Single-cell Transcriptome-wide Mendelian Randomization and Colocalization Converge on Astrocytic TRIM66 as a Candidate Driver and Potential Therapeutic Target for Trigeminal Neuralgia.
TL;DR
Astrocyte-specific regulation of TRIM66 may contribute to TN pathogenesis through neuroinflammatory pathways, offering a cell-type-resolved mechanistic perspective that complements existing models of TN biology.
Abstract
Background
Trigeminal Neuralgia (TN) is a disabling facial pain disorder with suboptimal pharmacological and surgical options. We hypothesized that genetic regulation of gene expression in specific brain cell types contributes to TN susceptibility and could nominate tractable therapeutic targets.
Methods
Single-cell cis-eQTLs from 183 neuropathology-free donors were used to instrument cell-type-specific expression. Variants surpassing genome-wide significance (P < 5×10-8) were LD-pruned (1000 Genomes Phase 3 European; r2 < 0.001; 10-Mb window) and harmonized; instruments with F < 10 were excluded. The final set comprised 1,746 Single Nucleotide Polymorphisms (SNPs) mapping to 1,745 eGenes. Two-Sample Mendelian Randomization (TwoSampleMR, R) tested eight brain cell types against TN risk in FinnGen (Release 12; 2,226 cases; 435,371 controls). Wald ratios were used for single-SNP instruments and inverse-variance weighting for multiple instruments. False Discovery Rate (FDR) control was applied within cell type. Colocalization (coloc, R) assessed shared causal variants.
Results
After pruning, 1,745 eGenes were analyzed across eight cell types. A single signal met within multiple-testing control: higher astrocytic Tripartite motif-containing 66 (TRIM66) expression associated with increased TN risk (Wald ratio; β = 0.3038, standard error (SE) = 0.0884, P = 5.87×10-4; odds ratio (OR) = 1.36, 95% confidence interval (CI) 1.14-1.61; FDR = 0.0869). Colocalization supported a shared causal variant between astrocytic TRIM66 expression and TN (PP.H4 = 0.81).
Discussion
Astrocyte-specific regulation of TRIM66 may contribute to TN pathogenesis through neuroinflammatory pathways, offering a cell-type-resolved mechanistic perspective that complements existing models of TN biology.
Conclusion
Genetic evidence suggests a potential role of astrocyte-mediated regulation of TRIM66 in TN susceptibility. Convergent MR and colocalization suggest TRIM66 as a potential cell-type-resolved candidate warranting further functional validation and therapeutic exploration.