Meta-analysis of gene coexpression networks in the post-mortem prefrontal cortex of patients with schizophrenia and unaffected controls

Meeta Mistry,Jesse Gillis,Paul Pavlidis

doi:10.1186/1471-2202-14-105

Abstract

BackgroundGene expression profiling of the postmortem human brain is part of the effort to understand the neuropathological underpinnings of schizophrenia. Existing microarray studies have identified a large number of genes as candidates, but efforts to generate an integrated view of molecular and cellular changes underlying the illness are few. Here, we have applied a novel approach to combining coexpression data across seven postmortem human brain studies of schizophrenia.ResultsWe generated separate coexpression networks for the control and schizophrenia prefrontal cortex and found that differences in global network properties were small. We analyzed gene coexpression relationships of previously identified differentially expressed ‘schizophrenia genes’. Evaluation of network properties revealed differences for the up- and down-regulated ‘schizophrenia genes’, with clustering coefficient displaying particularly interesting trends. We identified modules of coexpressed genes in each network and characterized them according to disease association and cell type specificity. Functional enrichment analysis of modules in each network revealed that genes with altered expression in schizophrenia associate with modules representing biological processes such as oxidative phosphorylation, myelination, synaptic transmission and immune function. Although a immune-function enriched module was found in both networks, many of the genes in the modules were different. Specifically, a decrease in clustering of immune activation genes in the schizophrenia network was coupled with the loss of various astrocyte marker genes and the schizophrenia candidate genes.ConclusionOur novel network-based approach for evaluating gene coexpression provides results that converge with existing evidence from genetic and genomic studies to support an immunological link to the pathophysiology of schizophrenia.

Highlights

Gene expression profiling of the postmortem human brain is part of the effort to understand the neuropathological underpinnings of schizophrenia
We constructed two gene coexpression networks; one representing the control human prefrontal cortex and the other representing the prefrontal cortex in schizophrenia
The schizophrenia and control groups had no significant differences in age and PMI (Table 1)

Summary

Introduction

Gene expression profiling of the postmortem human brain is part of the effort to understand the neuropathological underpinnings of schizophrenia. We have applied a novel approach to combining coexpression data across seven postmortem human brain studies of schizophrenia. Gene expression profiling of the postmortem human brain has been frequently used as a means to investigate patterns of molecular disruption in the brains of patients with schizophrenia. Evaluating the broader network structure allows us to detect modularity in the graph, or groups of densely connected nodes with sparse connections between groups. Characterization of these ‘modules’ can convey useful information as they may be associated with specific molecular complexes or functions, yielding hypotheses that would be difficult to ascertain based on a gene-by-gene analysis. One can evaluate differences between condition-specific networks to help elucidate systems level molecular dysfunction

Methods

Results

Discussion

Conclusion