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; Ulrich Schotten; Monika Stoll; Larisa G. Tereshchenko; Patricia B Munroe; Et al.

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. SantolallaColleen 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, Ulrich Schotten, Monika Stoll, Larisa G. Tereshchenko^*, Patricia B Munroe^*, Et al.

^*Corresponding author for this work

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

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
Number of pages	16
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-36997-w
Publication status	Published - 1 Dec 2023

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10.1038/s41467-023-36997-wLicence: CC BY

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., ... Et al. (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{422ce8b4b9c740929c2fa8f790f7a8c1,

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.",

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 Ulrich Schotten and Monika Stoll and Tereshchenko, {Larisa G.} and Munroe, {Patricia B} and {Et al.}",

note = "Funding Information: All study acknowledgements can be found in Supplementary Note 3, and study funding information in Supplementary Note 4. W.J.Y acknowledges support by an MRC grant MR/R017468/1. A.A is supported by an NHLBI award K24HL148521. A.L.P.R is supported in part by CNPq (310679/2016-8 and 465518/2014-1) and by FAPEMIG (PPM-00428-17 and RED-00081-16). E.T-S is supported by Brazilian Ministry of Health (National Program of Genomics and Precision Health), Brazilian Conselho Nacional de Desenvolvimento Cient{\'i}fico e Tecnologico (CNPq), Funda{\c c}{\~a}o de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG, RED00314-16). M.F.L-C is supported by Brazilian Ministry of Health (DECIT/MS, EPIGEN-Brazil Project), Brazilian Ministry of Science and Technology (Financiadora de Estudos e Projetos (FINEP), Brazilian Conselho Nacional de Desenvolvimento Cient{\'i}fico e Tecnologico (CNPq), Funda{\c c}{\~a}o de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG)). M.L.S is supported by Brazilian Conselho Nacional de Desenvolvimento Cient{\'i}fico e Tecnologico (CNPq), Third- World Academy of Science (TWAS), Fogarty International Center of the US National Institutes of Health (D43 TW007393). P.B.M, A.T, P.D.L and M.O acknowledge support by an MRC grant MR/N025083/1. P.B.M, H.R.W, A.T and P.D.L acknowledge the NIHR Barts Biomedical Research Centre at Queen Mary University of London. P.D.L is also supported by UCL/UCLH Biomedicine NIHR, Barts Heart Centre Biomedical Research Centre. J.R acknowledges support from the European Union{\textquoteright}s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No.786833, and the “Mar{\'i}a Zambrano” fellowship through the European Union-NextGenerationEU. N.S is supported by grants AHA19SFRN348300063, R01HL141989, Medic One Foundation, Laughlin Family. U.S received funding from the Netherlands Heart Foundation (CVON2014-09, RACE V Reappraisal of Atrial Fibrillation: Interaction between hyperCoagulability, Electrical remodeling, and Vascular Destabilization in the Progression of AF), the European Union (ITN Network Personalize AF: Personalized Therapies for Atrial Fibrillation: a translational network, grant number 860974; MAESTRIA: Machine Learning Artificial Intelligence Early Detection Stroke Atrial Fibrillation, grant number 965286). S.T is supported by a Junior 1 Clinical Research Scholar award from the Fonds de Recherche du Qu{\'e}bec-Sant{\'e} (FRQS). J.L.I is supported by CACHET. M.O was supported by The John and Birthe Meyer Foundation and The Hallas-M{\o}ller Emerging Investigator Novo Nordisk (NNF17OC0031204). C.H is supported by an MRC University Unit Programme Grant MC_UU_00007/10 (QTL in Health and Disease). C.A and A.B were supported by NIH grants R01HL142825, and U01HG007416. D.D was supported by NIH grants R01HL138737 and T32HL139439. N.G, C.N and T.H are supported by the Novo Nordisk Foundation (Grant number NNF18CC0034900). H.M is supported by the CHARGE infrastructure grant (HL105756). J-W.B is funded by the Research Project CVON-AI (2018B017) financed by the PPP Allowance made available by Top Sector Life Sciences & Health to the Dutch Heart Foundation to stimulate public-private partnerships. D.M-K is supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023). J.F.W acknowledges support from the MRC Human Genetics Unit programme grant, “Quantitative traits in health and disease” (U. MC_UU_00007/10). L.R is funded by a University of Edinburgh studentship. P.N is supported by the MRC Human Genetics Unit programme grant, “Quantitative traits in health and disease” (U. MC_UU_00007/10). X.S was in receipt of a Starting Grant (2017-02543) from the Swedish Research Council (Vetenskapr{\aa}det). This research has been conducted using the UK Biobank Resource under Application Number 8256. This research used data assets made available by National Safe Haven as part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref MC_PC_20029). Copyright {\textcopyright} (2022), NHS Digital. Re-used with the permission of the NHS Digital [and/or UK Biobank]. All rights reserved. The authors also wish to acknowledge the CHARGE infrastructure grant (HL105756). Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

day = "1",

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

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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, Schotten, U , Stoll, M, Tereshchenko, LG, Munroe, PB & Et al. 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 - Schotten, Ulrich

AU - Stoll, Monika

AU - Tereshchenko, Larisa G.

