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, 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

Research output: Contribution to journalArticlepeer-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 languageEnglish (US)
Article number319
Pages (from-to)389-395
Number of pages7
JournalCirculation. Genomic and precision medicine
DOIs
StateAccepted/In press - 2020

Keywords

  • Atrial fibrillation
  • Electrophysiology
  • Exome
  • Genetic
  • Genome-wide association studies
  • Population

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

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