

AU - Wilson, James G.

AU - Orini, Michele

AU - Charron, Philippe

AU - Watkins, Hugh

AU - Kooperberg, Charles

AU - Lin, Henry J.

AU - Wilson, James F.

AU - Kanters, Jørgen K.

AU - Sotoodehnia, Nona

AU - Mifsud, Borbala

AU - Lambiase, Pier D.

AU - Tereshchenko, Larisa G.

AU - Munroe, Patricia B.

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

KW - Atlas

KW - Database

KW - Genome-wide association

KW - Heart

KW - Hypertrophic cardiomyopathy

KW - Model

KW - Protein

KW - Qrs-t angle

KW - Retinoic acid synthesis

KW - Variants

UR - https://www.scopus.com/pages/publications/85150240431

U2 - 10.1038/s41467-023-36997-w

DO - 10.1038/s41467-023-36997-w

M3 - Article

C2 - 36918541

AN - SCOPUS:85150240431

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1411

ER -

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

Abstract

Keywords

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