Atrial Fibrillation Genetics Update: Toward Clinical Implementation

Abstract

Atrial fibrillation (AF) is the most common heart rhythm disorder worldwide and may have serious cardiovascular health consequences. AF is associated with increased risk of stroke, dementia, heart failure, and death. There are several known robust, clinical risk predictors for AF, such as male sex, increasing age, and hypertension; however, during the last couple of decades, a substantive genetic component has also been established. Over the last 10 years, the discovery of novel AF-related genetic variants has accelerated, increasing our understanding of mechanisms behind AF. Current studies are focusing on mapping the polygenic structure of AF, improving risk prediction, therapeutic development, and patient-specific management. Nevertheless, it is still difficult for clinicians to interpret the role of genetics in AF prediction and management. Here, we provide an overview of relevant topics within the genetics of AF and attempt to provide some guidance on how to interpret genetic advances and their implementation into clinical decision-making.

Keywords: atrial fibrillation; genetics; genome-wide association studies (GWAS); heritability; personalized medicine; precision medicine; risk factors; whole genome sequencing.

Figure 1

An overview of genetic loci identified through GWAS performed for AF. The figure illustrates the number of identified loci for AF, based on the data listed in Table 1. The x axis represents which years the different GWAS for AF was performed. Under each year, the total number of cases included in all GWAS for AF the current year is listed, illustrating the relationship between the increasing sample sizes and the increasing number of AF-associated loci identified. The Y axes represent the number of genetic loci associated with AF. The red parts of the columns represent genetic loci that have not previously been reported in relation to AF. The black parts of the columns represent previously reported genetic loci associated with AF, making the total of each column reflect the total number of AF-associated loci at a given time.

Figure 2

The figure illustrates the main biological pathways implicated by AF-associated variants identified by GWAS and high-throughput sequencing; cardiac transcription factors and embryonic cardiogenesis, the architecture of the cardiac cells, and ion channel function. A selection of genes associated with AF through GWAS and high-throughput sequencing is listed for each pathway and can also be found in Tables 1, 2.

Figure 3

The missing heritability of AF can be revealed by focusing on mapping the polygenic structure of AF, improving risk prediction, therapeutic development, and patient-specific management. Details of suggested studies are described in Table 3. Future perspectives—translating AF genetics into clinical practice.