ABSTRACT Background Schizophrenia is a severe psychiatric disorder with a complex etiology involving genetic and environmental factors. Despite its profound impact, the molecular mechanisms underlying schizophrenia remain elusive. Emerging evidence suggests that DNA methylation, palmitoylation, and immune cell activity play critical roles in its pathogenesis. This study employs a multi‐omics approach to investigate the causal relationships among these factors and schizophrenia. Methods We utilized Mendelian randomization (MR), integrating expression, protein, and methylation quantitative trait loci (eQTL, pQTL, mQTL) to explore causal pathways in schizophrenia. Our approach involved (1) identifying palmitoylation‐related genes and assessing their causal effects on schizophrenia via two‐sample MR, validated by summary‐data‐based MR (SMR); (2) conducting mediation MR to examine upstream DNA methylation's role in gene regulation and its impact on schizophrenia; and (3) investigating downstream immune cell traits as mediators of gene effects on schizophrenia risk. Sensitivity analyses ensured robustness. Results We found a significant causal association between increased ZDHHC20 expression, a palmitoyltransferase, and elevated schizophrenia risk ( p < 0.05), confirmed by SMR. Upstream, DNA methylation at cg18095732 regulates ZDHHC20 , mediating 59.31% of its effect on schizophrenia ( p < 0.05). Downstream, CCR7 expression on naive CD8+ T cells mediates 33.35% of ZDHHC20 ’s influence on schizophrenia risk ( p < 0.05). Conclusions This study reveals a novel mechanistic axis in schizophrenia: DNA methylation‐ZDHHC20‐immune regulation, linking epigenetic modifications and palmitoylation to neuroimmune dysregulation. ZDHHC20 emerges as a potential therapeutic target, highlighting the value of multi‐omics in psychiatric disease research and suggesting avenues for targeted interventions addressing both neuronal and immune contributions.
Guo et al. (Fri,) studied this question.