Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation

Lu-Chen Weng; Amelia Weber Hall; Seung Hoan Choi; Sean J. Jurgens; Jeffrey Haessler; Nathan A. Bihlmeyer; Niels Grarup; Honghuang Lin; Alexander Teumer; Ruifang Li-Gao; Jie Yao; Xiuqing Guo; Jennifer A. Brody; Martina Müller-Nurasyid; Katharina Schramm; Niek Verweij; Marten E. van den Berg; Jessica van Setten; Aaron Isaacs; Julia Ramírez; Helen R. Warren; Sandosh Padmanabhan; Jan A. Kors; Rudolf A. de Boer; Peter van der Meer; Moritz F. Sinner; Melanie Waldenberger; Bruce M. Psaty; Kent D. Taylor; Uwe Völker; J. rgen K. Kanters; Man Li; Alvaro Alonso; Marco V. Perez; Ilonca Vaartjes; Michiel L. Bots; Paul L. Huang; Susan R. Heckbert; Henry J. Lin; Jelena Kornej; Patricia B. Munroe; Cornelia M. van Duijn; Folkert W. Asselbergs; Bruno H. Stricker; Pim van der Harst; Stefan Kääb; Annette Peters; Nona Sotoodehnia; Jerome I. Rotter; Dennis O. Mook-Kanamori; Marcus Dörr; Stephan B. Felix; Allan Linneberg; Torben Hansen; Dan E. Arking; Charles Kooperberg; Emelia J. Benjamin; Kathryn L. Lunetta; Patrick T. Ellinor; Steven A. Lubitz

doi:10.1161/CIRCGEN.119.002874

Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation

Lu-Chen Weng
, Amelia Weber Hall
, Seung Hoan Choi
, Sean J. Jurgens
, Jeffrey Haessler
, Nathan A. Bihlmeyer
, Niels Grarup
, Honghuang Lin
, Alexander Teumer
, Ruifang Li-Gao
, Jie Yao
, Xiuqing Guo
, Jennifer A. Brody
, Martina Müller-Nurasyid
, Katharina Schramm
, Niek Verweij
, Marten E. van den Berg
, Jessica van Setten
, Aaron Isaacs
, Julia Ramírez

Helen R. Warren, Sandosh Padmanabhan, Jan A. Kors, Rudolf A. de Boer, Peter van der Meer, Moritz F. Sinner, Melanie Waldenberger, Bruce M. Psaty, Kent D. Taylor, Uwe Völker, J. rgen K. Kanters, Man Li, Alvaro Alonso, Marco V. Perez, Ilonca Vaartjes, Michiel L. Bots, Paul L. Huang, Susan R. Heckbert, Henry J. Lin, Jelena Kornej, Patricia B. Munroe, Cornelia M. van Duijn, Folkert W. Asselbergs, Bruno H. Stricker, Pim van der Harst, Stefan Kääb, Annette Peters, Nona Sotoodehnia, Jerome I. Rotter, Dennis O. Mook-Kanamori, Marcus Dörr, Stephan B. Felix, Allan Linneberg, Torben Hansen, Dan E. Arking, Charles Kooperberg, Emelia J. Benjamin, Kathryn L. Lunetta, Patrick T. Ellinor, Steven A. Lubitz^*