AU - Munroe, Patricia B

AU - Et al.

N1 - Funding Information: All study acknowledgements can be found in Supplementary Note 3, and study funding information in Supplementary Note 4. W.J.Y acknowledges support by an MRC grant MR/R017468/1. A.A is supported by an NHLBI award K24HL148521. A.L.P.R is supported in part by CNPq (310679/2016-8 and 465518/2014-1) and by FAPEMIG (PPM-00428-17 and RED-00081-16). E.T-S is supported by Brazilian Ministry of Health (National Program of Genomics and Precision Health), Brazilian Conselho Nacional de Desenvolvimento Científico e Tecnologico (CNPq), Fundação de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG, RED00314-16). M.F.L-C is supported by Brazilian Ministry of Health (DECIT/MS, EPIGEN-Brazil Project), Brazilian Ministry of Science and Technology (Financiadora de Estudos e Projetos (FINEP), Brazilian Conselho Nacional de Desenvolvimento Científico e Tecnologico (CNPq), Fundação de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG)). M.L.S is supported by Brazilian Conselho Nacional de Desenvolvimento Científico e Tecnologico (CNPq), Third- World Academy of Science (TWAS), Fogarty International Center of the US National Institutes of Health (D43 TW007393). P.B.M, A.T, P.D.L and M.O acknowledge support by an MRC grant MR/N025083/1. P.B.M, H.R.W, A.T and P.D.L acknowledge the NIHR Barts Biomedical Research Centre at Queen Mary University of London. P.D.L is also supported by UCL/UCLH Biomedicine NIHR, Barts Heart Centre Biomedical Research Centre. J.R acknowledges support from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No.786833, and the “María Zambrano” fellowship through the European Union-NextGenerationEU. N.S is supported by grants AHA19SFRN348300063, R01HL141989, Medic One Foundation, Laughlin Family. U.S received funding from the Netherlands Heart Foundation (CVON2014-09, RACE V Reappraisal of Atrial Fibrillation: Interaction between hyperCoagulability, Electrical remodeling, and Vascular Destabilization in the Progression of AF), the European Union (ITN Network Personalize AF: Personalized Therapies for Atrial Fibrillation: a translational network, grant number 860974; MAESTRIA: Machine Learning Artificial Intelligence Early Detection Stroke Atrial Fibrillation, grant number 965286). S.T is supported by a Junior 1 Clinical Research Scholar award from the Fonds de Recherche du Québec-Santé (FRQS). J.L.I is supported by CACHET. M.O was supported by The John and Birthe Meyer Foundation and The Hallas-Møller Emerging Investigator Novo Nordisk (NNF17OC0031204). C.H is supported by an MRC University Unit Programme Grant MC_UU_00007/10 (QTL in Health and Disease). C.A and A.B were supported by NIH grants R01HL142825, and U01HG007416. D.D was supported by NIH grants R01HL138737 and T32HL139439. N.G, C.N and T.H are supported by the Novo Nordisk Foundation (Grant number NNF18CC0034900). H.M is supported by the CHARGE infrastructure grant (HL105756). J-W.B is funded by the Research Project CVON-AI (2018B017) financed by the PPP Allowance made available by Top Sector Life Sciences & Health to the Dutch Heart Foundation to stimulate public-private partnerships. D.M-K is supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023). J.F.W acknowledges support from the MRC Human Genetics Unit programme grant, “Quantitative traits in health and disease” (U. MC_UU_00007/10). L.R is funded by a University of Edinburgh studentship. P.N is supported by the MRC Human Genetics Unit programme grant, “Quantitative traits in health and disease” (U. MC_UU_00007/10). X.S was in receipt of a Starting Grant (2017-02543) from the Swedish Research Council (Vetenskaprådet). This research has been conducted using the UK Biobank Resource under Application Number 8256. This research used data assets made available by National Safe Haven as part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant ref MC_PC_20029). Copyright © (2022), NHS Digital. Re-used with the permission of the NHS Digital [and/or UK Biobank]. All rights reserved. The authors also wish to acknowledge the CHARGE infrastructure grant (HL105756). Publisher Copyright: © 2023, The Author(s).

PY - 2023/12/1

Y1 - 2023/12/1

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.

U2 - 10.1038/s41467-023-36997-w

DO - 10.1038/s41467-023-36997-w

M3 - Article

C2 - 36918541

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1411

ER -