Work

ZDHHC5 Mediates Immune Dysregulation Driving Generalized Anxiety Disorder Risk

Year: 2025

Type: article

Abstract: 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.

Source: Brain and Behavior

DOI: 10.1002/brb3.70818