^*Corresponding author for this work

Massachusetts General Hospital
Broad Institute of MIT and Harvard
Fred Hutchinson Cancer Research Center
Johns Hopkins University
University of Copenhagen
Framingham Heart Study
Boston University
German Centre for Cardiovascular Research
University of Greifswald
Leiden University
University of California at Los Angeles
University of Washington
Ludwig Maximilian University of Munich
Helmholtz Zentrum München - German Research Center for Environmental Health
Genomics
University of Groningen
Utrecht University
Maastricht University
Queen Mary University of London
University of Glasgow
Erasmus University Rotterdam
Kaiser Permanente
University of Utah
Emory University
Stanford University
University of Oxford
University College London
Royal Netherlands Academy of Arts and Sciences
German Center for Diabetes Research
Cardiovascular Research Center (L.-C.W
Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA (A.W.H., N.R.T., P.T.E.).
Broad Institute
The Johns Hopkins University School of Medicine
Danish PCD Centre, Pediatric Pulmonary Service, Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Rigshospitalet, Denmark , Copenhagen, Denmark.
Boston University & NHLBI's Framingham Heart Study
DZHK (German Center for Cardiovascular Research)
Leiden University Medical Center, Department of Medical Statistics, Leiden.
The Institute for Translational Genomics & Population Sciences at Harbor-UCLA Medical Center
The George Washington University School of Nursing, Washington, DC, USA.
Chair of Genetic Epidemiology
Genomics plc
Department of Epidemiology (M.E.v.d.B.)
Van Creveldkliniek, University Medical Center Utrecht, University Utrecht, Utrecht.
Department of Hematology Maastricht University Medical Center Maastricht The Netherlands.
MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, UK
Erasmus Universiteit: Department of Gastroenterology and Hepatology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands and the Department of Gastroenterology and Hepatology, Academic Medical Center, University Medical Center, Amsterdam,
University of Groningen, University Medical Center Groningen
Hospital of the Ludwig-Maximilians-University (LMU) Munich
University of Utah School of Medicine
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California; Department of Genetics, Stanford University School of Medicine, Stanford, California.
Erasmus University, Rotterdam: Department of Public health, Erasmus MC
Department of Internal Medicine (B.H.S.)
Cardiac Arrhythmia Service (P.T.E

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

Abstract

Background: The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD. Methods: Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies. Results: We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (TTN, CAND2, SCN10A, PITX2, CAV1, SYNPO2L, SOX5, TBX5, MYH6, RPL3L). The top variants at known sarcomere genes (TTN, MYH6) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A) were associated with longer PWD but lower AF risk. Conclusions: Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.

Original language	English
Pages (from-to)	387-395
Number of pages	9
Journal	Circulation: Genomic and Precision Medicine
Volume	13
Issue number	5
DOIs	https://doi.org/10.1161/CIRCGEN.119.002874
Publication status	Published - 1 Oct 2020
Externally published	Yes

Keywords

Atrial Fibrillation/ethnology
Cardiac Myosins/genetics
Connectin/genetics
Electrocardiography
Genetic Variation
Genome-Wide Association Study
Homeodomain Proteins/genetics
Humans
Myosin Heavy Chains/genetics
NAV1.8 Voltage-Gated Sodium Channel/genetics
Quantitative Trait Loci
Transcription Factors/genetics

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10.1161/CIRCGEN.119.002874

Cite this

Weng, L.-C., Hall, A. W., Choi, S. H., Jurgens, S. J., Haessler, J., Bihlmeyer, N. A., Grarup, N., Lin, H., Teumer, A., Li-Gao, R., Yao, J., Guo, X., Brody, J. A., Müller-Nurasyid, M., Schramm, K., Verweij, N., van den Berg, M. E., van Setten, J., Isaacs, A., ... Lubitz, S. A. (2020). Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation. Circulation: Genomic and Precision Medicine, 13(5), 387-395. https://doi.org/10.1161/CIRCGEN.119.002874

@article{5f5931c49a5a461a9a414ac5305b6ba3,

title = "Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation",

abstract = "Background: The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD. Methods: Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies. Results: We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (TTN, CAND2, SCN10A, PITX2, CAV1, SYNPO2L, SOX5, TBX5, MYH6, RPL3L). The top variants at known sarcomere genes (TTN, MYH6) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A) were associated with longer PWD but lower AF risk. Conclusions: Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.",

keywords = "Atrial Fibrillation/ethnology, Cardiac Myosins/genetics, Connectin/genetics, Electrocardiography, Genetic Variation, Genome-Wide Association Study, Homeodomain Proteins/genetics, Humans, Myosin Heavy Chains/genetics, NAV1.8 Voltage-Gated Sodium Channel/genetics, Quantitative Trait Loci, Transcription Factors/genetics",

