Genetic insights into the causal role of metabolic, immune, and microbial factors in migraine

Migraine is a highly prevalent neurological disorder that imposes significant personal and economic burdens worldwide. However, the causal relationships between these biological factors and migraine remain poorly understood. This study aimed to investigate these causal relationships using robust genetic epidemiological methods to identify potential therapeutic targets for improved migraine management. A two-sample Mendelian randomization (MR) approach was used to assess the causal roles of three major categories of biological factors: metabolites (metabolites, blood and urine biomarkers), immune (inflammatory factors and immune cells), and microbiota (intestinal and skin flora). Genetic instruments were derived from large-scale genome-wide association studies. Bayesian weighted MR (BWMR) analyses were conducted to validate the robustness of findings. Colocalization analyses were performed to determine whether significant associations were mediated through known migraine-related pathogenic or therapeutic genes. The study identified 95 putative causal factors for migraine, including 46 metabolites, 23 immune cell profiles, 5 inflammatory markers, 13 intestinal floras, and 8 skin floras. Among the metabolites, the alpha-ketoglutarate to ornithine ratio and the spermidine to choline ratio were significant risk factors, whereas alliin and (2,4 or 2,5)-dimethylphenol sulfate were identified as protective factors. No significant associations were observed for blood and urine biomarkers. Colocalization analyses indicated that these factors influence migraine risk through pathways independent of known pathogenic or therapeutic genes. This study provides novel genetic evidence supporting the causal roles of metabolites, inflammatory markers, immune cell profiles, and microbiota in migraine etiology. The findings highlight potential biomarkers and therapeutic targets for migraine management.