ZDHHC5 and ZDHHC14 promote depression via the mediation of double- negative T cells

This study aims to identify palmitoylation modification-related genes involved in depression and to explore the mechanism of gene action through the mediation of immune cells. We analyzed the latest reviews on palmitoylation, integrated palmitoylation-related gene loci, and extracted expression quantitative trait locus(eQTL) data for palmitoylation genes associated with depression. Through batch analysis, we initially identified positive genes and validated them using Mendelian randomization based on summary data(SMR) to pinpoint the target genes. Subsequently, we further conducted mediation analysis to explore the downstream mechanism of action of the target gene. In the results,Thirty-one palmitoylated genes were screened from the literature. After extracting eQTL data to obtain 22 co-located loci, batch analysis with depression yielded seven positive genes.Validation using SMR analysis identified ZDHHC5 (OR = 1.136755, P  = 1.14×10⁻⁹, P _SMR = 6.88×10⁻¹⁰) and ZDHHC14 (OR = 1.055997, P  = 2.29×10⁻⁹, P _SMR =0.02409) as the final target genes. The downstream mechanisms of action were explored using 731 immune cells. The results showed that: ZDHHC5 promotes depression through the mediating effects of effector memory double negative (CD4-negative and CD8-negative) (mediation effect = 0.065386) and CD28-negative double negative (CD4-negative and CD8-negative) percentage of T cells (CD28- DN (CD4-CD8-) % T cells) (mediation effect = 0.086404). ZDHHC14 promoted depression through EM DN (CD4-CD8-) AC (mediation effect = 0.129494). Our results indicated that double negative T cells played an important role in this study. Thus, we conclude that ZDHHC5 and ZDHHC14 promote depression via the mediation of double-negative T cells.