Abstract
Eating disorders (ED) and obsessive-compulsive disorder (OCD) exhibit significant clinical and genetic overlap, yet their shared molecular mechanisms remain unclear. We conducted a transcriptomic investigation of the dorsolateral prefrontal cortex (DLPFC) and caudate from 86 controls, 57 ED, and 27 OCD cases. ED was associated with robust differentially expressed genes (DEGs): 102 DEGs the DLPFC and 222 in the caudate (FDR < 1%) and replicated in an independent cohort. For OCD, no DEGs reached significance; however, meta-analysis with extant data identified 57 DEGs in the caudate. High concordance in transcriptomic changes was observed between ED and OCD in both regions (DLPFC r=0.67, caudate r=0.75). A combined ED+OCD analysis uncovered 233 DEGs in the DLPFC and 816 in the caudate, implicating disrupted GABAergic neuron function, neuroendocrine pathways, metabolism, and synaptic processes. Genetically regulated expression analysis identified nine genes with strong evidence for increasing ED risk, further validating these pathways. These findings reveal a shared molecular basis for ED and OCD, offering new insights into their pathobiology and potential therapeutic targets.