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

Circ Genom Precis Med. 2020 Oct;13(5):387-395. doi: 10.1161/CIRCGEN.119.002874. Epub 2020 Aug 21.

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; electrophysiology; exome; genetic; genome-wide association studies; population.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Atrial Fibrillation / ethnology
  • Atrial Fibrillation / genetics*
  • Atrial Fibrillation / physiopathology
  • 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

Substances

  • Connectin
  • Homeodomain Proteins
  • MYH6 protein, human
  • NAV1.8 Voltage-Gated Sodium Channel
  • SCN10A protein, human
  • TTN protein, human
  • Transcription Factors
  • homeobox protein PITX2
  • Cardiac Myosins
  • Myosin Heavy Chains