Exploring the causal relationships and mediating factors between depression, anxiety, panic, and atrial fibrillation: A multivariable Mendelian randomization study

Atrial fibrillation is a significant cardiovascular disease, and the increased risk of its occurrence may be influenced by mental disorders. Currently, the causal relationship between them remains controversial. Our aim is to ascertain the relationship between atrial fibrillation and mental disorders including depression, anxiety, and panic, as well as the risk factors mediating this relationship, through the judgment of genetic susceptibility.We utilized the summarized statistics from nine large-scale genome-wide association studies (in European populations), including depression (PGC, N = 807,553), anxiety (FinnGen, N = 429,209), panic (PGC, N = 230,878), diabetes (UK Biobank, N = 655,666), smoking (IEU, 607,291), hypertension (UK biobank, N = 463,010), obstructive sleep apnea (IEU, N = 476,853), obesity (UK biobank, N = 463,010), and AF (IEU, N = 1,030,836). By applying bidirectional two-sample Mendelian randomization and multivariable Mendelian randomization to depression, anxiety, panic, and AF, we analyzed their causal relationships and the independent influence of specific risk factors. Furthermore, a two-step MR approach was used to assess the mediating effects of diabetes, smoking, hypertension, obstructive sleep apnea, and obesity.Results from the Two-Sample Mendelian Randomization Inverse Variance Weighted Random Effects Model show: the occurrence of genetically predicted depression is related to an increased risk of atrial fibrillation (AF) (OR: 1.073; [95 % CI: 1.005-1.146] P < 0.05), and panic is more significantly associated than depression (OR: 1.017; [95 % CI: 1.008-1.027] P < 0.001), while anxiety has no causal relationship with the occurrence of AF (OR: 1.023; [95 % CI: 0.960-1.092], P > 0.05), and AF is not significantly related to the occurrence of depression, anxiety, or panic (P > 0.05). After correcting for the other two risk factors using multivariable Mendelian randomization, depression remains significantly related to the occurrence of AF (β: 0.075; 95 % CI: [0.006, 0.144], P < 0.05), while panic and anxiety are not related to the occurrence of AF. Among them, the risk factors for AF occurrence, hypertension and obesity, are mediators between depression and AF, with mediation proportions of 74.9 % and 14.3 %, respectively. The mediating effects of diabetes, smoking, and obstructive sleep apnea were found to be not statistically significant. The above results are robust after sensitivity analysis.Our results identified that the genetic susceptibility to depression is an independent risk factor for the occurrence of AF, and that hypertension and obesity can mediate this process. Panic also poses some risk to the onset of AF. This demonstrates that controlling hypertension and obesity for emotional management is of great importance in preventing the occurrence of AF.