Multi-omics reveal the role of nociception-related genes TNXB, CTNND1 and CBL in depression

Background: Recent studies have suggested a link between nociception and depression. However, the specific genes involved remain unclear. Methods: This study investigates this genetic link using multi-omics data. We collected nociception-related genes from the GeneCards database and integrated quantitative trait loci (mQTLs, eQTLs and pQTLs) data for gene expression, DNA methylation and protein expression. GWAS data from the IEU database served as the discovery cohort for depression, with FinnGen and GWAS Catalog data used for validation. Summary data-based Mendelian Randomization (SMR) analysis was employed to examine the interactions between nociception-related genes and depression, and colocalization analysis identified shared causal variants. The associations between depression and target gene expression in specific tissues and specific cell types were assessed using the GTEx v8 dataset and single-cell eQTL data. Results: SMR analysis revealed 215 mQTLs, 12 eQTLs, and 1 pQTL associated with depression in the discovery cohort. By integrating multi-omics evidence, we found that the hypermethylation of the TNXB gene (cg02272968, cg02432444, cg27624229) and the hypomethylation of the CTNND1 gene (cg16127573) and the P2RY6 gene (cg12889420) were found to upregulate their expression, potentially increasing the risk of depression. GTEx eQTL analysis confirmed CBL expression in the substantia nigra positively correlates with depression risk. However, none of the key genes were confirmed in the single-cell eQTL analysis. Conclusions: Our study emphasizes the importance of nociception-related genes, particularly TNXB, CTNND1 and CBL in the pathogenesis of depression. Future research should build on these findings for potential prevention and treatment strategies.