No abstract

Background: The prevalence of atrial fibrillation (AF) is increasing with an aging worldwide population, yet a comprehensive understanding of its causes and consequences remains limited. Objectives: To assess the causes and consequences of AF via a multi-directional Mendelian randomization (MR) analysis scanning thousands of traits in a hypothesis-free approach. Methods: We used publicly available GWAS data centralised and harmonised by the IEU open GWAS database. We assessed the potential causal role of 5048 exposures on risk of AF and the causal role of genetic liability to AF on 10,308 outcomes via two-sample MR analysis. Multivariable MR analysis was further conducted to explore the comparative role of identified risk factors. Results: MR analysis suggested that 55 out of 5048 exposure traits, including four proteins, play a causal role in AF (P < 1e-5 allowing for multiple comparisons). Multivariable analysis suggested that higher body mass index, height, systolic blood pressure as well as genetic liability to coronary artery diseases independently cause AF. Three out of the four proteins (DUSP13, TNFSF12 and IL6R) had a drug prioritising score for atrial fibrillation of 0.26, 0.38 and 0.88, respectively (values closer to 1 indicating stronger evidence of the protein as a potential drug target). Genetic liability to AF was linked to a higher risk of cardioembolic ischemic stroke. Conclusions: Body mass index, height, systolic blood pressure and genetic liability to coronary artery diseases are independent causal risk factors for AF. Several proteins including DUSP13, IL-6R and TNFSF12 may represent therapeutic potential for preventing AF.