Migraine immune cell gene targets and their relationship to psychiatric disorders

Background Migraine frequently co-occurs with psychiatric disorders, yet the immunogenetic mechanisms linking these conditions remain largely unexplored. Methods Using cis-eQTL data from 28 immune cell subtypes (1,925 donors) and GWAS summary statistics for migraine and five psychiatric disorders, we performed single-cell transcriptome-wide Mendelian randomization, Bayesian colocalization, genetic correlation, and cross-disease pleiotropy analyses. Independent replication was performed using external datasets. Results Migraine and its subtypes showed significant positive genetic correlations with all five psychiatric disorders (rg = 0.39–0.73). We identified 83 immune cell gene targets for migraine, 13 for migraine with aura, and 19 for migraine without aura. Among these, 6 targets showed shared associations with anxiety and 1 with depression. Three prioritized genes—HLA-A, CDK2AP1, and TTC24—demonstrated cross-disease pleiotropic effects. Notably, HLA-A in cDC1 exhibited discordant pleiotropy (protective for migraine with aura, risk for depression), with known drug–gene interactions involving antiepileptics and tricyclic antidepressants. Conclusions These findings suggest that immune cell–specific genes, particularly HLA-A, CDK2AP1, and TTC24, may bridge migraine and psychiatric disorders, offering potential candidates for further investigation into shared immunogenetic mechanisms. Clinical trial number Not applicable.