From trigeminal ganglion to cortex: ATG7 emerges as a key integrator of migraine pathways via multi-omics profiling

Migraine is a complex neurological disorder with poorly understood molecular mechanisms. Despite advances in genetic and omics research, the shared mechanisms between central and peripheral nervous systems in migraine pathogenesis remain unclear.

We employed a multi-omics approach, integrating human trigeminal ganglion (TG) single-nucleus RNA sequencing (snRNA-seq) data and expression quantitative trait loci (eQTL) data from eight major cortical cell types. Mendelian randomization (MR) analysis was used to prioritize susceptibility genes, followed by functional enrichment, molecular network mapping, and computational drug screening. Key findings were experimentally validated in the primary sensory cortex hindlimb area brain region and TG, given their established roles in pain processing.

We identified 586 migraine-associated genes in TG and 1,108 in the cortex, with 109 overlapping genes. These overlapping genes converge on pathways including autophagy and neuroinflammation, suggesting shared mechanisms of central and peripheral nervous systems. Five hub genes - HSP90AB1, EGFR, ERBB3, MET and ATG7 - were implicated in both TG and cortical tissues. Experimental validation identified five hub genes strongly linked to migraine, with ATG7 emerging as a key candidate. Immunofluorescence co-localization revealed ATG7's prominent expression in both cortical astrocytes and neurons, suggesting its dual role in glial and neuronal pathways underlying migraine pathophysiology. Western blot analysis revealed that in the S1HL brain region of migraine model mice, the protein level of LC3-II showed an increasing trend, while the expressions of both LC3-I and p62 exhibited decreasing trends compared to the control group. Furthermore, both the LC3-II/LC3-I ratio and the LC3-II/p62 ratio were significantly elevated in the model group, suggesting that the upregulation of ATG7 promotes the activation of autophagic flux in the migraine model, with the autophagic flux remaining unobstructed.

Our study provides novel insights into migraine's central and peripheral mechanisms, highlighting cell-type-specific genetic contributions and potential therapeutic targets. The integrative framework combining snRNA-seq, eQTL, GWAS, and MR enhances the understanding of migraine biology and accelerates drug discovery, offering a pathway toward more effective treatments.