Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

Ioanna Ntalla; Lu Chen Weng; James H. Cartwright; Amelia Weber Hall; Gardar Sveinbjornsson; Nathan R. Tucker; Seung Hoan Choi; Mark D. Chaffin; Carolina Roselli; Michael R. Barnes; Borbala Mifsud; Helen R. Warren; Caroline Hayward; Jonathan Marten; James J. Cranley; Maria Pina Concas; Paolo Gasparini; Thibaud Boutin; Ivana Kolcic; Ozren Polasek; Igor Rudan; Nathalia M. Araujo; Maria Fernanda Lima-Costa; Antonio Luiz P. Ribeiro; Renan P. Souza; Eduardo Tarazona-Santos; Vilmantas Giedraitis; Erik Ingelsson; Anubha Mahajan; Andrew P. Morris; Fabiola Del Greco M; Luisa Foco; Martin Gögele; Andrew A. Hicks; James P. Cook; Lars Lind; Cecilia M. Lindgren; Johan Sundström; Christopher P. Nelson; Muhammad B. Riaz; Nilesh J. Samani; Gianfranco Sinagra; Sheila Ulivi; Mika Kähönen; Pashupati P. Mishra; Nina Mononen; Kjell Nikus; Mark J. Caulfield; Anna Dominiczak; Sandosh Padmanabhan; May E. Montasser; Jeff R. O’Connell; Kathleen Ryan; Alan R. Shuldiner; Stefanie Aeschbacher; David Conen; Lorenz Risch; Sébastien Thériault; Nina Hutri-Kähönen; Terho Lehtimäki; Leo Pekka Lyytikäinen; Olli T. Raitakari; Catriona L.K. Barnes; Harry Campbell; Peter K. Joshi; James F. Wilson; Aaron Isaacs; Jan A. Kors; Cornelia M. van Duijn; Paul L. Huang; Vilmundur Gudnason; Tamara B. Harris; Lenore J. Launer; Albert V. Smith; Erwin P. Bottinger; Ruth J.F. Loos; Girish N. Nadkarni; Michael H. Preuss; Adolfo Correa; Hao Mei; James Wilson; Thomas Meitinger; Martina Müller-Nurasyid; Annette Peters; Melanie Waldenberger; Massimo Mangino; Timothy D. Spector; Michiel Rienstra; Yordi J. van de Vegte; Pim van der Harst; Niek Verweij; Stefan Kääb; Katharina Schramm; Moritz F. Sinner; Konstantin Strauch; Michael J. Cutler; Diane Fatkin; Barry London; Morten Olesen; Dan M. Roden; M. Benjamin Shoemaker; J. Gustav Smith; Mary L. Biggs; Joshua C. Bis; Jennifer A. Brody; Bruce M. Psaty; Kenneth Rice; Nona Sotoodehnia; Alessandro De Grandi; Christian Fuchsberger; Cristian Pattaro; Peter P. Pramstaller; Ian Ford; J. Wouter Jukema; Peter W. Macfarlane; Stella Trompet; Marcus Dörr; Stephan B. Felix; Uwe Völker; Stefan Weiss; Aki S. Havulinna; Antti Jula; Katri Sääksjärvi; Veikko Salomaa; Xiuqing Guo; Susan R. Heckbert; Henry J. Lin; Jerome I. Rotter; Kent D. Taylor; Jie Yao; Renée de Mutsert; Arie C. Maan; Dennis O. Mook-Kanamori; Raymond Noordam; Francesco Cucca; Jun Ding; Edward G. Lakatta; Yong Qian; Kirill V. Tarasov; Daniel Levy; Honghuang Lin; Christopher H. Newton-Cheh; Kathryn L. Lunetta; Alison D. Murray; David J. Porteous; Blair H. Smith; Bruno H. Stricker; André Uitterlinden; Marten E. van den Berg; Jeffrey Haessler; Rebecca D. Jackson; Charles Kooperberg; Ulrike Peters; Alexander P. Reiner; Eric A. Whitsel; Alvaro Alonso; Dan E. Arking; Eric Boerwinkle; Georg B. Ehret; Elsayed Z. Soliman; Christy L. Avery; Stephanie M. Gogarten; Kathleen F. Kerr; Cathy C. Laurie; Amanda A. Seyerle; Adrienne Stilp; Solmaz Assa; M. Abdullah Said; M. Yldau van der Ende; Pier D. Lambiase; Michele Orini; Julia Ramirez; Stefan Van Duijvenboden; David O. Arnar; Daniel F. Gudbjartsson; Hilma Holm; Patrick Sulem; Gudmar Thorleifsson; Rosa B. Thorolfsdottir; Unnur Thorsteinsdottir; Emelia J. Benjamin; Andrew Tinker; Kari Stefansson; Patrick T. Ellinor; Yalda Jamshidi; Steven A. Lubitz; Patricia B. Munroe

