ZDHHC5 Mediates Immune Dysregulation Driving Generalized Anxiety Disorder Risk

Objective To investigate genes associated with palmitoylation modification implicated in generalized anxiety disorder (GAD), and to elucidate the mechanistic roles of these genes via immune cell‐mediated pathways. Methods Utilizing large‐scale genetic datasets, genes categorized as palmitoylation‐expression quantitative trait loci (eQTL) were identified by intersecting palmitoylation‐related genes (as compiled from the most recent reviews) with genome‐wide eQTL datasets. A two‐sample Mendelian randomization (MR) methodology was applied to investigate the causal relationship between palmitoylation‐eQTL genes and GAD, with further verification conducted through summary‐data‐based Mendelian randomization (SMR) to establish the final target genes. Subsequently, the underlying mechanisms of these genes were examined through immune cell‐mediated processes. Results Twenty‐two palmitoylation‐eQTL gene loci were identified, among which five demonstrated a notable link to GAD: PPT2 (odds ratio [OR] = 0.844, p = 0.007), ZDHHC5 (OR = 1.101, p = 0.017), ZDHHC13 (OR = 1.175, p < 0.001), ZDHHC20 (OR = 0.874, p = 0.003), and ZDHHC24 (OR = 0.806, p < 0.001). ZDHHC5 and ZDHHC13 were validated as final target genes through SMR analysis. Mediation MR analysis revealed that SSC‐A on CD4+ T cells (mediation proportion: 36.4%) served as a mediating factor for ZDHHC5. Conclusion The findings indicate that ZDHHC5 contributes to the pathogenesis of GAD by modulating SSC‐A on CD4+ T cells, thereby offering novel targets for the investigation of GAD pathophysiology.