Horizontal pleiotropy assessed by MR-Egger intercepts was minimal for NAFLD (intercept = 0.026, P = 0.059), chronic HBV (intercept = 0.020, P = 0.490), and viral hepatitis (intercept = 0.004, P = 0.868), whereas primary biliary cholangitis exhibited a marginally significant pleiotropy signal (intercept = −0.088; P < 0.05).
However, the detection of a highly significant direct effect independent of BMI underscores that the residual ∼19.3% risk points toward the intrinsic biological overlaps mentioned above, such as MDD-induced systemic low-grade inflammation or gut microbiota dysbiosis, which can directly promote hepatic steatosis even in the absence of overt obesity. 4.3 Disentangling viral hepatitis: confounding vs. hidden causality Our study revealed intriguing discrepancies regarding viral hepatitis.