Rare coding variants in MYH6 are associated with atrial fibrillation: results from 45,596 exomes representing the general population

Abstract

Abstract Background Atrial Fibrillation (AF) is the most common cardiac arrhythmia, and it is associated with serious complications; including an increased risk of stroke, heart failure, and death. It affects around 5% of the population above 65 years of age, and it is estimated that 2% of healthcare expenses are related to AF. The causes of AF are complex, and includes structural heart disease, hypertension, diabetes and genetic risk factors. To date 166 unique genetic loci have been identified to be associated with AF. While AF has traditionally been regarded as an electrical disease, structural genes, including the sarcomere gene, titin (TTN), has been associated with the disease. Recently, a large genome wide association study associated common variants in the gene MYH6 with AF. The gene encodes the protein alpha myosin heavy chain, and has previously been associated with sick-sinus syndrome and structural heart disease. Purpose We hypothesized that genetic variants in the sarcomere gene MYH6 were more prevalent in AF patients than non-AF patients supporting that this gene is important for the development of AF. Methods We analysed publicly available data from the UK Biobank, combining exome-sequencing data and health-related information on 45,596 participants. Using next-generation sequencing, we then examined the genetic variation in MYH6 in a cohort of 383 Danish, early-onset AF patients. The patients had onset of AF before age 40, had normal echocardiogram, and no other cardiovascular disease at onset of AF. Genetic variants were filtered by minor allele frequency (MAF) in the Genome Aggregation Database (GnomAD), and only rare variants with MAF<1% were included. We then predicted the potential deleteriousness of the variants using combined annotation dependent depletion (CADD) score. Results We found rare coding variants in MYH6 to be significantly associated with AF in exome-sequencing data on 45,596 participants from the UK Biobank (p=0.038). In our cohort of 383 Danish, early-onset AF patients with no other cardiovascular disease, we identified 12 rare, missense variants in MYH6. Of these variants, three were novel, and 11 had CADD scores >20, suggesting them to be in the top 1% of likely deleterious variants. Conclusion We identified rare genetic variants in MYH6 to be significantly associated with AF in a large population-based cohort. We also identified 12 rare coding variants in a highly selected cohort of early-onset AF patients. Most of these variants were predicted to be deleterious. Our results indicate that rare variants in MYH6 may increase susceptibility to AF, thus elaborating on the understanding of the pathophysiological mechanisms of AF, and the role of structural genes in the development of AF. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Novo Nordisk Foundation Pre-Graduate Scholarships