doi:10.1038/s41467-020-15706-x

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

Ioanna Ntalla
, Lu Chen Weng
, James H. Cartwright
, Amelia Weber Hall
, Gardar Sveinbjornsson
, Nathan R. Tucker
, Seung Hoan Choi
, Mark D. Chaffin
, Carolina Roselli
, Michael R. Barnes
, Borbala Mifsud
, Helen R. Warren
, Caroline Hayward
, Jonathan Marten
, James J. Cranley
, Maria Pina Concas
, Paolo Gasparini
, Thibaud Boutin
, Ivana Kolcic
, Ozren Polasek

Igor Rudan, Nathalia M. Araujo, Maria Fernanda Lima-Costa, Antonio Luiz P. Ribeiro, Renan P. Souza, Eduardo Tarazona-Santos, Vilmantas Giedraitis, Erik Ingelsson, Anubha Mahajan, Andrew P. Morris, Fabiola Del Greco M, Luisa Foco, Martin Gögele, Andrew A. Hicks, James P. Cook, Lars Lind, Cecilia M. Lindgren, Johan Sundström, Christopher P. Nelson, Muhammad B. Riaz, Nilesh J. Samani, Gianfranco Sinagra, Sheila Ulivi, Mika Kähönen, Pashupati P. Mishra, Nina Mononen, Kjell Nikus, Mark J. Caulfield, Anna Dominiczak, Sandosh Padmanabhan, May E. Montasser, Jeff R. O’Connell, Kathleen Ryan, Alan R. Shuldiner, Stefanie Aeschbacher, David Conen, Lorenz Risch, Sébastien Thériault, Nina Hutri-Kähönen, Terho Lehtimäki, Leo Pekka Lyytikäinen, Olli T. Raitakari, Catriona L.K. Barnes, Harry Campbell, Peter K. Joshi, James F. Wilson, Aaron Isaacs, Jan A. Kors, Cornelia M. van Duijn, Paul L. Huang, Vilmundur Gudnason, Tamara B. Harris, Lenore J. Launer, Albert V. Smith, Erwin P. Bottinger, Ruth J.F. Loos, Girish N. Nadkarni, Michael H. Preuss, Adolfo Correa, Hao Mei, James Wilson, Thomas Meitinger, Martina Müller-Nurasyid, Annette Peters, Melanie Waldenberger, Massimo Mangino, Timothy D. Spector, Michiel Rienstra, Yordi J. van de Vegte, Pim van der Harst, Niek Verweij, Stefan Kääb, Katharina Schramm, Moritz F. Sinner, Konstantin Strauch, Michael J. Cutler, Diane Fatkin, Barry London, Morten Olesen, Dan M. Roden, M. Benjamin Shoemaker, J. Gustav Smith, Mary L. Biggs, Joshua C. Bis, Jennifer A. Brody, Bruce M. Psaty, Kenneth Rice, Nona Sotoodehnia, Alessandro De Grandi, Christian Fuchsberger, Cristian Pattaro, Peter P. Pramstaller, Ian Ford, J. Wouter Jukema, Peter W. Macfarlane, Stella Trompet, Marcus Dörr, Stephan B. Felix, Uwe Völker, Stefan Weiss, Aki S. Havulinna, Antti Jula, Katri Sääksjärvi, Veikko Salomaa, Xiuqing Guo, Susan R. Heckbert, Henry J. Lin, Jerome I. Rotter, Kent D. Taylor, Jie Yao, Renée de Mutsert, Arie C. Maan, Dennis O. Mook-Kanamori, Raymond Noordam, Francesco Cucca, Jun Ding, Edward G. Lakatta, Yong Qian, Kirill V. Tarasov, Daniel Levy, Honghuang Lin, Christopher H. Newton-Cheh, Kathryn L. Lunetta, Alison D. Murray, David J. Porteous, Blair H. Smith, Bruno H. Stricker, André Uitterlinden, Marten E. van den Berg, Jeffrey Haessler, Rebecca D. Jackson, Charles Kooperberg, Ulrike Peters, Alexander P. Reiner, Eric A. Whitsel, Alvaro Alonso, Dan E. Arking, Eric Boerwinkle, Georg B. Ehret, Elsayed Z. Soliman, Christy L. Avery, Stephanie M. Gogarten, Kathleen F. Kerr, Cathy C. Laurie, Amanda A. Seyerle, Adrienne Stilp, Solmaz Assa, M. Abdullah Said, M. Yldau van der Ende, Pier D. Lambiase, Michele Orini, Julia Ramirez, Stefan Van Duijvenboden, David O. Arnar, Daniel F. Gudbjartsson, Hilma Holm, Patrick Sulem, Gudmar Thorleifsson, Rosa B. Thorolfsdottir, Unnur Thorsteinsdottir, Emelia J. Benjamin, Andrew Tinker, Kari Stefansson, Patrick T. Ellinor, Yalda Jamshidi, Steven A. Lubitz, Patricia B. Munroe^*

