In addition to strengthening the link between OCD pathophysiology and synaptic dysfunction in cortical and striatal brain regions, RNAseq and enrichment analysis allowed us to identify novel signaling pathways that may be disrupted in OCD subjects (Fig. 2). We find that gene sets related to cytosolic membrane components (cluster 2) and transmembrane transport (cluster 3) contain similar numbers of up and downregulated gene sets, suggesting complex differential regulation between OCD and unaffected comparison subjects. Cluster 2 pathways are comprised of genes encoding cytosolic proteins associated with receptors, such as G proteins and regulatory subunits, as well as other cytosolic components that are critical for intracellular signaling and interact with proteins found in cluster 1. Cluster 3 contains genes that regulate glucose and carbohydrate transport and may indicate different metabolic needs in the OFC and striatum of OCD subjects. This would be consistent with human imaging studies finding hyperactivity and increased glucose metabolism in these regions in OCD24–26, and could be related to the changes in cell type expression profiles observed in our cell type deconvolution (Fig. 3). For example, the metabolic needs of astrocytes, whose expression profile is increased in OCD (Fig. 3A), differ from that of neurons55.
