Abstract
BACKGROUND: Non-alcoholic Fatty Liver Disease (NAFLD) is highly prevalent and increasingly recognized as a multisystem condition with bidirectional links to the brain-liver axis. While most prior work emphasized "liver-to-brain" effects, whether anxiety disorders increase the risk of Non-alcoholic Fatty Liver Disease remains unclear. METHODS: We employed Mendelian randomization (MR) analysis using Genome-wide association study (GWAS) data to investigate whether genetically predicted anxiety disorders play a causal role in NAFLD risk. We then validated our findings using a prospective cohort of 393,229 participants from the UK Biobank, with a median follow-up of 12.6 years. RESULTS: Our MR analysis provides suggestive evidence for a potential causal effect of genetically predicted anxiety disorders on NAFLD (odds ratio [OR] = 1.73, 95% confidence interval [CI]: 1.12-2.67, P = 0.013). This finding was further supported by the UK Biobank prospective study, which demonstrated that baseline anxiety was associated with increased incident NAFLD risk even after adjusting for potential confounding factors (hazard ratio [HR] = 1.630, 95% CI: 1.488-1.786, P < 0.001). Notably, participants with anxiety exhibited elevated liver fat content at follow-up magnetic resonance imaging, as assessed through follow-up magnetic resonance imaging, irrespective of gender (P < 0.001). CONCLUSION: Our study provides converging evidence from genetic and observational data suggesting that anxiety disorders may be associated with an increased risk of NAFLD onset. This relationship necessitates a reconsideration of both NAFLD management and pharmacotherapy for anxiety disorders, advocating for a shift from a specialized clinical focus to a comprehensive community-level strategy for addressing non-communicable diseases (NCDs).