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<p>Obsessive–compulsive disorder (OCD) affects 1–3% of the global population and ranks among the top ten most disabling medical conditions. While abnormalities in cortico-striato-thalamo-cortical circuits have been implicated in OCD pathophysiology, the molecular mechanisms underlying these neural aberrations remain incompletely understood. Protein palmitoylation, a reversible post-translational modification, is essential for neuronal development and synaptic function, potentially affecting neurotransmitter systems linked to OCD. We employed Mendelian randomization (MR) to explore causal relationships between the expression of palmitoylation-related genes, imaging-derived phenotypes (IDPs), and OCD susceptibility. Analysis of 22 palmitoylation-related genes revealed that decreased expression of the palmitoyl acyltransferase ZDHHC4 significantly increases OCD risk (OR = 0.882, 95% CI: 0.831–0.935, <i>p</i> = 2.73 × 10<sup>−5</sup>), a finding that remained robust across multiple sensitivity analyses. In a survey of 183 IDPs associated with OCD, ZDHHC4 expression significantly influenced 46 imaging measures. Mediation analysis revealed that the IDP ICA100 edge 531, representing functional connectivity between the left dorsolateral prefrontal cortex and bilateral orbitofrontal cortex, significantly mediated the relationship between ZDHHC4 expression and OCD risk (19.9%, <i>p</i> = 0.005). These findings establish a novel causal pathway linking ZDHHC4-mediated palmitoylation to altered brain activity in frontal-orbital circuits and subsequent OCD susceptibility. This integrated molecular-neural circuit framework provides new insights into OCD pathophysiology and identifies palmitoylation pathways as potential therapeutic targets for this debilitating neuropsychiatric disorder.</p>

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ZDHHC4 Influences Obsessive–Compulsive Disorder Risk Through Imaging-Derived Phenotypes: A Mendelian Randomization Study

  • 期刊论文

  • 发表日期：

    2025年8月2日

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  • Ying Huang,
  • Huanxian Luo,
  • Jieping Huang,
  • Xuejiao Hou

摘要

Obsessive–compulsive disorder (OCD) affects 1–3% of the global population and ranks among the top ten most disabling medical conditions. While abnormalities in cortico-striato-thalamo-cortical circuits have been implicated in OCD pathophysiology, the molecular mechanisms underlying these neural aberrations remain incompletely understood. Protein palmitoylation, a reversible post-translational modification, is essential for neuronal development and synaptic function, potentially affecting neurotransmitter systems linked to OCD. We employed Mendelian randomization (MR) to explore causal relationships between the expression of palmitoylation-related genes, imaging-derived phenotypes (IDPs), and OCD susceptibility. Analysis of 22 palmitoylation-related genes revealed that decreased expression of the palmitoyl acyltransferase ZDHHC4 significantly increases OCD risk (OR = 0.882, 95% CI: 0.831–0.935, p = 2.73 × 10−5), a finding that remained robust across multiple sensitivity analyses. In a survey of 183 IDPs associated with OCD, ZDHHC4 expression significantly influenced 46 imaging measures. Mediation analysis revealed that the IDP ICA100 edge 531, representing functional connectivity between the left dorsolateral prefrontal cortex and bilateral orbitofrontal cortex, significantly mediated the relationship between ZDHHC4 expression and OCD risk (19.9%, p = 0.005). These findings establish a novel causal pathway linking ZDHHC4-mediated palmitoylation to altered brain activity in frontal-orbital circuits and subsequent OCD susceptibility. This integrated molecular-neural circuit framework provides new insights into OCD pathophysiology and identifies palmitoylation pathways as potential therapeutic targets for this debilitating neuropsychiatric disorder.