Fifteen Genetic Loci Associated with the Electrocardiographic P Wave

Ingrid E. Christophersen; Jared W. Magnani; Xiaoyan Yin; John Barnard; Lu Chen Weng; Dan E. Arking; Maartje N. Niemeijer; Steven A. Lubitz; Christy L. Avery; Qing Duan; Stephan B. Felix; Joshua C. Bis; Kathleen F. Kerr; Aaron Isaacs; Martina Müller-Nurasyid; Christian Müller; Kari E. North; Alex P. Reiner; Lesley F. Tinker; Jan A. Kors; Alexander Teumer; Astrid Petersmann; Moritz F. Sinner; Petra Buzkova; Jonathan D. Smith; David R. Van Wagoner; Uwe Völker; Melanie Waldenberger; Annette Peters; Thomas Meitinger; Marian C. Limacher; Kirk C. Wilhelmsen; Bruce M. Psaty; Albert Hofman; Andre Uitterlinden; Bouwe P. Krijthe; Zhu Ming Zhang; Renate B. Schnabel; Stefan Kääb; Cornelia Van Duijn; Jerome I. Rotter; Nona Sotoodehnia; Marcus Dörr; Yun Li; Mina K. Chung; Elsayed Z. Soliman; Alvaro Alonso; Eric A. Whitsel; Bruno H. Stricker; Emelia J. Benjamin; Susan R. Heckbert; Patrick T. Ellinor

doi:10.1161/CIRCGENETICS.116.001667

Fifteen Genetic Loci Associated with the Electrocardiographic P Wave

Ingrid E. Christophersen, Jared W. Magnani, Xiaoyan Yin, John Barnard, Lu Chen Weng, Dan E. Arking, Maartje N. Niemeijer, Steven A. Lubitz, Christy L. Avery, Qing Duan, Stephan B. Felix, Joshua C. Bis, Kathleen F. Kerr, Aaron Isaacs, Martina Müller-Nurasyid, Christian Müller, Kari E. North, Alex P. Reiner, Lesley F. Tinker, Jan A. KorsAlexander Teumer, Astrid Petersmann, Moritz F. Sinner, Petra Buzkova, Jonathan D. Smith, David R. Van Wagoner, Uwe Völker, Melanie Waldenberger, Annette Peters, Thomas Meitinger, Marian C. Limacher, Kirk C. Wilhelmsen, Bruce M. Psaty, Albert Hofman, Andre Uitterlinden, Bouwe P. Krijthe, Zhu Ming Zhang, Renate B. Schnabel, Stefan Kääb, Cornelia Van Duijn, Jerome I. Rotter, Nona Sotoodehnia, Marcus Dörr, Yun Li, Mina K. Chung, Elsayed Z. Soliman, Alvaro Alonso, Eric A. Whitsel, Bruno H. Stricker, Emelia J. Benjamin, Susan R. Heckbert, Patrick T. Ellinor

School of Medicine

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

21 Scopus citations

Abstract

The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies. Methods and Results - We included 44 456 individuals, of which 6778 (16%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant (P<5×10^-8) novel loci and replicated a prior association with SCN10A. We identified 3 loci at SCN5A, TBX5, and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction. Conclusions - We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias.

Original language	English (US)
Article number	e001667
Journal	Circulation: Cardiovascular Genetics
Volume	10
Issue number	4
DOIs	https://doi.org/10.1161/CIRCGENETICS.116.001667
State	Published - Aug 1 2017

Keywords

arrhythmia
atrial function
electrocardiography
genetic variation
genome-wide association study

ASJC Scopus subject areas

Genetics
Cardiology and Cardiovascular Medicine
Genetics(clinical)

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10.1161/CIRCGENETICS.116.001667

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Christophersen, I. E., Magnani, J. W., Yin, X., Barnard, J., Weng, L. C., Arking, D. E., Niemeijer, M. N., Lubitz, S. A., Avery, C. L., Duan, Q., Felix, S. B., Bis, J. C., Kerr, K. F., Isaacs, A., Müller-Nurasyid, M., Müller, C., North, K. E., Reiner, A. P., Tinker, L. F., ... Ellinor, P. T. (2017). Fifteen Genetic Loci Associated with the Electrocardiographic P Wave. Circulation: Cardiovascular Genetics, 10(4), Article e001667. https://doi.org/10.1161/CIRCGENETICS.116.001667

Christophersen, IE, Magnani, JW, Yin, X, Barnard, J, Weng, LC, Arking, DE, Niemeijer, MN, Lubitz, SA, Avery, CL, Duan, Q, Felix, SB, Bis, JC, Kerr, KF, Isaacs, A, Müller-Nurasyid, M, Müller, C, North, KE, Reiner, AP, Tinker, LF, Kors, JA, Teumer, A, Petersmann, A, Sinner, MF, Buzkova, P, Smith, JD, Van Wagoner, DR, Völker, U, Waldenberger, M, Peters, A, Meitinger, T, Limacher, MC, Wilhelmsen, KC, Psaty, BM, Hofman, A, Uitterlinden, A, Krijthe, BP, Zhang, ZM, Schnabel, RB, Kääb, S, Van Duijn, C, Rotter, JI, Sotoodehnia, N, Dörr, M, Li, Y, Chung, MK, Soliman, EZ, Alonso, A, Whitsel, EA, Stricker, BH, Benjamin, EJ, Heckbert, SR & Ellinor, PT 2017, 'Fifteen Genetic Loci Associated with the Electrocardiographic P Wave', Circulation: Cardiovascular Genetics, vol. 10, no. 4, e001667. https://doi.org/10.1161/CIRCGENETICS.116.001667

