Genetic Aspects of Lone Atrial Fibrillation: What Do We Know?

Atrial fibrillation (AF) is the most common cardiac arrhythmia. A subgroup of patients presents with AF without traditional risk factors and is diagnosed before the age of 60 years. Such patients are commonly referred as having “lone AF” and comprise 10-20% of all cases. A number of studies have demonstrated that AF, and in particular lone AF, have a substantial genetic component. Genome-wide association studies (GWAS) have indicated that common single-nucleotide polymorphisms (SNPs) have a role in the development of AF. Furthermore, rare variants in genes encoding cardiac gap junction proteins, signalling molecules, ion channels, and accessory subunits have been associated with lone AF in several recent genetic reports. Most of these reports show gain-of-function or loss-of-function mutations, leading to increased risk of lone AF. To date, the pathophysiological mechanisms responsible for AF are not fully understood, and it is likely that this arrhythmia represents a final common phenotype of multiple. This review focuses on the genetic basis of lone AF and the role of both common and rare variants in the susceptibility of developing lone AF. Furthermore, three conceptual pathogenetic models of lone AF are discussed.