Abstract
The objective was to evaluate potential genetic associations between biliary system disorders and cortical and subcortical brain structural changes using Mendelian randomization analyses. This study focused on 4 diseases, including primary sclerosing cholangitis, cholecystitis, intrahepatic cholangiocarcinoma, and gallstone disease, and total bilirubin levels as indicators of biliary system disorders. Genome-wide association studies summary statistics from the ENIGMA consortium were utilized to assess the directional associations between these biliary system diseases and changes in brain structure, including the cerebral cortex (N = 51,665) and subcortical brain structures (N = 30,717). Inverse variance weighted was the primary method for conducting MR analysis. Furthermore, sensitivity analysis was conducted to evaluate the robustness of our findings. At the regional level, a decrease in the thickness of the pars opercularis was supposedly linked to genetically predicted total bilirubin levels (P = .00014). Decreased cortical thickness and surface area of the paracentral lobule were nominally associated with genetically predicted cholecystitis (PTH = .024; PSA = .042). Genetically predicted gallstone disease was correlated with an increased surface area of the transverse temporal gyrus (P = .023), while it was nominally associated with decreased thickness of the transverse temporal gyrus (P = .015), inferior parietal gyrus (P = .042), and middle temporal gyrus (P = .017). Furthermore, genetically predicted intrahepatic cholangiocarcinoma was associated with decreased thickness of the pars opercularis (P = .026) and surface area of the superior parietal gyrus (P = .013), while the thickness of the para hippocampal gyrus was increased without global weighted (P = .012) and with global weighted (P = .022). By comparison, genetically predicted primary sclerosing cholangitis was associated with a modest increase in the surface area of the para hippocampal gyrus, both with global weighted (P = .015) and without global weighted (P = .012), and was also linked to the increased thickness of the paracentral lobule (P = .016). No significant evidence of multiple testing effects or heterogeneity was observed. The research suggests an association between changes in the cerebral cortex and biliary system disorders, indicating an indirect impact of these abnormalities on cortical structures.