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; Jørgen 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

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 RamírezHelen 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, Jørgen 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

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 64440 individuals (56943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230000 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

Keywords

Atrial fibrillation
Electrophysiology
Exome
Genetic
Genome-wide association studies
Population
genetic
atrial fibrillation
exome
electrophysiology
genome-wide association studies
population

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10.1161/CIRCGEN.119.002874

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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., ... Mook-Kanamori, D. O. (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{6e1572d22d1a4201a8bf343a14add0e5,

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 64440 individuals (56943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230000 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, genetic, atrial fibrillation, exome, electrophysiology, genome-wide association studies, population",

author = "Weng, {Lu Chen} 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{\o}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.}",

note = "Funding Information: Dr Weng is supported by an American Heart Association (AHA) Postdoctoral Fellowship Award (17POST33660226). This work was supported by an AHA Strategically Focused Research Networks (SFRN) postdoctoral fellowship to Drs. Weng and Hall (18SFRN34110082). Funded in part by training grant (National Institute of General Medical Sciences) 5T32GM07814 (Dr Bihlmeyer) and R01HL116747 (Drs Arking and Bihlmeyer), and R01 HL111089 (Dr Arking). This material is based on work supported by the National Science Foundation Graduate Research Fellowship under Grant No. DGE-1232825 (Dr Bihlmeyer). Any opinion, findings, and conclusions or recommendations expressed in this material are those of the authors(s) and do not necessarily reflect the views of the National Science Foundation. Additional support was provided by AHA grant 16EIA26410001 (Dr Alonso) and National, Heart, Lung and Blood Institute grant K24HL148521 (Dr Alonso). Dr Ram{\'i}rez was supported by Medical Research Council grant MR/N025083/1, by the People Programme (Marie Curie Actions) of the European Union{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement no. 608765 and from the European Union{\textquoteright}s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 786833. Dr Sotoodehnia is supported by the following grants from the National Institutes of Health (NIH): R01HL141989, HL116747, and R01 HL111089, and by the Laughlin Family Fund. Dr Kornej was supported by the European Union{\textquoteright}s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 838259. Dr Benjamin is supported by NIH grants HHSN26818HV00006R; 75N92019D00031; R01HL092577; 1R01HL128914; and American Heart Association 18SFRN34110082. Dr Lunetta is supported by R01 HL092577, AHA 18SFRN34230127, and 18SFRN34150007. Dr Ellinor is supported by the Fondation Leducq (14CVD01), by grants from the NIH (1RO1HL092577, R01HL128914, K24HL105780), and by a grant from the AHA (18SFRN34110082). Dr Lubitz is supported by NIH grant 1R01HL139731 and AHA 18SFRN34250007. Additional funding and acknowledgments for each participating study are provided in the Data Supplement. Publisher Copyright: {\textcopyright} 2020 American Heart Association, Inc.",

year = "2020",

month = oct,

day = "1",

doi = "10.1161/CIRCGEN.119.002874",

language = "English",

volume = "13",

pages = "387--395",

number = "5",

}

Weng, LC, 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, 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, Kääb, S, Peters, A, Sotoodehnia, N, Rotter, JI & Mook-Kanamori, DO 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, Jørgen 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.

N1 - Funding Information: Dr Weng is supported by an American Heart Association (AHA) Postdoctoral Fellowship Award (17POST33660226). This work was supported by an AHA Strategically Focused Research Networks (SFRN) postdoctoral fellowship to Drs. Weng and Hall (18SFRN34110082). Funded in part by training grant (National Institute of General Medical Sciences) 5T32GM07814 (Dr Bihlmeyer) and R01HL116747 (Drs Arking and Bihlmeyer), and R01 HL111089 (Dr Arking). This material is based on work supported by the National Science Foundation Graduate Research Fellowship under Grant No. DGE-1232825 (Dr Bihlmeyer). Any opinion, findings, and conclusions or recommendations expressed in this material are those of the authors(s) and do not necessarily reflect the views of the National Science Foundation. Additional support was provided by AHA grant 16EIA26410001 (Dr Alonso) and National, Heart, Lung and Blood Institute grant K24HL148521 (Dr Alonso). Dr Ramírez was supported by Medical Research Council grant MR/N025083/1, by the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement no. 608765 and from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 786833. Dr Sotoodehnia is supported by the following grants from the National Institutes of Health (NIH): R01HL141989, HL116747, and R01 HL111089, and by the Laughlin Family Fund. Dr Kornej was supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 838259. Dr Benjamin is supported by NIH grants HHSN26818HV00006R; 75N92019D00031; R01HL092577; 1R01HL128914; and American Heart Association 18SFRN34110082. Dr Lunetta is supported by R01 HL092577, AHA 18SFRN34230127, and 18SFRN34150007. Dr Ellinor is supported by the Fondation Leducq (14CVD01), by grants from the NIH (1RO1HL092577, R01HL128914, K24HL105780), and by a grant from the AHA (18SFRN34110082). Dr Lubitz is supported by NIH grant 1R01HL139731 and AHA 18SFRN34250007. Additional funding and acknowledgments for each participating study are provided in the Data Supplement. Publisher Copyright: © 2020 American Heart Association, Inc.

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 64440 individuals (56943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230000 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 64440 individuals (56943 European, 5681 African, 1186 Hispanic, 630 Asian) and ≈230000 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 - genetic

KW - atrial fibrillation

KW - exome

KW - electrophysiology

KW - genome-wide association studies

KW - population

UR - http://www.scopus.com/inward/record.url?scp=85094219796&partnerID=8YFLogxK

U2 - 10.1161/CIRCGEN.119.002874

DO - 10.1161/CIRCGEN.119.002874

M3 - Article

C2 - 32822252

AN - SCOPUS:85094219796

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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