Atrial fibrillation-a complex polygenetic disease

Abstract

Atrial fibrillation (AF) is the most common type of arrhythmia. Epidemiological studies have documented a substantial genetic component. More than 160 genes have been associated with AF during the last decades. Some of these were discovered by classical linkage studies while the majority relies on functional studies or genome-wide association studies. In this review, we will evaluate the genetic basis of AF and the role of both common and rare genetic variants in AF. Rare variants in multiple ion-channel genes as well as gap junction and transcription factor genes have been associated with AF. More recently, a growing body of evidence has implicated structural genes with AF. An increased burden of atrial fibrosis in AF patients compared with non-AF patients has also been reported. These findings challenge our traditional understanding of AF being an electrical disease. We will focus on several quantitative landmark papers, which are transforming our understanding of AF by implicating atrial cardiomyopathies in the pathogenesis. This new AF research field may enable better diagnostics and treatment in the future.

Fig. 1. AF mechanisms.

Genetic variants in genes encoding different ion-channels, transcription factors and myocardial structural components predispose to atrial fibrillation (AF) through different pathways that lead to increased automaticity and reentry activity.

Fig. 2. Genetic correlation with AF.

LD score regression revealing genetic correlation between AF (65,446 cases and >500,000 controls) and other phenotypes. Phenotypes with negative log10(P) are displayed on the y-axis. X-axis show genetic correlation (rg). Dots are estimated values with thick lines indicating mean standard error (SE) and thin lines 1.96 SE. Significant association after Bonferroni corrections is denoted with green color. Nominal significance is denoted with violet color and non-significant correlations with grey. SEs and p values were derived from using block jackknife resampling. Modified from Hadji-Turdeghal et al. [63].

Fig. 3. AF and atrial cardiomyopathy.

Structural rearrangement in the heart seems to play a key role in atrial cardiomyopathy and in AF, here illustrated with a transmitted electron microscopy (TEM) image of the cardiomyocyte of a patient with AF and atrial cardiomyopathy. A Heart and B cardiomyocyte from AF patient with atrial cardiomyopathy, and C TEM imaging of sarcomere from AF patient with atrial cardiomyopathy affected by fibrotic changes (light areas). The sarcomeres look disrupted with poorly defined M-lines and I-bands, and fuzzy Z-lines (green arrows) and the mitochondria show an increased amount of cristae and ballooning (red arrows). D For comparison, schematic, and TEM imaging of sarcomere from patient without AF. AF; atrial fibrillation.