Abstract
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.
Highlights
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 recently proposed a technique known as “morphometric similarity mapping” [3], which quantifies the similarity between cortical areas in terms of multiple MRI parameters measured
Morphometric similarity was significantly reduced in frontal and temporal cortical areas and significantly increased in parietal cortical areas. This pattern was consistent across three independent datasets with different samples, locations, scanners, and scanning parameters. What does this MRI phenotype of psychosis represent? Morphometric similarity quantifies the correspondence or kinship of two cortical areas in terms of multiple macrostructural features and microstructural features [e.g., fractional anisotropy (FA)] that are measurable by MRI
Summary
Schizophrenia has been conceived as a disorder of brain connectivity, but it is unclear how this network phenotype is related to the underlying genetics. There was 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. 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. 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. We begin to see how combining genomics and imaging can give a more integrative understanding of schizophrenia, which might inform future treatments
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