^*Corresponding author for this work

Genomics and Translational Biomedicine

Queen Mary University of London
Massachusetts General Hospital
Broad Institute
deCODE Genetics
University of Groningen
University of Edinburgh
IRCCS Ospedale Infantile Burlo Garofolo - Trieste
University of Trieste
University of Split
Split University Hospital
Psychiatric Hospital Sveti Ivan
Universidade Federal de Minas Gerais
Fundação Oswaldo Cruz
Uppsala University
Stanford University
University of Oxford
University of Liverpool
University of Manchester
EURAC Research
University of Leicester
Glenfield Hospital
Tampere University
Fimlab Laboratories
University of Glasgow
University of Maryland, Baltimore
University of Basel
Population Health Research Institute, Ontario
University of Bern
Labormedizinisches Zentrum Dr. Risch
Private University of the Principality of Liechtenstein
Université Laval
University of Turku
Maastricht University
Erasmus University Rotterdam
Icelandic Heart Association
University of Iceland
National Institutes of Health
University of Michigan, Ann Arbor
Icahn School of Medicine at Mount Sinai
University of Mississippi
German Centre for Cardiovascular Research
Helmholtz Zentrum München - German Research Center for Environmental Health
Technical University of Munich
Ludwig Maximilian University of Munich
German Center for Diabetes Research
King's College London
NIHR Biomedical Research Centre at Guy’s and St Thomas’ Foundation Trust
Genomics plc
Primary Children's Medical Center
Victor Chang Cardiac Research Institute
St. Vincent’s Hospital
University of New South Wales
University of Iowa
University of Copenhagen
Vanderbilt University
Lund University
University of Washington
Kaiser Permanente
Leiden University
University of Greifswald
National Institute for Health and Welfare
University of Helsinki
University of California at Los Angeles
University of Sassari
National Heart Lung and Blood Institute’s and Boston University’s Framingham Heart Study
Boston University
University of Aberdeen
University of Dundee
Fred Hutchinson Cancer Research Center
Ohio State University
University of North Carolina at Chapel Hill
Emory University
Johns Hopkins University
University of Texas Health Science Center at Houston
University of Geneva
Wake Forest University
Barts Health NHS Trust
University College London
Landspitali University Hospital
St. George's University of London

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

83 Citations (Scopus)

Abstract

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

Original language	English
Article number	2542
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15706-x
Publication status	Published - 1 Dec 2020

Access to Document

10.1038/s41467-020-15706-x

Cite this

Ntalla, I., Weng, L. C., Cartwright, J. H., Hall, A. W., Sveinbjornsson, G., Tucker, N. R., Choi, S. H., Chaffin, M. D., Roselli, C., Barnes, M. R., Mifsud, B., Warren, H. R., Hayward, C., Marten, J., Cranley, J. J., Concas, M. P., Gasparini, P., Boutin, T., Kolcic, I., ... Munroe, P. B. (2020). Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction. Nature Communications, 11(1), Article 2542. https://doi.org/10.1038/s41467-020-15706-x

