Purine Metabolism-Related Pathogenic Genes in Trigeminal Neuralgia: A Multiomics Mendelian Randomization Study

To investigate the association between purine metabolism-related genes and trigeminal neuralgia (TN) using multiomics approaches.

A multiomics summary-data-based Mendelian randomization (SMR) approach was applied to investigate associations between purine metabolism-related genes and TN. Genome-wide association study (GWAS) data from FinnGen R10 were integrated with blood-derived DNA methylation quantitative trait loci (mQTL), expression quantitative trait loci (eQTL), and protein quantitative trait loci (pQTL) datasets. Associations were evaluated by colocalization and replication in UKBB (G6_TRINEU) and FinnGen R12. Drug-target MR analysis used blood eQTL variants as proxies for gene expression. GEO transcriptomic and single-cell RNA sequencing (scRNA-seq) datasets and GTEx brain tissue eQTL data provided expression and tissue-level validation. Functional enrichment, protein-protein interaction network, and druggability analyses were performed.

SMR analysis identified 238 mQTLs (127 genes), 30 eQTLs, and 3 pQTLs associated with TN. Colocalization supported 96 mQTLs (23 genes), 18 eQTLs, and 3 pQTLs, with 42 mQTLs and the CNOT7 eQTL validated in UKBB. POMGNT2 showed genetically predicted associations with TN at both gene and protein levels. Integrative analysis highlighted ATP6V0E2, PLAT, and VKORC1 with evidence of epigenetic regulation. Drug-target MR provided supportive evidence that genetically proxied expression of CNOT7 and PLAT may be associated with lower TN risk. Transcriptomic validation showed downregulation of ATP6V0E2, PLAT, and CNOT7 after trigeminal nerve injury. Brain eQTL analysis supported the association of CNOT7 with TN across multiple brain regions. scRNA-seq revealed cell-type-specific expression patterns of prioritized genes in trigeminal ganglion tissues. Functional enrichment indicated involvement in stress response, metabolism, and genome maintenance pathways. PPI analysis identified six hub genes: ABCB1, COMT, GFM1, MDH2, NRAS, and TXN. Druggability analysis showed that ATP6V0E2, PLAT, and VKORC1 are targetable by existing drugs.

This study prioritizes purine metabolism-linked genes showing genetically supported associations with TN and highlights potential biological pathways and therapeutic targets.