Because post-mortem studies of psychiatric disease have typically relied on whole tissue homogenates63, they have traditionally been agnostic about the potential contributions of genetically and phenotypically distinct cell types to disease pathology. Here we addressed this limitation by using a deconvolutional approach to estimate cell type-specific fractions of whole tissue homogenates from OCD subjects and unaffected comparison subjects. We performed this analysis both using mouse single cell RNA-sequencing (scRNAseq) (Fig. 3) and human single nucleus RNA-sequencing (snRNAseq) (Fig. S4) data obtained from the striatum and cortex to generate signature matrices; both approaches generated similar conclusions. Here we present the data from the mouse signature matrix in the main text because nuclear RNA only accounts for 20–50% of RNA molecules in a neuron64, and more genes were reliably sampled from the scRNA sequencing experiment. Importantly, this analysis does not differentiate between differences in cell type-specific fractions due to changes in absolute cell number, or due to changes in the transcriptional activity of single cells. We do observe that OCD subjects have lower cell type expression profiles of medium spiny neurons, the
