A system-level transcriptomic analysis of schizophrenia using postmortem brain tissue samples.

Abstract

CONTEXT Schizophrenia is a common, highly heritable, neurodevelopmental mental illness, characterized by genetic heterogeneity. OBJECTIVE To identify abnormalities in the transcriptome organization among older persons with schizophrenia and controls. DESIGN Weighted gene coexpression network analysis based on microarray transcriptomic profiling. SETTING Research hospital. PATIENTS Postmortem brain tissue samples from 4 different cerebrocortical regions (the dorsolateral prefrontal cortex, the middle temporal area, the temporopolar area, and the anterior cingulate cortex) from 21 persons with schizophrenia and 19 controls. MAIN OUTCOME MEASURES Results from gene expression microarray analysis, from analysis of coexpression networks, and from module eigengene, module preservation, and enrichment analysis of schizophrenia-related genetic variants. RESULTS The oligodendrocyte, microglial, mitochondrial, and neuronal (GABAergic and glutamatergic) modules were associated with disease status. Enrichment analysis of genome-wide association studies in schizophrenia and other illnesses demonstrated that the neuronal (GABAergic and glutamatergic) and oligodendrocyte modules are enriched for genetically associated variants, whereas the microglial and mitochondrial modules are not, providing independent support for more direct involvement of these gene expression networks in schizophrenia. Interregional coexpression network analysis showed that the gene expression patterns that typically differentiate the frontal, temporal, and cingulate cortices in controls diminish significantly in persons with schizophrenia. CONCLUSIONS These results support the existence of convergent molecular abnormalities in schizophrenia, providing a molecular neuropathological basis for the disease.