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Microglia-like cells derived from patients with obsessive-compulsive disorder and social anxiety disorder

ABSTRACT: Microglia are central to neuroimmune surveillance and synaptic remodeling, yet their contribution to obsessive–compulsive disorder (OCD) remains unclear. Here, we generated patient-derived microglia-like cells (iMGs) from OCD (n = 19), social anxiety disorder (SAD; n = 16), and healthy control (HC; n = 20) participants to identify the molecular and functional alterations in OCD-iMGs and to find therapeutic targets capable of restoring their functions. Bulk transcriptomic profiling of iMGs identified a selective reduction of MDM2 in OCD-iMGs. Notably, MDM2 mRNA was negatively correlated with Dimensional Obsessive-Compulsive Scale (DOCS) scores. Functional assays in siRNA-transfected primary microglia demonstrated that MDM2 knockdown impaired synaptosome phagocytosis and blunted LPS induced inflammatory responses, validating MDM2 as a mechanistic node. A Connectivity Map analysis nominated bortezomib, and subsequent experiments showed that bortezomib restored MDM2 expression and rescued phagocytic and immune functions in both MDM2-deficient microglia and OCD-iMGs. Collectively, these findings implicate microglial MDM2 reduction as a feature of OCD with direct functional consequences.

ORGANISM(S): Homo sapiens

PROVIDER: GSE308457 | GEO | 2025/12/31

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE308457_Normalized_counts.csv.gz	Csv
	GSE308457_Raw_reads.csv.gz	Csv

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Project description:Anorexia nervosa (AN), bulimia nervosa (BN), and obsessive-compulsive disorder (OCD) are complex psychiatric disorders with shared obsessive features, thought to arise from the interaction of multiple genes of small effect with environmental factors. Potential candidate genes for AN, BN, and OCD have been identified through clinical association and neuroimaging studies; however, recent genome-wide association studies of eating disorders (ED) so far have failed to report significant findings. Additionally, few if any studies have interrogated postmortem brain tissue for evidence of eQTLs associated with candidate genes, which has particular promise as an approach to elucidating molecular mechanisms of association. We therefore selected single nucleotide polymorphisms (SNPs) based on candidate gene studies for AN, BN, and OCD from the literature, and examined the association of these SNPs with gene expression across the lifespan in prefrontal cortex of a non-psychiatric control cohort (N=268). Several risk-predisposing SNPs were significantly associated with gene expression among control subjects. We then measured gene expression in the prefrontal cortex of cases previously diagnosed with obsessive psychiatric disorders, e.g., eating disorders (ED; N=15), and obsessive-compulsive disorder/obsessive-compulsive personality disorder or tics (OCD/OCPD/Tic; N=16), and non-psychiatric controls (N=102) and identified 6 and 286 genes that were differentially expressed between ED compared to controls and OCD cases compared to controls, respectively (FDR < 5%). However, none of the clinical risk SNPs were among the eQTLs and none were significantly associated with gene expression within the broad obsessive cohort, suggesting larger sample sizes or other brain regions may be required to identify candidate molecular mechanisms of clinical association in postmortem brain datasets. Gene expression data from the dorsolateral prefrontal cortex (DLPFC) from postmortem tissue on 133 subjects - 15 eating disorder (ED) patients, 16 obessive compulsive disorder (OCD) patients, and 102 non-psychiatric controls - run on the Illumina HumanHT-12 v3 microarray

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Microglia-like cells derived from patients with obsessive-compulsive disorder and social anxiety disorder

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