Bidirectional Mendelian Randomization Analysis of 338 Cerebrospinal-Fluid Metabolites and Cluster-Headache Risk

Background: Cluster headache (CH) is a rare but highly disabling primary headache disorder characterized by severe unilateral attacks and autonomic symptoms. The metabolic mechanisms underlying CH remain poorly understood. Objective: To investigate the potential causal effects of cerebrospinal fluid (CSF) metabolite levels on CH risk, and to explore possible reverse causal effects of CH on CSF metabolites, using a bidirectional Mendelian randomization (MR) approach. Methods: < 0.01). The primary causal estimates were derived using the inverse-variance weighted (IVW) method under a random-effects model, complemented by MR-Egger, weighted median, and MR-PRESSO sensitivity tests. Multiple testing correction was performed using both Bonferroni and false discovery rate (FDR) approaches. Results: In the forward MR analysis, 11 CSF metabolites were significantly associated with CH risk (P 0.05). Conclusion: This bidirectional MR study provides the first genetic evidence linking central metabolic alterations to CH susceptibility. While these results highlight potential metabolic biomarkers and mechanistic pathways, the findings remain preliminary due to modest statistical power and should be replicated in larger and ethnically diverse cohorts.