The genetics of atrial fibrillation

Abstract

A substantial genetic contribution to the etiology of atrial fibrillation has emerged in the last decade, and has bolstered links between this arrhythmia and other forms of heart disease. In this article, we will summarize the work that has defined the inherited diathesis toward atrial fibrillation, outline the genetic studies to date, and characterize the roadblocks to a complete mechanistic understanding of this common arrhythmia. Clinical genetic work has demonstrated a large heritable contribution in atrial fibrillation, with studies in lone forms of the arrhythmia suggesting a traditional monogenic syndrome with reduced penetrance. Several Mendelian loci for typical forms of atrial fibrillation have been identified but the genes have not yet been cloned. Rare forms of familial atrial fibrillation are caused by mutations in potassium channel genes, and there are single families with mutations in a nuclear pore and a natriuretic peptide gene, respectively. Common loci with small effects are now being identified in genome-wide association (GWA) studies, including a locus on chromosome 4q25. These loci explain less than 10% of the inherited contribution to the arrhythmia, suggesting there are major contributions that have not yet been uncovered. Although great strides have been made in exploring the genetics of atrial fibrillation, the paroxysmal and asymptomatic nature of the phenotype challenges investigators as they seek the mechanistic basis of the arrhythmia.