Transcriptional profiling of monocytes in early-onset obsessive-compulsive disorder, Tourette syndrome and autism spectrum disorder

Background: Neurodevelopmental disorders such as early-onset obsessive-compulsive disorder (OCD), Tourette syndrome (TS), and autism spectrum disorder (ASD) are overlapping syndromes that include a set of dimensional traits that extend to the general population, such as repetitive and restrictive behaviors (RRB) and sensory phenomena (SP). Several lines of evidence suggest that immune dysfunction, including peripheral monocytes and microglia, may have a role in the pathophysiology of OCD, TS and ASD. In this study we aimed to explore monocyte dysregulation in a cohort of children and adolescents diagnosed with OCD, TS, and ASD and identify transcriptional differences across groups.

Methods: A total of 65 participants aged 6–17 with a main diagnosis of OCD (n=24), TS (n=20), or ASD (n=21) were included. RRBs and SP were assessed using the Repetitive Behaviour Scale-Revised (RBS-R) and the University of Sao Paulo-Sensory Phenomena Scale (USP-SPS). Peripheral monocytes from all participants were purified and cultured both under basal conditions and under exposure to lipopolysaccharide (LPS) to stimulate immune response. Transcriptional activity was assessed in monocytes using RNA sequencing. Differential expression, gene-set enrichment and pathway analyses (KEGG) were performed.

Results: RRBs and SP were identified as transdiagnostic features across OCD, TS, and ASD. The RBS-R mean was 17.3 ± 14.9, while SP severity, reported by 90% of participants, had a mean of 5.3 ± 3.8, with no significant group differences in total RRB or USP-SPS

scores. Significant transcriptional differences were observed in monocytes both under basal conditions and after LPS stimulation between the three groups (FDR < 0.05; |log2FC| >1). The analysis of unstimulated monocytes showed 43 genes downregulated and 21 upregulated in OCD patients compared to ASD, 14 downregulated and 84 upregulated in TS compared to ASD, and 37 downregulated and 101 upregulated in TS compared to OCD. After LPS stimulation, 34 genes were downregulated and 21 upregulated in OCD patients compared to ASD, 3 downregulated in TS compared to ASD, and 43 downregulated and 21 upregulated in TS compared to OCD. As expected, significant gene expression changes were observed in monocytes from patients of the three diagnostic groups in response to LPS (ASD: 175 genes downregulated and 467 upregulated; OCD: 195 downregulated and 481 upregulated; TS: 276 downregulated, 652 upregulated). Transcriptional changes induced by LPS were mainly related to inflammation, interferon apoptosis, lysosome, cellular metabolism, and cell adhesion pathways.

Conclusions: We report preliminary findings of monocyte dysregulation in children and adolescents with neurodevelopmental disorders. The results indicate transcriptional differences both at baseline and following LPS activation across diagnostic groups (OCD, TS, and ASD) and suggest that monocytes from patients with Tourette syndrome exhibit the greatest activation in response to LPS stimulation. Further analysis is needed to characterize monocyte dysfunction in neurodevelopmental disorders and disentangle the specific role in disease severity.

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