Twenty-five immune cell-specific genes are causally associated with migraine.
Genes such as CDC42 and HAX1 are implicated across multiple immune cell types.
Subtype-specific analyses indicate different gene effects in migraine with aura and without aura.
Genetic correlation links identified genes to comorbid conditions like depression and gastrointestinal disorders.
PheWAS analysis suggests few adverse associations for prioritized genes.
Drug repurposing identified FDA-approved medications as potential migraine therapies.
Simplified
BACKGROUND: Migraine is a highly prevalent neurological disorder with complex pathophysiology and limited treatment efficacy. Emerging evidence suggests immune cell involvement in migraine, but the specific regulatory mechanisms remain unclear. This study aimed to identify immune cell-type-specific genetic drivers of migraine and prioritize potential therapeutic targets.
METHODS: We conducted a (MR) analysis integrating (sc-eQTL) data from 14 immune cell types with large-scale genome-wide association studies (GWAS) of migraine. Colocalization analysis, protein-protein interaction (PPI) networks, linkage disequilibrium score regression (LDSC), phenome-wide association studies (PheWAS), and drug repurposing databases were utilized to validate findings and assess therapeutic potential and safety.
RESULTS: We identified 25 immune cell-specific causally associated with migraine, including CDC42, NELFCD, HOXB3, HAX1, and FHL3. Several genes, such as CDC42 and HAX1, were implicated across multiple immune cell types. Subtype-specific analyses revealed differential gene effects in migraine with aura (MA) and without aura (MO). Genetic correlation and pleiotropy analyses linked eGenes to comorbid traits such as depression, gastrointestinal disorders, and blood pressure. PheWAS suggested minimal adverse associations for prioritized genes like GINM1 and TMA7. Drug repurposing identified FDA-approved agents, including hydroxychloroquine sulfate (NELFCD) and bazedoxifene (CDC42), as potential migraine therapies.
CONCLUSION: This study reveals immune cell-specific genetic contributors to migraine and highlights druggable targets for therapeutic development. Integrating sc-eQTL with multi-omics and pharmacological data provides a novel framework for precision medicine in migraine.
Key numbers
25
Identified
Causally associated immune cell-specific linked to migraine
55,116
Migraine cases
Migraine cases from the primary dataset
445,232
Controls
Controls from the primary dataset
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Declarations. Ethics approval and consent to participate: Ethical approval was obtained for each of the original GWAS. No individual-level or identifiable data were accessed. Therefore, no new ethical review board approval was required. Consent for publication: This manuscript does not include details, images, or videos relating to an individual person; therefore, consent for publication is not needed beyond the informed consent provided by all study participants as described above. Competing interests: The authors declare no competing interests.
