Emerging directions in the genetics of atrial fibrillation

Abstract

Atrial fibrillation (AF) is the most common arrhythmia and is associated with increased morbidity. As the population ages and the prevalence of AF continues to rise, the socioeconomic consequences of AF will become increasingly burdensome. Although there are well-defined clinical risk factors for AF, a significant heritable component is also recognized. To identify the molecular basis for the heritability of AF, investigators have used a combination of classical Mendelian genetics, candidate gene screening, and genome-wide association studies. However, these avenues have, as yet, failed to define the majority of the heritability of AF. The goal of this review is to describe the results from both candidate gene and genome-wide studies, as well as to outline potential future avenues for creating a more complete understanding of AF genetics. Ultimately, a more comprehensive view of the genetic underpinnings for AF will lead to the identification of novel molecular pathways and improved risk prediction of this complex arrhythmia.

Keywords: arrhythmias, cardiac; atrial fibrillation; genetics.

Figure 1. Known genetic pathways for AF pathogenesis

Schematic of known AF-related genes derived from previous studies. Genes listed include those where coding variation was identified in familial AF and candidate gene screens, as well as the genes suggested to be implicated in AF based upon GWAS. Names listed in red indicate those identified by familial studies and candidate gene screens. Those listed in gray are gene targets implicated by GWAS.

Figure 2. Graded relative risk of atrial fibrillation in European and Japanese populations

The risk of atrial fibrillation is plotted according to the estimated atrial fibrillation risk alleles, relative to that among individuals with the most common number of estimated risk alleles for all genome-wide significant atrial fibrillation susceptibility loci. Data is plotted from individuals of European ancestry from AFGen and Japanese ancestry from BioBank Japan. Right axis denotes the population frequency of each category. Error bars represent the 95% confidence intervals. Adapted from Lubitz et. al, JACC 2014.

Figure 3. Future directions for the study of GWAS risk loci

Initial analyses of common variation have yielded 9 susceptibility loci for atrial fibrillation. Future pathways for confirming the causative variation include: Identification of subthreshold loci by increasing sample size or reduced sample heterogeneity in GWAS, fine mapping or direct sequencing of known risk loci for increased resolution of the causal region, in silico analyses of locus function to determine potential regulatory regions/causal variation, evaluation of AF candidate genes in model systems, and expression quantitative trait loci mapping to link common variation to altered gene expression in relevant tissues.