Bidirectional causality between liver dysfunction and migraine: A mediating Mendelian randomization study

Migraine, a highly disabling neurological disorder, has garnered significant attention regarding its association with hepatic metabolism. Observational studies suggest that bilirubin and aspartate aminotransferase (AST) may influence migraine risk, but the confounding effects require rigorous resolution. We aimed to investigate whether genetically predicted levels of bilirubin and AST have a causal effect on migraine risk and to explore potential mediating pathways via brain structural or hepatic biomarkers. This study employed a two-sample Mendelian randomization (MR) framework to evaluate the causal effects of serum bilirubin and AST on migraine using data from the Integrative Epidemiology Unit Open Genome-Wide Association Study Project (IEU OpenGWAS Project). The inverse-variance weighting (IVW) method was used as the core approach, supplemented by MR-Egger and weighted median methods for validation. Robustness was ensured through pleiotropy tests, heterogeneity tests, and leave-one-out analyses. Elevated bilirubin significantly increased migraine risk (OR = 1.055, 95% CI: 1.018-1.093, P = .003), of which 32% was mediated through cortical thickness in the left fusiform gyrus-lingual gyrus region, as estimated using two-step MR mediation analysis. Elevated AST also increased migraine risk (OR = 1.100, 95% CI: 1.026-1.179, P = .007), with 12% mediated by γ-glutamyl transferase (GGT). The direct effects accounted for 68% and 88%, respectively. Liver function markers bilirubin and AST are genetic risk factors for migraine, with their effects partially mediated by specific brain structural changes (bilirubin) and hepatic metabolic networks (AST-GGT). Clinically, enhanced monitoring of migraine risk in patients with liver dysfunction is warranted, along with exploration of liver-brain axis-targeted intervention strategies.