Multi-omics Genetic Prioritization and Cross-species Analysis of Mitochondrial Genes in Trigeminal Neuralgia

To identify mitochondrial genes associated with trigeminal neuralgia (TN) and characterize their expression in patient blood and experimental trigeminal nerve injury. We integrated methylation, expression, and protein quantitative trait loci with FinnGen TN genome-wide association data, focusing on MitoCarta3.0 genes. Summary-data-based Mendelian randomization, heterogeneity testing, colocalization, and tissue-specific analyses prioritized candidates. An exploratory case-control expression analysis measured candidate-gene expression by reverse-transcription quantitative polymerase chain reaction in pretreatment blood from 12 patients with TN and 12 controls; experimental analyses examined blood and selected tissues from six rats with infraorbital nerve chronic constriction injury (ION-CCI) and six sham-operated rats. Longitudinal behavioral testing characterized the injury model. NIT2, HDHD3, and GRHPR overlapped across the three molecular screens. Colocalization supported NIT2 in the anterior cingulate cortex (PP.H4 = 0.949) and GRHPR in tibial nerve (PP.H4 = 0.818). All three genes showed increased expression in patient blood (all false-discovery-rate q < 0.001). HDHD3 and GRHPR also increased in rat blood (both q = 0.0188), and GRHPR increased in the injured infraorbital nerve (q = 0.0076). Genetically predicted higher GRHPR expression was associated with lower TN risk. Human genetics and cross-species expression analyses identify mitochondrial candidates associated with TN and trigeminal nerve injury. The protective genetic direction and injury-associated expression of GRHPR support a hypothesis of compensatory metabolic adaptation in trigeminal pain.