Cortical patterning of abnormal morphometric similarity in psychosis is associated with brain expression of schizophrenia-related genes

Significance Despite significant research, the biological mechanisms underlying schizophrenia are still unclear. We shed light on structural brain differences in psychosis using an approach called morphometric similarity mapping, which quantifies the structural similarity between brain regions. Morphometric similarity was globally reduced in psychosis patients in three independent datasets, implying that patients’ brain regions were more differentiated from each other and less interconnected. Similarity was especially decreased in frontal and temporal regions. This anatomical pattern was correlated with expression of genes enriched for nervous system development and synaptic signaling and genes previously associated with schizophrenia and antipsychotic treatments. Therefore, we begin to see how combining genomics and imaging can give a more integrative understanding of schizophrenia, which might inform future treatments.
Schizophrenia has been conceived as a disorder of brain connectivity, but it is unclear how this network phenotype is related to the underlying genetics. We used morphometric similarity analysis of MRI data as a marker of interareal cortical connectivity in three prior case–control studies of psychosis: in total, n = 185 cases and n = 227 controls. Psychosis was associated with globally reduced morphometric similarity in all three studies. There was also a replicable pattern of case–control differences in regional morphometric similarity, which was significantly reduced in patients in frontal and temporal cortical areas but increased in parietal cortex. Using prior brain-wide gene expression data, we found that the cortical map of case–control differences in morphometric similarity was spatially correlated with cortical expression of a weighted combination of genes enriched for neurobiologically relevant ontology terms and pathways. In addition, genes that were normally overexpressed in cortical areas with reduced morphometric similarity were significantly up-regulated in three prior post mortem studies of schizophrenia. We propose that this combined analysis of neuroimaging and transcriptional data provides insight into how previously implicated genes and proteins as well as a number of unreported genes in their topological vicinity on the protein interaction network may drive structural brain network changes mediating the genetic risk of schizophrenia.