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

Area of Science:

• Neurology
• Hepatology
• Genetics
• Metabolomics

Background:

• Migraine is a disabling neurological disorder with potential links to hepatic metabolism.
• Observational studies suggest associations between bilirubin, aspartate aminotransferase (AST), and migraine risk, but causality remains unclear.
• Confounding factors necessitate rigorous investigation into the causal relationship between liver function markers and migraine.

Purpose of the Study:

• To investigate the causal effect of genetically predicted serum bilirubin and AST levels on migraine risk.
• To explore potential mediating pathways of these effects through brain structural or hepatic biomarkers.
• To elucidate the role of the liver-brain axis in migraine pathophysiology.

Main Methods:

• Two-sample Mendelian randomization (MR) framework utilizing data from the IEU OpenGWAS Project.
• Inverse-variance weighting (IVW) as the primary analytical method, supported by MR-Egger and weighted median methods.
• Pleiotropy, heterogeneity, and leave-one-out analyses were conducted to ensure robustness and validity.

Main Results:

• Genetically predicted elevated bilirubin significantly increased migraine risk (OR=1.055, P=0.003), with 32% mediation via cortical thickness.
• Genetically predicted elevated AST also increased migraine risk (OR=1.100, P=0.007), with 12% mediation by gamma-glutamyl transferase (GGT).
• Direct effects of bilirubin and AST on migraine risk were substantial (68% and 88%, respectively).

Conclusions:

• Serum bilirubin and AST act as genetic risk factors for migraine.
• The causal effects are partially mediated by brain structural changes (bilirubin) and hepatic metabolic pathways (AST-GGT).
• Clinical monitoring of migraine risk in individuals with liver dysfunction is recommended, alongside research into liver-brain axis interventions.