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title = "Fifteen Genetic Loci Associated with the Electrocardiographic P Wave",

abstract = "The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies. Methods and Results - We included 44 456 individuals, of which 6778 (16%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant (P<5×10-8) novel loci and replicated a prior association with SCN10A. We identified 3 loci at SCN5A, TBX5, and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction. Conclusions - We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias.",

keywords = "arrhythmia, atrial function, electrocardiography, genetic variation, genome-wide association study",

author = "Christophersen, {Ingrid E.} and Magnani, {Jared W.} and Xiaoyan Yin and John Barnard and Weng, {Lu Chen} and Arking, {Dan E.} and Niemeijer, {Maartje N.} and Lubitz, {Steven A.} and Avery, {Christy L.} and Qing Duan and Felix, {Stephan B.} and Bis, {Joshua C.} and Kerr, {Kathleen F.} and Aaron Isaacs and Martina M{\"u}ller-Nurasyid and Christian M{\"u}ller and North, {Kari E.} and Reiner, {Alex P.} and Tinker, {Lesley F.} and Kors, {Jan A.} and Alexander Teumer and Astrid Petersmann and Sinner, {Moritz F.} and Petra Buzkova and Smith, {Jonathan D.} and {Van Wagoner}, {David R.} and Uwe V{\"o}lker and Melanie Waldenberger and Annette Peters and Thomas Meitinger and Limacher, {Marian C.} and Wilhelmsen, {Kirk C.} and Psaty, {Bruce M.} and Albert Hofman and Andre Uitterlinden and Krijthe, {Bouwe P.} and Zhang, {Zhu Ming} and Schnabel, {Renate B.} and Stefan K{\"a}{\"a}b and {Van Duijn}, Cornelia and Rotter, {Jerome I.} and Nona Sotoodehnia and Marcus D{\"o}rr and Yun Li and Chung, {Mina K.} and Soliman, {Elsayed Z.} and Alvaro Alonso and Whitsel, {Eric A.} and Stricker, {Bruno H.} and Benjamin, {Emelia J.} and Heckbert, {Susan R.} and Ellinor, {Patrick T.}",

note = "Publisher Copyright: {\textcopyright} 2017 American Heart Association, Inc.",

year = "2017",

month = aug,

day = "1",

doi = "10.1161/CIRCGENETICS.116.001667",

language = "English (US)",

volume = "10",

journal = "Circulation: Cardiovascular Genetics",

issn = "1942-325X",

publisher = "Lippincott Williams and Wilkins Ltd.",

number = "4",

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TY - JOUR

T1 - Fifteen Genetic Loci Associated with the Electrocardiographic P Wave

AU - Christophersen, Ingrid E.

AU - Magnani, Jared W.

AU - Yin, Xiaoyan

AU - Barnard, John

AU - Weng, Lu Chen

AU - Arking, Dan E.

AU - Niemeijer, Maartje N.

AU - Lubitz, Steven A.

AU - Avery, Christy L.

AU - Duan, Qing

AU - Felix, Stephan B.

AU - Bis, Joshua C.

AU - Kerr, Kathleen F.

AU - Isaacs, Aaron

AU - Müller-Nurasyid, Martina

AU - Müller, Christian

AU - North, Kari E.

AU - Reiner, Alex P.

AU - Tinker, Lesley F.

AU - Kors, Jan A.

AU - Teumer, Alexander

AU - Petersmann, Astrid

AU - Sinner, Moritz F.

AU - Buzkova, Petra

AU - Smith, Jonathan D.

AU - Van Wagoner, David R.

AU - Völker, Uwe

AU - Waldenberger, Melanie

AU - Peters, Annette

AU - Meitinger, Thomas

AU - Limacher, Marian C.

AU - Wilhelmsen, Kirk C.

AU - Psaty, Bruce M.

AU - Hofman, Albert

AU - Uitterlinden, Andre

AU - Krijthe, Bouwe P.

AU - Zhang, Zhu Ming

AU - Schnabel, Renate B.

AU - Kääb, Stefan

AU - Van Duijn, Cornelia

AU - Rotter, Jerome I.

AU - Sotoodehnia, Nona

AU - Dörr, Marcus

AU - Li, Yun

AU - Chung, Mina K.

AU - Soliman, Elsayed Z.

AU - Alonso, Alvaro

AU - Whitsel, Eric A.

AU - Stricker, Bruno H.

AU - Benjamin, Emelia J.

AU - Heckbert, Susan R.

AU - Ellinor, Patrick T.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies. Methods and Results - We included 44 456 individuals, of which 6778 (16%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant (P<5×10-8) novel loci and replicated a prior association with SCN10A. We identified 3 loci at SCN5A, TBX5, and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction. Conclusions - We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias.

AB - The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies. Methods and Results - We included 44 456 individuals, of which 6778 (16%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant (P<5×10-8) novel loci and replicated a prior association with SCN10A. We identified 3 loci at SCN5A, TBX5, and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction. Conclusions - We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias.

KW - arrhythmia

KW - atrial function

KW - electrocardiography

KW - genetic variation

KW - genome-wide association study

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U2 - 10.1161/CIRCGENETICS.116.001667

DO - 10.1161/CIRCGENETICS.116.001667

M3 - Article

C2 - 28794112

AN - SCOPUS:85028918298

SN - 1942-325X

VL - 10

JO - Circulation: Cardiovascular Genetics

JF - Circulation: Cardiovascular Genetics

IS - 4

M1 - e001667

ER -

Fifteen Genetic Loci Associated with the Electrocardiographic P Wave

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