Triangulating the link between depression and liver disease: An integrative analysis of genetic, observational, and research trend data

Background The relationship between major depressive disorder (MDD) and liver diseases is complex, with causal links poorly understood. This study aimed to disentangle causal, mediated, and confounded links between MDD and liver diseases. Methods We integrated three approaches: a trend analysis of 2004 to 2024 publications; a two-sample Mendelian randomization, or MR, analysis assessing genetic causal effects of MDD on liver diseases; and an observational analysis of the NHANES 2007 to 2020 cohort using survey-weighted regression and formal causal mediation analysis to evaluate clinical pathways. Results MR analysis provided genetic evidence for a causal effect of MDD on NAFLD (OR = 1.233, 95% CI: 1.015–1.496), chronic HBV (OR = 1.607, 95% CI: 1.155–2.235), and viral hepatitis (OR = 1.515, 95% CI: 1.053–2.180), but not chronic HCV. In NHANES, the clinical MDD-NAFLD association (AOR = 1.35) became non-significant after adjusting for BMI (AOR = 1.07, P = 0.500), with formal mediation analysis revealing that BMI significantly mediates 80.70% of this risk. Furthermore, MDD showed no independent association with advanced liver fibrosis ( P = 0.500). Conversely, a strong observational association was found for chronic HCV (AOR = 2.52) despite the null MR finding; however, this was entirely attenuated after adjusting for illicit drug use (AOR = 1.59, P = 0.072). No significant association was found for chronic HBV. Conclusion MDD increases liver disease risk via distinct pathways. The genetic MDD-NAFLD link appears largely mediated by obesity clinically, manifesting primarily as steatosis rather than direct fibrogenesis. The strong MDD-HCV association reflects socio-behavioral confounding, while the causal MDD-HBV link remains an under-recognized risk. These findings underscore the importance of managing obesity in psychiatric care and integrating mental health screening in hepatology.