Liver Diseases and Brain Disorders: Genetic Mechanisms and Biomarker Pathways in a Prospective Cohort Study From the <scp>UK</scp> Biobank

Population-based evidence directly linking liver diseases to brain disorders is limited, and its genetic and biochemical associations remain unclear. Our aim is to examine the links between liver diseases and brain disorders. This prospective cohort study utilized data from 492 059 participants in the UK Biobank. We identified 508 cases of alcoholic liver disease (ALD), 583 cases of non-alcoholic fatty liver disease (NAFLD), and 557 cases of viral hepatitis (VH) based on International Classification of Diseases (ICD) codes. Initially, we employed multiple linear and logistic regression to assess associations between liver diseases, polygenic risk score (PRS), inflammatory and metabolic biomarkers, and brain function. Cox proportional hazard models were then applied to determine the impact of liver diseases on the incidence of brain disorders. Ultimately, structural equation models were used to explore potential genetic and biomarker pathways. During a median follow-up of 14.46 years, participants with ALD, NAFLD, and VH demonstrated poorer cognition, mental health, and motor function compared to the healthy group, with p < 0.05 for false discovery rate (FDR-Q < 0.05). They exhibited increased risks for dementia (hazard ratios [HRs]: 2.28-4.10; FDR-Q < 0.001), major depressive disorder (HRs: 2.25-3.23; FDR-Q < 0.001), and generalized anxiety disorder (HRs: 1.70-2.66; FDR-Q < 0.01). Additionally, C-reactive protein, neutrophil-to-lymphocyte ratio, platelets, and low-density lipoprotein lipid components mediated the associations between PRS, liver diseases, and brain disorders. Our findings demonstrated that liver diseases were risk factors for brain disorders, with genetic and biochemical associations contributing to these risks.