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 M. Del Greco; Luisa Foco; Martin Gogele; Andrew A. Hicks; James P. Cook; Lars Lind; Cecilia M. Lindgren; Johan Sundstrom; Christopher P. Nelson; Muhammad B. Riaz; Nilesh J. Samani; Gianfranco Sinagra; Sheila Ulivi; Mika Kahonen; 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; Sebastien Theriault; Nina Hutri-Kahonen; Terho Lehtimaki; Leo-Pekka Lyytikainen; 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 Smith; Erwin P. Bottinger; Ruth J. F. Loos; Girish N. Nadkarni; Michael H. Preuss; Adolfo Correa; Hao Mei; James Wilson; Thomas Meitinger; Martina Mueller-Nurasyid; Annette Peters; Melanie Waldenberger; Massimo Mangino; Timothy D. Spector; Michiel Rienstra; Yordi J. van de Vegte; Pim van der Harst; Niek Verweij; Stefan Kaab; 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 Doerr; Stephan B. Felix; Uwe Voelker; Stefan Weiss; Aki S. Havulinna; Antti Jula; Katri Saaksjarvi; Veikko Salomaa; Xiuqing Guo; Susan R. Heckbert; Henry J. Lin; Jerome Rotter; Kent D. Taylor; Jie Yao; Renee de Mutsert; Arie C. Maan; Dennis O. Mook-Kanamori; Raymond Noordam; Francesco Cucca; Jun Ding; Edward G. Lakatta; Yong Qian; Kirill Tarasov; Daniel Levy; Honghuang Lin; Christopher H. Newton-Cheh; Kathryn L. Lunetta; Alison D. Murray; David J. Porteous; Blair H. Smith; Bruno H. Stricker; Andre 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 PolasekIgor 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 M. Del Greco, Luisa Foco, Martin Gogele, Andrew A. Hicks, James P. Cook, Lars Lind, Cecilia M. Lindgren, Johan Sundstrom, Christopher P. Nelson, Muhammad B. Riaz, Nilesh J. Samani, Gianfranco Sinagra, Sheila Ulivi, Mika Kahonen, 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, Sebastien Theriault, Nina Hutri-Kahonen, Terho Lehtimaki, Leo-Pekka Lyytikainen, 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 Smith, Erwin P. Bottinger, Ruth J. F. Loos, Girish N. Nadkarni, Michael H. Preuss, Adolfo Correa, Hao Mei, James Wilson, Thomas Meitinger, Martina Mueller-Nurasyid, Annette Peters, Melanie Waldenberger, Massimo Mangino, Timothy D. Spector, Michiel Rienstra, Yordi J. van de Vegte, Pim van der Harst, Niek Verweij, Stefan Kaab, 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 Doerr, Stephan B. Felix, Uwe Voelker, Stefan Weiss, Aki S. Havulinna, Antti Jula, Katri Saaksjarvi, Veikko Salomaa, Xiuqing Guo, Susan R. Heckbert, Henry J. Lin, Jerome Rotter, Kent D. Taylor, Jie Yao, Renee de Mutsert, Arie C. Maan, Dennis O. Mook-Kanamori, Raymond Noordam, Francesco Cucca, Jun Ding, Edward G. Lakatta, Yong Qian, Kirill Tarasov, Daniel Levy, Honghuang Lin, Christopher H. Newton-Cheh, Kathryn L. Lunetta, Alison D. Murray, David J. Porteous, Blair H. Smith, Bruno H. Stricker, Andre 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

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

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. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.

Original language	English
Article number	2542
Number of pages	12
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15706-x
Publication status	Published - 21 May 2020

Keywords

GENOME-WIDE ASSOCIATION
ATRIAL-FIBRILLATION
MUTATIONS
RISK
DURATION
CARDIOMYOPATHY
CALCINEURIN
BRADYCARDIA
DECREASE
ELEMENTS

Access to Document

10.1038/s41467-020-15706-xLicence: CC BY

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{ac28258f90374a8297c2d7fc9bd7e84a,

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. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.",

keywords = "GENOME-WIDE ASSOCIATION, ATRIAL-FIBRILLATION, MUTATIONS, RISK, DURATION, CARDIOMYOPATHY, CALCINEURIN, BRADYCARDIA, DECREASE, ELEMENTS",

author = "Ioanna Ntalla and Lu-Chen Weng 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}, {Fabiola M.} and Luisa Foco and Martin Gogele and Hicks, {Andrew A.} and Cook, {James P.} and Lars Lind and Lindgren, {Cecilia M.} and Johan Sundstrom and Nelson, {Christopher P.} and Riaz, {Muhammad B.} and Samani, {Nilesh J.} and Gianfranco Sinagra and Sheila Ulivi and Mika Kahonen 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'Connell, {Jeff R.} and Kathleen Ryan and Shuldiner, {Alan R.} and Stefanie Aeschbacher and David Conen and Lorenz Risch and Sebastien Theriault and Nina Hutri-Kahonen and Terho Lehtimaki and Leo-Pekka Lyytikainen 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 Albert Smith 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 Mueller-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 Kaab 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 Shoemaker, {M. Benjamin} and Smith, {J. Gustav} 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 Jukema, {J. Wouter} and Macfarlane, {Peter W.} and Stella Trompet and Marcus Doerr and Felix, {Stephan B.} and Uwe Voelker and Stefan Weiss and Havulinna, {Aki S.} and Antti Jula and Katri Saaksjarvi and Veikko Salomaa and Xiuqing Guo and Heckbert, {Susan R.} and Lin, {Henry J.} and Jerome Rotter and Taylor, {Kent D.} and Jie Yao and {de Mutsert}, Renee 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 Kirill Tarasov 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 Andre 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 Said, {M. Abdullah} and {van der Ende}, {M. Yldau} 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 = "Funding Information: I.N. became a full-time employee of Gilead Sciences Ltd following submission of the manuscript. S.A.L. receives sponsored research support from Bristol Myers Squibb/ Pfizer, Bayer AG, and Boehringer Ingelheim, and has consulted for Bristol Myers Squibb/Pfizer and Bayer AG. P.T.E. is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases. P. T.E. has also served on advisory boards or consulted for Bayer AG, Quest Diagnostics, and Novartis. M.J.C. is Chief Scientist for Genomics England, a UK Government company. B.M.P. serves on the DSMB of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. V.S. has participated in a conference trip sponsored by Novo Nordisk and received a modest honorarium for participating in an advisory board meeting. K.S., H.H., P.S., G.S., G.T., R.B.T., U.T., D.O.A., D.F.G. are employed by deCODE genetics/ Amgen Inc. E.I. is employed by GlaxoSmithKline. A.M. is employed by Genentech Inc. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = may,