@article{570f705e335648479ffb4e731f4d720d,

title = "Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction",

abstract = "The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5\% to 62.6\%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.",

author = "Ioanna Ntalla and Weng, \{Lu Chen\} and Cartwright, \{James H.\} and Hall, \{Amelia Weber\} and Gardar Sveinbjornsson and Tucker, \{Nathan R.\} and Choi, \{Seung Hoan\} and Chaffin, \{Mark D.\} and Carolina Roselli and Barnes, \{Michael R.\} and Borbala Mifsud and Warren, \{Helen R.\} and Caroline Hayward and Jonathan Marten and Cranley, \{James J.\} and Concas, \{Maria Pina\} and Paolo Gasparini and Thibaud Boutin and Ivana Kolcic and Ozren Polasek and Igor Rudan and Araujo, \{Nathalia M.\} and Lima-Costa, \{Maria Fernanda\} and Ribeiro, \{Antonio Luiz P.\} and Souza, \{Renan P.\} and Eduardo Tarazona-Santos and Vilmantas Giedraitis and Erik Ingelsson and Anubha Mahajan and Morris, \{Andrew P.\} and \{Del Greco M\}, Fabiola and Luisa Foco and Martin G{\"o}gele and Hicks, \{Andrew A.\} and Cook, \{James P.\} and Lars Lind and Lindgren, \{Cecilia M.\} and Johan Sundstr{\"o}m and Nelson, \{Christopher P.\} and Riaz, \{Muhammad B.\} and Samani, \{Nilesh J.\} and Gianfranco Sinagra and Sheila Ulivi and Mika K{\"a}h{\"o}nen and Mishra, \{Pashupati P.\} and Nina Mononen and Kjell Nikus and Caulfield, \{Mark J.\} and Anna Dominiczak and Sandosh Padmanabhan and Montasser, \{May E.\} and O{\textquoteright}Connell, \{Jeff R.\} and Kathleen Ryan and Shuldiner, \{Alan R.\} and Stefanie Aeschbacher and David Conen and Lorenz Risch and S{\'e}bastien Th{\'e}riault and Nina Hutri-K{\"a}h{\"o}nen and Terho Lehtim{\"a}ki and Lyytik{\"a}inen, \{Leo Pekka\} and Raitakari, \{Olli T.\} and Barnes, \{Catriona L.K.\} and Harry Campbell and Joshi, \{Peter K.\} and Wilson, \{James F.\} and Aaron Isaacs and Kors, \{Jan A.\} and \{van Duijn\}, \{Cornelia M.\} and Huang, \{Paul L.\} and Vilmundur Gudnason and Harris, \{Tamara B.\} and Launer, \{Lenore J.\} and Smith, \{Albert V.\} and Bottinger, \{Erwin P.\} and Loos, \{Ruth J.F.\} and Nadkarni, \{Girish N.\} and Preuss, \{Michael H.\} and Adolfo Correa and Hao Mei and James Wilson and Thomas Meitinger and Martina M{\"u}ller-Nurasyid and Annette Peters and Melanie Waldenberger and Massimo Mangino and Spector, \{Timothy D.\} and Michiel Rienstra and \{van de Vegte\}, \{Yordi J.\} and \{van der Harst\}, Pim and Niek Verweij and Stefan K{\"a}{\"a}b and Katharina Schramm and Sinner, \{Moritz F.\} and Konstantin Strauch and Cutler, \{Michael J.\} and Diane Fatkin and Barry London and Morten Olesen and Roden, \{Dan M.\} and \{Benjamin Shoemaker\}, M. and \{Gustav Smith\}, J. and Biggs, \{Mary L.\} and Bis, \{Joshua C.\} and Brody, \{Jennifer A.\} and Psaty, \{Bruce M.\} and Kenneth Rice and Nona Sotoodehnia and \{De Grandi\}, Alessandro and Christian Fuchsberger and Cristian Pattaro and Pramstaller, \{Peter P.\} and Ian Ford and \{Wouter Jukema\}, J. and Macfarlane, \{Peter W.\} and Stella Trompet and Marcus D{\"o}rr and Felix, \{Stephan B.\} and Uwe V{\"o}lker and Stefan Weiss and Havulinna, \{Aki S.\} and Antti Jula and Katri S{\"a}{\"a}ksj{\"a}rvi and Veikko Salomaa and Xiuqing Guo and Heckbert, \{Susan R.\} and Lin, \{Henry J.\} and Rotter, \{Jerome I.\} and Taylor, \{Kent D.\} and Jie Yao and \{de Mutsert\}, Ren{\'e}e and Maan, \{Arie C.\} and Mook-Kanamori, \{Dennis O.\} and Raymond Noordam and Francesco Cucca and Jun Ding and Lakatta, \{Edward G.\} and Yong Qian and Tarasov, \{Kirill V.\} and Daniel Levy and Honghuang Lin and Newton-Cheh, \{Christopher H.\} and Lunetta, \{Kathryn L.\} and Murray, \{Alison D.\} and Porteous, \{David J.\} and Smith, \{Blair H.\} and Stricker, \{Bruno H.\} and Andr{\'e} Uitterlinden and \{van den Berg\}, \{Marten E.\} and Jeffrey Haessler and Jackson, \{Rebecca D.\} and Charles Kooperberg and Ulrike Peters and Reiner, \{Alexander P.\} and Whitsel, \{Eric A.\} and Alvaro Alonso and Arking, \{Dan E.\} and Eric Boerwinkle and Ehret, \{Georg B.\} and Soliman, \{Elsayed Z.\} and Avery, \{Christy L.\} and Gogarten, \{Stephanie M.\} and Kerr, \{Kathleen F.\} and Laurie, \{Cathy C.\} and Seyerle, \{Amanda A.\} and Adrienne Stilp and Solmaz Assa and \{Abdullah Said\}, M. and \{Yldau van der Ende\}, M. and Lambiase, \{Pier D.\} and Michele Orini and Julia Ramirez and \{Van Duijvenboden\}, Stefan and Arnar, \{David O.\} and Gudbjartsson, \{Daniel F.\} and Hilma Holm and Patrick Sulem and Gudmar Thorleifsson and Thorolfsdottir, \{Rosa B.\} and Unnur Thorsteinsdottir and Benjamin, \{Emelia J.\} and Andrew Tinker and Kari Stefansson and Ellinor, \{Patrick T.\} and Yalda Jamshidi and Lubitz, \{Steven A.\} and Munroe, \{Patricia B.\}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-15706-x",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

