Precision Target Discovery for Migraine: An Integrated GWAS-eQTL-PheWAS Pipeline

Migraine is a complex neurological disorder that severely compromises quality of life. Current therapies remain inadequate, creating an urgent need for precision medicine approaches. To bridge this gap, we integrated genome-wide association studies (GWASs) and multi-tissue expression quantitative trait loci (eQTL) data. Using Mendelian randomization (SMR/HEIDI) to identify putatively causal genes, followed by colocalization analysis, protein-protein interaction networks, and gene enrichment, we prioritized druggable targets. Phenome-wide association studies (PheWASs) further assessed their potential safety profiles. We identified 31 migraine-associated genes in whole blood, 20 in brain tissue, and 9 genes shared by both whole blood and brain regions. Among 13 druggable genes identified from the DGIdb and supporting literature, 10 passed colocalization validation. Eight genes (TGFB3, CHRNB1, BACE2, THRA, NCOR2, NR1D1, CHD4, REV3L) showed interactions with known drug targets, enabling the computational prediction of 41 potential repurposable drugs. Based on target druggability, PPI (protein-protein interaction) and favorable PheWAS profiles, NR1D1, THRA, NCOR2, and CHD4 are prioritized for drug development. Additionally, MICU1, UFL1, LY6G5C, and PPP1CC emerged as novel pathophysiological factors. This study establishes a multi-omics framework for precision migraine therapy, translating genetic insights into clinically actionable targets.