Transcriptome alterations are enriched for synapse-associated genes in the striatum of subjects with obsessive-compulsive disorder

Sean C Piantadosi,Lora L Mcclain,Jiebiao Wang,Sara A Springer,Brittany L Chamberlain,Lambertus Klei,Susanne E Ahmari,Bernie Devlin,David A Lewis

doi:10.1038/s41398-021-01290-1

Sean C Piantadosi, Lora L Mcclain + Show 7 more

Open Access

https://doi.org/10.1038/s41398-021-01290-1

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Abstract

Obsessive-compulsive disorder (OCD) is a chronic and severe psychiatric disorder for which effective treatment options are limited. Structural and functional neuroimaging studies have consistently implicated the orbitofrontal cortex (OFC) and striatum in the pathophysiology of the disorder. Recent genetic evidence points to involvement of components of the excitatory synapse in the etiology of OCD. However, the transcriptional alterations that could link genetic risk to known structural and functional abnormalities remain mostly unknown. To assess potential transcriptional changes in the OFC and two striatal regions (caudate nucleus and nucleus accumbens) of OCD subjects relative to unaffected comparison subjects, we sequenced messenger RNA transcripts from these brain regions. In a joint analysis of all three regions, 904 transcripts were differentially expressed between 7 OCD versus 8 unaffected comparison subjects. Region-specific analyses highlighted a smaller number of differences, which concentrated in caudate and nucleus accumbens. Pathway analyses of the 904 differentially expressed transcripts showed enrichment for genes involved in synaptic signaling, with these synapse-associated genes displaying lower expression in OCD subjects relative to unaffected comparison subjects. Finally, we estimated that cell type fractions of medium spiny neurons were lower whereas vascular cells and astrocyte fractions were higher in tissue of OCD subjects. Together, these data provide the first unbiased examination of differentially expressed transcripts in both OFC and striatum of OCD subjects. These transcripts encoded synaptic proteins more often than expected by chance, and thus implicate the synapse as a vulnerable molecular compartment for OCD.

Highlights

Obsessive-compulsive disorder (OCD), a chronic psychiatric illness, has a lifetime prevalence of 1–3%, affects approximately 50 million people worldwide, and can lead to significant impairment[1,2,3]
Here, we highlight two levels of analysis for differentially expressed genes (DEG): from three regions treated jointly (OFC, caudate, and nucleus accumbens), which we refer to as global analysis; and from each brain region considered separately, which we refer to as regional analysis
We first determined a parsimonious model for gene expression as a function of diagnosis (OCD versus unaffected comparison subjects) and other predictors

Summary

Introduction

Obsessive-compulsive disorder (OCD), a chronic psychiatric illness, has a lifetime prevalence of 1–3%, affects approximately 50 million people worldwide, and can lead to significant impairment[1,2,3]. Many patients continue to experience substantial symptoms and OCD, as well as obsessive-compulsive characteristics, indicate that genetic factors explain between 27% and 47% of the phenotypic variance[7,8,9,10]. Candidate gene association studies point to the glutamate transporter gene SLC1A111–15 and the glutamate receptor genes GRIN2B16,17 and GRIK218–20. Genome-wide association studies (GWAS), though underpowered, converge on excitatory synaptic signaling as a potential source of dysfunction[21,22,23].

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