Cell-type-specific gene regulation in migraine and its subtypes links genetic risk to brain structure

Migraine is a highly prevalent and disabling neurological disorder characterized by marked clinical heterogeneity, particularly between migraine with aura (MA) and migraine without aura (MO). Although genome-wide association studies (GWASs) have identified numerous risk loci, the cell-type-specific regulatory mechanisms linking genetic variation to brain structure and migraine susceptibility remain unclear. We integrated brain cell-type-specific cis-expression quantitative trait loci (eQTL) from single-nucleus RNA sequencing with large-scale GWAS summary statistics for overall migraine, MA, and MO using a Mendelian randomization (MR) framework. Causal effects of gene expression on migraine outcomes were assessed, followed by analyses linking prioritized genes to brain imaging-derived phenotypes and evaluating mediation by brain structural traits. Colocalization, spatiotemporal expression, and drug-gene interaction analyses were used to support causal inference and translational relevance. We identified 24 brain cell-type-specific genes with significant cis-eQTLs (eGenes) showing evidence of causal associations with overall migraine, largely confined to a single cell type. Subtype-stratified analyses further revealed four eGenes specific to MA and six eGenes specific to MO. MO-associated eGenes showed broader cellular involvement and enrichment at the 17q21.31 inversion locus. These eGenes exerted widespread effects on gray matter macrostructure and white matter microstructure. Two-step MR identified one significant potential mediation pathway for overall migraine and 15 for MO. Spatiotemporal analyses revealed cell-type-specific developmental expression profiles of significant eGenes, and drug-gene interaction analyses prioritized six potentially druggable genes, including CYP2D6 and HLA-C. This study delineates a cell-type-resolved causal framework linking gene regulation, brain structure, and migraine susceptibility, revealing subtype-specific mechanisms and highlighting translationally relevant targets.