author = "Lu-Chen Weng and Hall, \{Amelia Weber\} and Choi, \{Seung Hoan\} and Jurgens, \{Sean J.\} and Jeffrey Haessler and Bihlmeyer, \{Nathan A.\} and Niels Grarup and Honghuang Lin and Alexander Teumer and Ruifang Li-Gao and Jie Yao and Xiuqing Guo and Brody, \{Jennifer A.\} and Martina M{\"u}ller-Nurasyid and Katharina Schramm and Niek Verweij and \{van den Berg\}, \{Marten E.\} and \{van Setten\}, Jessica and Aaron Isaacs and Julia Ram{\'i}rez and Warren, \{Helen R.\} and Sandosh Padmanabhan and Kors, \{Jan A.\} and \{de Boer\}, \{Rudolf A.\} and \{van der Meer\}, Peter and Sinner, \{Moritz F.\} and Melanie Waldenberger and Psaty, \{Bruce M.\} and Taylor, \{Kent D.\} and Uwe V{\"o}lker and Kanters, \{J. rgen K.\} and Man Li and Alvaro Alonso and Perez, \{Marco V.\} and Ilonca Vaartjes and Bots, \{Michiel L.\} and Huang, \{Paul L.\} and Heckbert, \{Susan R.\} and Lin, \{Henry J.\} and Jelena Kornej and Munroe, \{Patricia B.\} and \{van Duijn\}, \{Cornelia M.\} and Asselbergs, \{Folkert W.\} and Stricker, \{Bruno H.\} and \{van der Harst\}, Pim and Stefan K{\"a}{\"a}b and Annette Peters and Nona Sotoodehnia and Rotter, \{Jerome I.\} and Mook-Kanamori, \{Dennis O.\} and Marcus D{\"o}rr and Felix, \{Stephan B.\} and Allan Linneberg and Torben Hansen and Arking, \{Dan E.\} and Charles Kooperberg and Benjamin, \{Emelia J.\} and Lunetta, \{Kathryn L.\} and Ellinor, \{Patrick T.\} and Lubitz, \{Steven A.\}",

year = "2020",

month = oct,

day = "1",

doi = "10.1161/CIRCGEN.119.002874",

language = "English",

volume = "13",

pages = "387--395",

journal = "Circulation: Genomic and Precision Medicine",

issn = "2574-8300",

publisher = "Lippincott Williams and Wilkins Ltd.",

number = "5",

}

Weng, L-C, Hall, AW, Choi, SH, Jurgens, SJ, Haessler, J, Bihlmeyer, NA, Grarup, N, Lin, H, Teumer, A, Li-Gao, R, Yao, J, Guo, X, Brody, JA, Müller-Nurasyid, M, Schramm, K, Verweij, N, van den Berg, ME, van Setten, J, Isaacs, A, Ramírez, J, Warren, HR, Padmanabhan, S, Kors, JA, de Boer, RA, van der Meer, P, Sinner, MF, Waldenberger, M, Psaty, BM, Taylor, KD, Völker, U, Kanters, JRK, Li, M, Alonso, A, Perez, MV, Vaartjes, I, Bots, ML, Huang, PL, Heckbert, SR, Lin, HJ, Kornej, J, Munroe, PB, van Duijn, CM, Asselbergs, FW, Stricker, BH, van der Harst, P, Kääb, S, Peters, A, Sotoodehnia, N, Rotter, JI, Mook-Kanamori, DO, Dörr, M, Felix, SB, Linneberg, A, Hansen, T, Arking, DE, Kooperberg, C, Benjamin, EJ, Lunetta, KL, Ellinor, PT & Lubitz, SA 2020, 'Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation', Circulation: Genomic and Precision Medicine, vol. 13, no. 5, pp. 387-395. https://doi.org/10.1161/CIRCGEN.119.002874

TY - JOUR

T1 - Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation

AU - Weng, Lu-Chen

AU - Hall, Amelia Weber

AU - Choi, Seung Hoan

AU - Jurgens, Sean J.

AU - Haessler, Jeffrey

AU - Bihlmeyer, Nathan A.

AU - Grarup, Niels

AU - Lin, Honghuang

AU - Teumer, Alexander

AU - Li-Gao, Ruifang

AU - Yao, Jie

AU - Guo, Xiuqing

AU - Brody, Jennifer A.

AU - Müller-Nurasyid, Martina

AU - Schramm, Katharina

AU - Verweij, Niek

AU - van den Berg, Marten E.