day = "21",

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

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Ntalla, I, Weng, L-C, 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, FM, Foco, L, Gogele, M, Hicks, AA, Cook, JP, Lind, L, Lindgren, CM, Sundstrom, J, Nelson, CP, Riaz, MB, Samani, NJ, Sinagra, G, Ulivi, S, Kahonen, 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, Theriault, S, Hutri-Kahonen, N, Lehtimaki, T, Lyytikainen, L-P, 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, A, Bottinger, EP, Loos, RJF, Nadkarni, GN, Preuss, MH, Correa, A, Mei, H, Wilson, J, Meitinger, T, Mueller-Nurasyid, M, Peters, A, Waldenberger, M, Mangino, M, Spector, TD, Rienstra, M, van de Vegte, YJ, van der Harst, P, Verweij, N, Kaab, S, Schramm, K, Sinner, MF, Strauch, K, Cutler, MJ, Fatkin, D, London, B, Olesen, M, Roden, DM, Shoemaker, MB, Smith, JG, Biggs, ML, Bis, JC, Brody, JA, Psaty, BM, Rice, K, Sotoodehnia, N, De Grandi, A, Fuchsberger, C, Pattaro, C, Pramstaller, PP, Ford, I, Jukema, JW, Macfarlane, PW, Trompet, S, Doerr, M, Felix, SB, Voelker, U, Weiss, S, Havulinna, AS, Jula, A, Saaksjarvi, K, Salomaa, V, Guo, X, Heckbert, SR, Lin, HJ, Rotter, J, Taylor, KD, Yao, J, de Mutsert, R, Maan, AC, Mook-Kanamori, DO, Noordam, R, Cucca, F, Ding, J, Lakatta, EG, Qian, Y, Tarasov, K, 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, Said, MA, van der Ende, MY, 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, Fabiola M.

AU - Foco, Luisa

AU - Gogele, Martin

AU - Hicks, Andrew A.

AU - Cook, James P.

AU - Lind, Lars

AU - Lindgren, Cecilia M.

AU - Sundstrom, Johan

AU - Nelson, Christopher P.

AU - Riaz, Muhammad B.

AU - Samani, Nilesh J.

AU - Sinagra, Gianfranco

AU - Ulivi, Sheila

AU - Kahonen, 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 - Theriault, Sebastien

AU - Hutri-Kahonen, Nina

AU - Lehtimaki, Terho

AU - Lyytikainen, 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

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 - Mueller-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 - Kaab, 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 - Shoemaker, M. Benjamin

AU - Smith, J. Gustav

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 - Jukema, J. Wouter

AU - Macfarlane, Peter W.

AU - Trompet, Stella

AU - Doerr, Marcus

AU - Felix, Stephan B.

AU - Voelker, Uwe

AU - Weiss, Stefan

AU - Havulinna, Aki S.

AU - Jula, Antti

AU - Saaksjarvi, Katri

AU - Salomaa, Veikko

AU - Guo, Xiuqing

AU - Heckbert, Susan R.

AU - Lin, Henry J.

AU - Rotter, Jerome

AU - Taylor, Kent D.

AU - Yao, Jie

AU - de Mutsert, Renee

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

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, Andre

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 - Said, M. Abdullah

AU - van der Ende, M. Yldau

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.

N1 - Funding Information: I.N. became a full-time employee of Gilead Sciences Ltd following submission of the manuscript. S.A.L. receives sponsored research support from Bristol Myers Squibb/ Pfizer, Bayer AG, and Boehringer Ingelheim, and has consulted for Bristol Myers Squibb/Pfizer and Bayer AG. P.T.E. is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular diseases. P. T.E. has also served on advisory boards or consulted for Bayer AG, Quest Diagnostics, and Novartis. M.J.C. is Chief Scientist for Genomics England, a UK Government company. B.M.P. serves on the DSMB of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. V.S. has participated in a conference trip sponsored by Novo Nordisk and received a modest honorarium for participating in an advisory board meeting. K.S., H.H., P.S., G.S., G.T., R.B.T., U.T., D.O.A., D.F.G. are employed by deCODE genetics/ Amgen Inc. E.I. is employed by GlaxoSmithKline. A.M. is employed by Genentech Inc. Publisher Copyright: © 2020, The Author(s).

PY - 2020/5/21

Y1 - 2020/5/21

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. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.

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. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.

KW - GENOME-WIDE ASSOCIATION

KW - ATRIAL-FIBRILLATION

KW - MUTATIONS

KW - RISK

KW - DURATION

KW - CARDIOMYOPATHY

KW - CALCINEURIN

KW - BRADYCARDIA

KW - DECREASE

KW - ELEMENTS

U2 - 10.1038/s41467-020-15706-x

DO - 10.1038/s41467-020-15706-x

M3 - Article

C2 - 32439900

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2542

ER -