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number = "1",

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Ntalla, I, Weng, LC, Cartwright, JH, Hall, AW, Sveinbjornsson, G, Tucker, NR, Choi, SH, Chaffin, MD, Roselli, C, Barnes, MR, Mifsud, B, Warren, HR, Hayward, C, Marten, J, Cranley, JJ, Concas, MP, Gasparini, P, Boutin, T, Kolcic, I, Polasek, O, Rudan, I, Araujo, NM, Lima-Costa, MF, Ribeiro, ALP, Souza, RP, Tarazona-Santos, E, Giedraitis, V, Ingelsson, E, Mahajan, A, Morris, AP, Del Greco M, F, Foco, L, Gögele, M, Hicks, AA, Cook, JP, Lind, L, Lindgren, CM, Sundström, J, Nelson, CP, Riaz, MB, Samani, NJ, Sinagra, G, Ulivi, S, Kähönen, M, Mishra, PP, Mononen, N, Nikus, K, Caulfield, MJ, Dominiczak, A, Padmanabhan, S, Montasser, ME, O’Connell, JR, Ryan, K, Shuldiner, AR, Aeschbacher, S, Conen, D, Risch, L, Thériault, S, Hutri-Kähönen, N, Lehtimäki, T, Lyytikäinen, LP, Raitakari, OT, Barnes, CLK, Campbell, H, Joshi, PK, Wilson, JF, Isaacs, A, Kors, JA, van Duijn, CM, Huang, PL, Gudnason, V, Harris, TB, Launer, LJ, Smith, AV, Bottinger, EP, Loos, RJF, Nadkarni, GN, Preuss, MH, Correa, A, Mei, H, Wilson, J, Meitinger, T, Müller-Nurasyid, M, Peters, A, Waldenberger, M, Mangino, M, Spector, TD, Rienstra, M, van de Vegte, YJ, van der Harst, P, Verweij, N, Kääb, S, Schramm, K, Sinner, MF, Strauch, K, Cutler, MJ, Fatkin, D, London, B, Olesen, M, Roden, DM, Benjamin Shoemaker, M, Gustav Smith, J, Biggs, ML, Bis, JC, Brody, JA, Psaty, BM, Rice, K, Sotoodehnia, N, De Grandi, A, Fuchsberger, C, Pattaro, C, Pramstaller, PP, Ford, I, Wouter Jukema, J, Macfarlane, PW, Trompet, S, Dörr, M, Felix, SB, Völker, U, Weiss, S, Havulinna, AS, Jula, A, Sääksjärvi, K, Salomaa, V, Guo, X, Heckbert, SR, Lin, HJ, Rotter, JI, Taylor, KD, Yao, J, de Mutsert, R, Maan, AC, Mook-Kanamori, DO, Noordam, R, Cucca, F, Ding, J, Lakatta, EG, Qian, Y, Tarasov, KV, Levy, D, Lin, H, Newton-Cheh, CH, Lunetta, KL, Murray, AD, Porteous, DJ, Smith, BH, Stricker, BH, Uitterlinden, A, van den Berg, ME, Haessler, J, Jackson, RD, Kooperberg, C, Peters, U, Reiner, AP, Whitsel, EA, Alonso, A, Arking, DE, Boerwinkle, E, Ehret, GB, Soliman, EZ, Avery, CL, Gogarten, SM, Kerr, KF, Laurie, CC, Seyerle, AA, Stilp, A, Assa, S, Abdullah Said, M, Yldau van der Ende, M, Lambiase, PD, Orini, M, Ramirez, J, Van Duijvenboden, S, Arnar, DO, Gudbjartsson, DF, Holm, H, Sulem, P, Thorleifsson, G, Thorolfsdottir, RB, Thorsteinsdottir, U, Benjamin, EJ, Tinker, A, Stefansson, K, Ellinor, PT, Jamshidi, Y, Lubitz, SA & Munroe, PB 2020, 'Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction', Nature Communications, vol. 11, no. 1, 2542. https://doi.org/10.1038/s41467-020-15706-x

