Imaging transcriptomics identifies gene signatures associated with cortical thinning in schizophrenia

BACKGROUND: Schizophrenia, a debilitating neuropsychiatric disorder with profound socioeconomic consequences, manifests characteristic cortical thinning patterns observable through neuroimaging. While structural magnetic resonance imaging (MRI) studies consistently demonstrate these anatomical disturbances, their molecular signatures remain poorly understood. METHODS: We employed an integrative neuroimaging-transcriptomic approach, combining structural MRI data from 50 schizophrenia patients and 125 healthy controls with postmortem gene expression profiles from the Allen Human Brain Atlas. Spatial relationships between transcriptional patterns and cortical thickness variations were quantified using partial least squares regression. Subsequent analyses included gene ontology enrichment, cell-type deconvolution, and protein-protein interaction network. RESULTS: Schizophrenia patients demonstrated significant cortical thinning in limbic and paralimbic regions critical for emotional processing, including anterior cingulate and insular cortices. Imaging transcriptomic analyses revealed strong associations between cortical alterations and schizophrenia-risk genes STON2, ANK3, and KCNN3. Enriched biological pathways included stress-responsive signaling, calcium homeostasis, and synaptic plasticity. Cell-type analyses implicated excitatory and inhibitory neurons, together with microglia, while network analysis identified KCNB1, PTGS2, and TPT1 as central molecular hubs. CONCLUSIONS: This study reveals specific molecular correlates of cortical thinning in schizophrenia, highlighting biological mechanisms that may contribute to structural abnormalities. The identified genes and pathways offer potential therapeutic targets for addressing both neuroanatomical changes and affective disturbances in schizophrenia.