Major Depression as a Catalyst for Nonalcoholic Fatty Liver Disease: Insights From a Comprehensive Mendelian Randomization Study

<b>Background:</b> This study aimed to investigate the causal association between mental disorders and nonalcoholic fatty liver disease (NAFLD; now termed metabolic dysfunction-associated steatotic liver disease, MASLD) using Mendelian randomization (MR). <b>Methods:</b> A bidirectional two-sample MR approach was employed to evaluate the causal relationship between NAFLD and eight mental disorders: major depression, anxiety, bipolar disorder, schizophrenia, autism, post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), and eating disorders. The inverse-variance weighted (IVW) method was utilized to estimate causal effects, supported by MR-CAUSE and other sensitivity analyses to address pleiotropy and heterogeneity. Instrumental variables from genome-wide association studies were applied, and initial associations were examined using linkage disequilibrium score (LDSC) regression analysis. Furthermore, mediation analysis was conducted to identify potential mediators. <b>Results:</b> The MR analysis revealed significant positive associations between NAFLD occurrence and major depression (odds ratio [OR] = 1.294, <i>p</i> = 0.003), bipolar disorder (OR = 0.895, <i>p</i> = 0.004), and autism (OR = 1.118, <i>p</i> = 0.005). However, only the putative causal association of major depression on NAFLD remained statistically significant in further validation, including MR-CAUSE and sensitivity analyses, and was not attributable to linkage disequilibrium. No causal effect of NAFLD on mental disorders was found in reverse MR analysis. In LDSC regression, significant positive associations with NAFLD occurrence were observed for major depression (Rg = 0.538, <i>p</i> = 1.36<i>E</i> - 07), ADHD (Rg = 0.798, <i>p</i> = 1.10<i>E</i> - 08), and PTSD (Rg = 0.579, <i>p</i> = 0.009). Mediation analysis identified body mass index (39.33%, <i>p</i> = 0.017), waist-to-hip ratio (8.09%, <i>p</i> = 0.026), triglycerides (39.33%, <i>p</i> = 0.017), and serum concentration of large very low-density lipoprotein (VLDL) particles (8.76%, <i>p</i> = 0.032) as mediators of the causal effect of major depression on NAFLD occurrence. <b>Conclusion:</b> This study suggests a potential causal link between major depression and the development of NAFLD, underscoring the importance of considering major depression in the management of NAFLD patients.