TY - JOUR

T1 - Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

AU - Ntalla, Ioanna

AU - Weng, Lu Chen

AU - Cartwright, James H.

AU - Hall, Amelia Weber

AU - Sveinbjornsson, Gardar

AU - Tucker, Nathan R.

AU - Choi, Seung Hoan

AU - Chaffin, Mark D.

AU - Roselli, Carolina

AU - Barnes, Michael R.

AU - Mifsud, Borbala

AU - Warren, Helen R.

AU - Hayward, Caroline

AU - Marten, Jonathan

AU - Cranley, James J.

AU - Concas, Maria Pina

AU - Gasparini, Paolo

AU - Boutin, Thibaud

AU - Kolcic, Ivana

AU - Polasek, Ozren

AU - Rudan, Igor

AU - Araujo, Nathalia M.

AU - Lima-Costa, Maria Fernanda

AU - Ribeiro, Antonio Luiz P.

AU - Souza, Renan P.

AU - Tarazona-Santos, Eduardo

AU - Giedraitis, Vilmantas

AU - Ingelsson, Erik

AU - Mahajan, Anubha

AU - Morris, Andrew P.

AU - Del Greco M, Fabiola

AU - Foco, Luisa

AU - Gögele, Martin

AU - Hicks, Andrew A.

AU - Cook, James P.

AU - Lind, Lars

AU - Lindgren, Cecilia M.

AU - Sundström, Johan

AU - Nelson, Christopher P.

AU - Riaz, Muhammad B.

AU - Samani, Nilesh J.

AU - Sinagra, Gianfranco

AU - Ulivi, Sheila

AU - Kähönen, Mika

AU - Mishra, Pashupati P.

AU - Mononen, Nina

AU - Nikus, Kjell

AU - Caulfield, Mark J.

AU - Dominiczak, Anna

AU - Padmanabhan, Sandosh

AU - Montasser, May E.

AU - O’Connell, Jeff R.

AU - Ryan, Kathleen

AU - Shuldiner, Alan R.

AU - Aeschbacher, Stefanie

AU - Conen, David

AU - Risch, Lorenz

AU - Thériault, Sébastien

AU - Hutri-Kähönen, Nina

AU - Lehtimäki, Terho

AU - Lyytikäinen, Leo Pekka

AU - Raitakari, Olli T.

AU - Barnes, Catriona L.K.

AU - Campbell, Harry

AU - Joshi, Peter K.

AU - Wilson, James F.

AU - Isaacs, Aaron

AU - Kors, Jan A.

AU - van Duijn, Cornelia M.

AU - Huang, Paul L.

AU - Gudnason, Vilmundur

AU - Harris, Tamara B.

AU - Launer, Lenore J.

