Regional, functional and transcriptomic decoding of multidimensional brain structure alterations in obsessive-compulsive disorder

Studies of brain morphology in mental illness often incompletely characterize structural variation, focusing on a few neuroimaging phenotypes. Here we present a comprehensive morphological characterization in obsessive-compulsive disorder (OCD) using nine cortical and four subcortical phenotypes in a large sample (2255 OCD, 2264 controls). Spatially distinct patterns emerged across structural phenotypes, with cortical curvature alterations affecting default mode and frontoparietal networks, changes in structural similarity networks impacting sensorimotor regions, and widespread volume reductions associated with medication use. In brain-behavior predictive models, curvature phenotypes showed the strongest associations with clinical features. Cortical alterations, especially in structural similarity networks, were associated with specific gene expression patterns, implicating dysregulation of excitatory neurons. Transcriptomic data from tissue collected during neurosurgery revealed that genes downregulated in dorsolateral prefrontal cortex in OCD were involved in expression patterns linked to cortical alterations. These findings support the importance of a comprehensive approach to characterizing brain morphology and suggest that cortical curvature and structural similarity alterations reflect key pathophysiological processes in OCD.