AU - van Setten, Jessica

AU - Isaacs, Aaron

AU - Ramírez, Julia

AU - Warren, Helen R.

AU - Padmanabhan, Sandosh

AU - Kors, Jan A.

AU - de Boer, Rudolf A.

AU - van der Meer, Peter

AU - Sinner, Moritz F.

AU - Waldenberger, Melanie

AU - Psaty, Bruce M.

AU - Taylor, Kent D.

AU - Völker, Uwe

AU - Kanters, J. rgen K.

AU - Li, Man

AU - Alonso, Alvaro

AU - Perez, Marco V.

AU - Vaartjes, Ilonca

AU - Bots, Michiel L.

AU - Huang, Paul L.

AU - Heckbert, Susan R.

AU - Lin, Henry J.

AU - Kornej, Jelena

AU - Munroe, Patricia B.

AU - van Duijn, Cornelia M.

AU - Asselbergs, Folkert W.

AU - Stricker, Bruno H.

AU - van der Harst, Pim

AU - Kääb, Stefan

AU - Peters, Annette

AU - Sotoodehnia, Nona

AU - Rotter, Jerome I.

AU - Mook-Kanamori, Dennis O.

AU - Dörr, Marcus

AU - Felix, Stephan B.

AU - Linneberg, Allan

AU - Hansen, Torben

AU - Arking, Dan E.

AU - Kooperberg, Charles

AU - Benjamin, Emelia J.

AU - Lunetta, Kathryn L.

AU - Ellinor, Patrick T.

AU - Lubitz, Steven A.

PY - 2020/10/1

Y1 - 2020/10/1

N2 - Background: The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD. Methods: Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies. Results: We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (TTN, CAND2, SCN10A, PITX2, CAV1, SYNPO2L, SOX5, TBX5, MYH6, RPL3L). The top variants at known sarcomere genes (TTN, MYH6) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A) were associated with longer PWD but lower AF risk. Conclusions: Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.

AB - Background: The P-wave duration (PWD) is an electrocardiographic measurement that represents cardiac conduction in the atria. Shortened or prolonged PWD is associated with atrial fibrillation (AF). We used exome-chip data to examine the associations between common and rare variants with PWD. Methods: Fifteen studies comprising 64 440 individuals (56 943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230 000 variants were used to examine associations with maximum PWD across the 12-lead ECG. Meta-analyses summarized association results for common variants; gene-based burden and sequence kernel association tests examined low-frequency variant-PWD associations. Additionally, we examined the associations between PWD loci and AF using previous AF genome-wide association studies. Results: We identified 21 common and low-frequency genetic loci (14 novel) associated with maximum PWD, including several AF loci (TTN, CAND2, SCN10A, PITX2, CAV1, SYNPO2L, SOX5, TBX5, MYH6, RPL3L). The top variants at known sarcomere genes (TTN, MYH6) were associated with longer PWD and increased AF risk. However, top variants at other loci (eg, PITX2 and SCN10A) were associated with longer PWD but lower AF risk. Conclusions: Our results highlight multiple novel genetic loci associated with PWD, and underscore the shared mechanisms of atrial conduction and AF. Prolonged PWD may be an endophenotype for several different genetic mechanisms of AF.

KW - Atrial Fibrillation/ethnology

KW - Cardiac Myosins/genetics

KW - Connectin/genetics

KW - Electrocardiography

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Homeodomain Proteins/genetics

KW - Humans

KW - Myosin Heavy Chains/genetics

KW - NAV1.8 Voltage-Gated Sodium Channel/genetics

KW - Quantitative Trait Loci

KW - Transcription Factors/genetics

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85094219796&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/32822252

U2 - 10.1161/CIRCGEN.119.002874

DO - 10.1161/CIRCGEN.119.002874

M3 - Article

C2 - 32822252

SN - 2574-8300

VL - 13

SP - 387

EP - 395

JO - Circulation: Genomic and Precision Medicine

JF - Circulation: Genomic and Precision Medicine

IS - 5

ER -

Genetic Determinants of Electrocardiographic P-Wave Duration and Relation to Atrial Fibrillation

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