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 Mueller-Nurasyid; Katharina Schramm; Niek Verweij; Marten E. van den Berg; Jessica van Setten; Aaron Isaacs; Julia Ramirez; 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 Voelker; Jorgen 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 Kaeaeb; Annette Peters; Nona Sotoodehnia; Jerome I. Rotter; Dennis O. Mook-Kanamori; Marcus Doerr; 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 Mueller-Nurasyid, Katharina Schramm, Niek Verweij, Marten E. van den Berg, Jessica van Setten, Aaron Isaacs, Julia RamirezHelen 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 Voelker, Jorgen 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 Kaeaeb, Annette Peters, Nona Sotoodehnia, Jerome I. Rotter, Dennis O. Mook-Kanamori, Marcus Doerr, 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

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

7 Citations (Web of Science)

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 approximate to 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
Article number	002874
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 - Oct 2020

Keywords

atrial fibrillation
electrophysiology
exome
genetic
genome-wide association studies
population
MYOSIN HEAVY-CHAIN
RISK
ASSOCIATION
RECURRENCE
EXPRESSION
INDEXES
PROTEIN
HMGA2
MYH6

Access to Document

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., Mueller-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. [002874]. https://doi.org/10.1161/CIRCGEN.119.002874

@article{09218eae959340808aaa1d6c25e3193a,

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 approximate to 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, electrophysiology, exome, genetic, genome-wide association studies, population, MYOSIN HEAVY-CHAIN, RISK, ASSOCIATION, RECURRENCE, EXPRESSION, INDEXES, PROTEIN, HMGA2, MYH6",

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 Mueller-Nurasyid and Katharina Schramm and Niek Verweij and {van den Berg}, {Marten E.} and {van Setten}, Jessica and Aaron Isaacs and Julia Ramirez 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 Voelker and Kanters, {Jorgen 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 Kaeaeb and Annette Peters and Nona Sotoodehnia and Rotter, {Jerome I.} and Mook-Kanamori, {Dennis O.} and Marcus Doerr 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,

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, Mueller-Nurasyid, M, Schramm, K, Verweij, N, van den Berg, ME, van Setten, J, Isaacs, A, Ramirez, J, Warren, HR, Padmanabhan, S, Kors, JA, de Boer, RA, van der Meer, P, Sinner, MF, Waldenberger, M, Psaty, BM, Taylor, KD, Voelker, U, Kanters, JK, 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, Kaeaeb, S, Peters, A, Sotoodehnia, N, Rotter, JI, Mook-Kanamori, DO, Doerr, 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, 002874, 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 - Mueller-Nurasyid, Martina

AU - Schramm, Katharina

AU - Verweij, Niek

AU - van den Berg, Marten E.

AU - van Setten, Jessica

AU - Isaacs, Aaron

AU - Ramirez, 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 - Voelker, Uwe

AU - Kanters, Jorgen 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 - Kaeaeb, Stefan

AU - Peters, Annette

AU - Sotoodehnia, Nona

AU - Rotter, Jerome I.

AU - Mook-Kanamori, Dennis O.

AU - Doerr, 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

Y1 - 2020/10

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 approximate to 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 approximate to 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

KW - electrophysiology

KW - exome

KW - genetic

KW - genome-wide association studies

KW - population

KW - MYOSIN HEAVY-CHAIN

KW - RISK

KW - ASSOCIATION

KW - RECURRENCE

KW - EXPRESSION

KW - INDEXES

KW - PROTEIN

KW - HMGA2

KW - MYH6

U2 - 10.1161/CIRCGEN.119.002874

DO - 10.1161/CIRCGEN.119.002874

M3 - Article

C2 - 32822252

VL - 13

SP - 387

EP - 395

JO - Circulation: Genomic and Precision Medicine

JF - Circulation: Genomic and Precision Medicine

SN - 2574-8300

IS - 5

M1 - 002874

ER -