Cerebellar neurocan gene expression is a common pathogenic factor of trigeminal neuralgia and depression

Trigeminal neuralgia (TN) is a severe neuropathic pain disorder characterized by sudden, electric shock-like facial pain. It frequently co-occurs with depression and these conditions often exacerbate each other. However, their shared pathogenic mechanisms remain poorly understood In this study, neuroimaging data were integrated with whole-genome sequencing data to identify common genetic risk factors. Initially, single nucleotide polymorphisms (SNPs) associated with both conditions were identified through whole-genome analysis. Gene-tissue associations were then elucidated using the S-PrediXcan and summary data-based Mendelian Randomization (SMR) methods. These findings were further validated through neuroimaging analysis and animal experiments. Whole-genome analysis identified SNPs shared by TN and depression. The neurocan (NCAN) gene was significantly associated with both disorders and showed a cerebellum-specific expression pattern. Neuroimaging revealed significant differences in brain function and structure between TN and depression patients, primarily localized in the temporal lobe, frontal lobe, and cerebellum. Animal experiments corroborated these findings, showing that elevated cerebellar NCAN expression is closely linked to the onset and progression of both TN and depression. The study identifies the NCAN gene and cerebellar dysfunction as shared potential pathogenic factors between TN and depression. These findings provide new insights into the common mechanisms underlying these comorbid conditions and suggest potential implications for developing targeted therapeutic strategies.