BackgroundAlthough the exact etiology of obsessive-compulsive disorder (OCD) is unknown, there is growing evidence of a role for immune dysregulation in the pathophysiology of the disease, especially in the innate immune system including the microglia. To test this hypothesis, we studied inflammatory markers in monocytes from pediatric patients with OCD and from healthy controls.MethodsWe determined the percentages of total monocytes, CD16+ monocytes, and classical (CD14highCD16−), intermediate (CD14highCD16low), and non-classical (CD14lowCD16high) monocyte subsets in 102 patients with early-onset OCD and in 47 healthy controls. Moreover, proinflammatory cytokine production (GM-CSF, IL-1β, IL-6, IL-8, and TNF-α) was measured by multiplex Luminex analysis in isolated monocyte cultures, in basal conditions, after exposure to lipopolysaccharide (LPS) to stimulate immune response or after exposure to LPS and the immunosuppressant dexamethasone.ResultsOCD patients had significantly higher percentages of total monocytes and CD16+ monocytes than healthy controls, mainly due to an increase in the intermediate subset but also in the non-classical monocytes. Monocytes from OCD patients released higher amounts of GM-CSF, IL-1β, IL-6, IL-8, and TNF-α than healthy controls after exposure to LPS. However, there were no significant differences in basal cytokine production or the sensitivity of monocytes to dexamethasone treatment between both groups. Based on monocyte subset distribution and cytokine production after LPS stimulation, patients receiving psychoactive medications seem to have an intermediate inflammatory profile, that is, lower than non-medicated OCD individuals and higher than healthy controls.ConclusionsThese results strongly support the involvement of an enhanced proinflammatory innate immune response in the etiopathogenesis of early-onset OCD.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-1042-z) contains supplementary material, which is available to authorized users.

Abstract Gene–environment (GxE) interactions have been related to psychosis spectrum disorders, involving multiple common genetic variants in multiple genes with very small effect sizes, and several environmental factors that constitute a dense network of exposures named the exposome. Here, we aimed to analyze GxE in a cohort of 310 first-episode psychotic (FEP) and 236 healthy controls, by using aggregate scores estimated in large populations such as the polygenic risk score for schizophrenia and (PRS-SCZ) and the Maudsley environmental risk score (ERS). In contrast to previous findings, in our study, the PRS-SCZ did not discriminate cases from controls, but the ERS score explained a similar percentage of the variance as in other studies using similar approaches. Our study supports a positive additive interaction, indicating synergy between genetic susceptibility to schizophrenia (PRS-SCZ dichotomized according to the highest quartile distribution of the control population) and the exposome (ERS > 75% of the controls). This additive interaction showed genetic and environmental dose dependence. Our study shows that the use of aggregate scores derived from large and powered studies instead of statistics derived from specific sample characteristics is a powerful tool for the study of the effects of GxE on the risk of psychotic spectrum disorders. In conclusion, by using a genetic risk score and an ERS we have provided further evidence for the role of GxE in psychosis.

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To identify potential candidate genes for future pharmacogenetic studies of antipsychotic (AP)-induced extrapyramidal symptoms (EPS), we used gene expression arrays to analyze changes induced by risperidone in mice strains with different susceptibility to EPS. We proposed a systems biology analytical approach that combined the identification of gene co-expression modules related to AP treatment, the construction of protein-protein interaction networks with genes included in identified modules and finally, gene set enrichment analysis of constructed networks. In response to risperidone, mice strain with susceptibility to develop EPS showed downregulation of genes involved in the mammalian target of rapamycin (mTOR) pathway and biological processes related to this pathway. Moreover, we also showed differences in the phosphorylation pattern of the ribosomal protein S6 (rpS6), which is a major downstream effector of mTOR. The present study provides new evidence of the involvement of the mTOR pathway in AP-induced EPS and offers new and valuable markers for pharmacogenetic studies.