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Loss-of-Function Variants in Cytoskeletal Genes Are Associated with Early-Onset Atrial Fibrillation

Oliver Bundgaard Vad1,2, Christian Paludan-Müller1,2, Gustav Ahlberg1,2

  • 1.Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.

Journal of Clinical Medicine
|February 5, 2020
PubMed

Insights

Rare genetic variants in cytoskeletal genes linked to dilated cardiomyopathy are associated with early-onset atrial fibrillation (AF). This suggests a potential role for these variants in developing atrial cardiomyopathy, contributing to AF onset before age 50.

Area of Science:

  • Cardiovascular Genetics
  • Cardiac Arrhythmias
  • Cardiomyopathies

Background:

  • Atrial fibrillation (AF) is a common arrhythmia linked to severe health risks.
  • Titin-truncating variants (TTNtv) and other gene variants are associated with AF and cardiomyopathies.
  • Early-onset AF requires understanding its underlying genetic causes.

Purpose of the Study:

  • To investigate the association between early-onset AF and loss-of-function variants in DCM-associated cytoskeletal genes.
  • To identify specific genes and variants contributing to AF in individuals with early disease onset.
  • To explore genetic correlations between AF and other cardiovascular traits.

Main Methods:

  • Targeted sequencing of 527 Scandinavian individuals with early-onset AF (onset <50 years) and 383 controls.
  • Analysis of rare loss-of-function variants in genes encoding cytoskeletal proteins, including DMD, PDLIM3, and FKTN.
  • Genetic correlation analyses using publicly available genome-wide association study (GWAS) data.

Main Results:

  • Six individuals with early-onset AF carried rare loss-of-function variants in DMD, PDLIM3, or FKTN; two variants were novel.
  • Loss-of-function variants in cytoskeletal genes showed a significant association with early-onset AF (p=0.044).
  • Significant genetic correlation was found between AF and non-ischemic cardiomyopathy (p=0.0003).

Conclusions:

  • Rare loss-of-function variants in cytoskeletal genes, previously linked to dilated cardiomyopathy (DCM), may contribute to early-onset AF.
  • These variants might play a role in the development of atrial cardiomyopathy, leading to AF.
  • The findings highlight a potential genetic link between cytoskeletal protein dysfunction and early-onset atrial fibrillation.

Keywords:
arrhythmiaatrial fibrillationcardiologycardiomyopathygeneticsnext-generation sequencing

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