AU - Smith, Albert V.

AU - Bottinger, Erwin P.

AU - Loos, Ruth J.F.

AU - Nadkarni, Girish N.

AU - Preuss, Michael H.

AU - Correa, Adolfo

AU - Mei, Hao

AU - Wilson, James

AU - Meitinger, Thomas

AU - Müller-Nurasyid, Martina

AU - Peters, Annette

AU - Waldenberger, Melanie

AU - Mangino, Massimo

AU - Spector, Timothy D.

AU - Rienstra, Michiel

AU - van de Vegte, Yordi J.

AU - van der Harst, Pim

AU - Verweij, Niek

AU - Kääb, Stefan

AU - Schramm, Katharina

AU - Sinner, Moritz F.

AU - Strauch, Konstantin

AU - Cutler, Michael J.

AU - Fatkin, Diane

AU - London, Barry

AU - Olesen, Morten

AU - Roden, Dan M.

AU - Benjamin Shoemaker, M.

AU - Gustav Smith, J.

AU - Biggs, Mary L.

AU - Bis, Joshua C.

AU - Brody, Jennifer A.

AU - Psaty, Bruce M.

AU - Rice, Kenneth

AU - Sotoodehnia, Nona

AU - De Grandi, Alessandro

AU - Fuchsberger, Christian

AU - Pattaro, Cristian

AU - Pramstaller, Peter P.

AU - Ford, Ian

AU - Wouter Jukema, J.

AU - Macfarlane, Peter W.

AU - Trompet, Stella

AU - Dörr, Marcus

AU - Felix, Stephan B.

AU - Völker, Uwe

AU - Weiss, Stefan

AU - Havulinna, Aki S.

AU - Jula, Antti

AU - Sääksjärvi, Katri

AU - Salomaa, Veikko

AU - Guo, Xiuqing

AU - Heckbert, Susan R.

AU - Lin, Henry J.

AU - Rotter, Jerome I.

AU - Taylor, Kent D.

AU - Yao, Jie

AU - de Mutsert, Renée

AU - Maan, Arie C.

AU - Mook-Kanamori, Dennis O.

AU - Noordam, Raymond

AU - Cucca, Francesco

AU - Ding, Jun

AU - Lakatta, Edward G.

AU - Qian, Yong

AU - Tarasov, Kirill V.

AU - Levy, Daniel

AU - Lin, Honghuang

AU - Newton-Cheh, Christopher H.

AU - Lunetta, Kathryn L.

AU - Murray, Alison D.

AU - Porteous, David J.

AU - Smith, Blair H.

AU - Stricker, Bruno H.

AU - Uitterlinden, André

AU - van den Berg, Marten E.

AU - Haessler, Jeffrey

AU - Jackson, Rebecca D.

AU - Kooperberg, Charles

AU - Peters, Ulrike

AU - Reiner, Alexander P.

AU - Whitsel, Eric A.

AU - Alonso, Alvaro

AU - Arking, Dan E.

AU - Boerwinkle, Eric

AU - Ehret, Georg B.

AU - Soliman, Elsayed Z.

AU - Avery, Christy L.

AU - Gogarten, Stephanie M.

AU - Kerr, Kathleen F.

AU - Laurie, Cathy C.

AU - Seyerle, Amanda A.

AU - Stilp, Adrienne

AU - Assa, Solmaz

AU - Abdullah Said, M.

AU - Yldau van der Ende, M.

AU - Lambiase, Pier D.

AU - Orini, Michele

AU - Ramirez, Julia

AU - Van Duijvenboden, Stefan

AU - Arnar, David O.

AU - Gudbjartsson, Daniel F.

AU - Holm, Hilma

AU - Sulem, Patrick

AU - Thorleifsson, Gudmar

AU - Thorolfsdottir, Rosa B.

AU - Thorsteinsdottir, Unnur

AU - Benjamin, Emelia J.

AU - Tinker, Andrew

AU - Stefansson, Kari

AU - Ellinor, Patrick T.

AU - Jamshidi, Yalda

AU - Lubitz, Steven A.

AU - Munroe, Patricia B.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

AB - The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

UR - https://www.scopus.com/pages/publications/85085157192

U2 - 10.1038/s41467-020-15706-x

DO - 10.1038/s41467-020-15706-x

M3 - Article

C2 - 32439900

AN - SCOPUS:85085157192

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2542

ER -

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

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