Migraine-driven causal genes in ischemic stroke

Migraine, most notably migraine with aura, elevates the risk of ischaemic stroke, though the underlying causal molecular connections have not been fully elucidated. This study sought to uncover migraine-associated causal genes that confer susceptibility to ischaemic stroke and to dissect their cell-type-specific functional mechanisms operating within the neurovascular unit. We combined publicly available human transcriptomic resources, genetics-driven causal inference, machine-learning-assisted biomarker screening, mouse-derived single-cell and spatial transcriptomic atlases, immune-cell deconvolution, and in-silico molecular docking. Twenty migraine-related genes were detected with causal associations to ischaemic-stroke risk. We prioritised three consensus hub genes: CD79A, PKN2, and PRKDC. In stroke patients, CD79A was significantly downregulated, while PKN2 and PRKDC exhibited elevated expression; their reliable diagnostic capacity was further confirmed in an independent external cohort. Single-cell and spatial transcriptomic profiling mapped these hub genes to endothelial, myeloid and glial cell populations residing within a dynamic inflammatory-vascular pathological niche in mouse ischaemic brain lesions. Mechanistic analyses pointed to perturbed mitochondrial energy homeostasis and dysregulated adaptive immune responses as downstream consequences modulated by these hub genes. Molecular-docking simulations demonstrated high-affinity interactions between Tamibarotene, Dirithromycin and the three encoded hub proteins, highlighting these compounds as promising candidates for drug repurposing. Collectively, our multi-omics analysis pinpoints CD79A, PKN2 and PRKDC as migraine-derived causal targets for ischaemic stroke, delivers cell- and spatial-resolved mechanistic perspectives on neurovascular-unit injury, and puts forward lead compounds awaiting further pre-clinical validation.