Unravelling the liver- brain connection: a twosample mendelian randomization study investigating the causal relationship between nafld and cortical structure

Background: Non-alcoholic fatty liver disease (NAFLD) has been linked to cognitive decline and neuropsychiatric conditions, implying a potential connection between NAFLD and brain health. However, the causal association between NAFLD and cortical changes remains uncertain. This study aimed to examine the causal impact of NAFLD on cortical structures using a two-sample Mendelian randomization (MR) approach.Methods: Summary data from genome-wide association studies (GWAS) for NAFLD were gathered from large-scale cohorts. Surface area (SA) and cortical thickness (TH) measurements were derived from Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium magnetic resonance imaging (MRI) data of 33,992 participants. Inverse-variance weighted (IVW) served as the primary method. Additional sensitivity analyses, including MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), MR-Egger, and weighted median procedures, were conducted to detect heterogeneity and pleiotropy.Results: Our MR analysis revealed that NAFLD led to notable alterations in cortical structures, particularly in the pars orbitalis gyrus. Specifically, genetically predicted NAFLD was linked to a decrease in TH (beta =-0.008 mm, 95 % CI:-0.013 mm to-0.004 mm, P = 3.00 x 10-4) within this region. No significant heterogeneity and pleiotropy were identified.Conclusion: The two-sample MR study supports the existence of a liver-brain axis by demonstrating a causal association between NAFLD and changes in cortical structures. These findings emphasize the potential association between NAFLD and brain health, which could have implications for preventing and treating cognitive deficits and neuropsychiatric conditions in patients with NAFLD.