Insights into modifiable risk factors of atrial fibrillation: a comprehensive Mendelian randomization study

Abstract Background Numerous observational studies suggest that modifiable risk factors contribute to the onset of atrial fibrillation (AF). This study aims to assess the causal relationship between 46 modifiable risk factors and AF. Methods Univariable, multivariate, and mediation Mendelian randomization (MR) analyses were employed to examine the causal relationship between 46 modifiable risk factors and AF. Summary-level data from genome-wide association studies (GWAS) meta-analysis and FinnGen consortium were utilized for both discovery and replication. The combined results were analyzed using a fixed-effect model to confirm the robustness of the findings. Results Among 46 modifiable risk factors, both the discovery dataset and the combined results confirmed that alcohol consumption, smoke consumption, job involves heavy manual or physical work, sleep apnea syndrome, trunk fat mass, body fat percentage, whole body fat mass, waist circumference, body mass index, basal metabolic rate, poor health status, diastolic blood pressure, systolic blood pressure, glycosylated hemoglobin type A1C (HbA1C), lipoprotein A, serum uric acid, coronary artery disease, myocardial infarction, heart failure, hypertension, hyperthyroidism, and negative emotions increased the risk of AF (P < .05 and false discovery rate–adjusted P < .05). Conversely, college or university degree, impedance of whole body, and heart rate were associated with a decreased risk of AF (P < .05 and false discovery rate–adjusted P < .05). Multivariate MR identified sleep apnea syndrome, basal metabolic rate, diastolic blood pressure, systolic blood pressure, HbA1C, lipoprotein A, serum uric acid, coronary artery disease, myocardial infarction, heart failure, and hypertension as risk factors for AF. Conclusion Our findings offer new and comprehensive evidence demonstrating the confirmed causal effects of various risk factors on AF among Europeans. Larger-scale GWAS will be necessary to further validate these causal associations in the future. Highlights Our study investigated the causal association between 46 modifiable risk factors and AF under a two-sample MR framework. This comprehensive MR study confirmed that alcohol consumption, smoke consumption, job involves heavy manual or physical work, sleep apnea syndrome, trunk fat mass, body fat percentage, whole body fat mass, waist circumference, body mass index, basal metabolic rate, poor health status, diastolic blood pressure, systolic blood pressure, HbA1C, lipoprotein A, serum uric acid, coronary artery disease, myocardial infarction, heart failure, hypertension, hyperthyroidism, negative emotions, college or university degree, impedance of whole body, and heart rate contribute causally to the onset and development of AF. No significant association was found between lipid levels and AF. Key messages What is already known on this topic: Previous studies have identified several risk factors associated with AF, yet the precise causal relationships between these factors and the development of AF remain unclear, highlighting the need for further research. What this study adds: This study systematically evaluates the causal association of 46 modifiable risk factors with AF by combining data from two independent GWAS datasets. How this study might affect research, practice, or policy: The discovery of AF-related risk factors provides valuable knowledge for early identification and intervention strategies for AF patients.