Identifying precise brain regions and cell types associated with Obsessive-Compulsive Disorder and related diagnoses using genomics - PROJECT SUMMARY A joint analysis of the genetic architecture of major psychiatric disorders published in 2022 revealed four broad factors (neurodevelopmental, psychotic, internalizing, and compulsive) that underlie genetic correlations among these disorders. The compulsive factor is largely driven by three disorders that, until quite recently, have been understudied in psychiatric genetics: obsessive-compulsive disorder (OCD), Tourette syndrome (TS), and anorexia nervosa (AN). Thankfully, thus far in 2025, the Psychiatric Genomics Consortium (PGC) working groups for all three of these disorders have published or submitted significantly expanded genome-wide association studies (GWAS), creating an opportunity to gain etiological insights into these ‘compulsive disorders.’ This is significant because we have a limited understanding of the neurobiology of OCD, TS, and AN, and no FDA-approved medications have been specifically developed for any of these conditions. Furthermore, all three conditions are increasingly being treated with brain stimulation methods (e.g., transcranial magnetic stimulation and deep brain stimulation), yet the neurostimulation field has a poor understanding of which brain regions to target, leading to non-response in many patients. In this study, we will combine the latest genomic data for OCD, TS, and AN with the most recent single-cell gene expression atlases to enhance our understanding of the brain regions and cell types associated with these disorders and identify rational brain targets for stimulation. In Aim 1, we will test for enrichment of factor-level and disorder-specific OCD, TS, and AN summary statistics with cell types defined by a recent transcriptomic census of the entire human brain (>3 million cells). We expect this analysis to prioritize specific neuronal clusters involved in one or more of these conditions. In Aim 2, we will add a developmental context by extending these analyses to single-cell transcriptome data from human fetal and childhood brains. We will also introduce a spatial context by developing novel approaches to assess the enrichment of human genomic findings with a new single-cell spatial transcriptomic atlas of the whole mouse brain. We expect these analyses to refine our understanding of the neurocircuitry of OCD, TS, and AN. All analyses will include all major psychiatric disorders included in the aforementioned joint factor analysis to compare and contrast compulsive disorders with neurodevelopmental, psychotic, and internalizing disorders. Overall, we believe that integrating the latest genomic data on compulsive disorders with novel transcriptomic atlases will enhance our understanding of the etiology of these conditions and ultimately impact the treatment of these understudied disorders.
