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

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• Obsessive-compulsive disorder (OCD) is a disabling condition linked to cortico-striato-thalamo-cortical circuit dysfunction.
• The molecular underpinnings of OCD pathophysiology, particularly involving protein modifications like palmitoylation, are not fully understood.

Purpose of the Study:

• To investigate the causal relationship between palmitoylation-related gene expression, brain imaging phenotypes, and OCD susceptibility using Mendelian randomization.
• To identify specific genes and neural pathways involved in OCD.

Main Methods:

• Mendelian randomization (MR) analysis was performed on 22 palmitoylation-related genes.
• Imaging-derived phenotypes (IDPs) and mediation analysis were used to explore neural circuit involvement.
• Sensitivity analyses confirmed the robustness of the findings.

Main Results:

• Reduced expression of the palmitoyl acyltransferase ZDHHC4 gene was significantly associated with increased OCD risk.
• ZDHHC4 expression influenced 46 imaging measures, notably functional connectivity in frontal-orbital circuits (ICA100 edge 531).
• Mediation analysis confirmed that altered functional connectivity mediated the link between ZDHHC4 expression and OCD.

Conclusions:

• A novel causal pathway implicating ZDHHC4-mediated palmitoylation in altered frontal-orbital brain activity and OCD susceptibility was established.
• This research provides new insights into OCD pathophysiology.
• Palmitoylation pathways represent potential therapeutic targets for OCD.