A Gene Co-Expression Network in Whole Blood of Schizophrenia Patients Is Independent of Antipsychotic-Use and Enriched for Brain-Expressed Genes

Abstract

Despite large-scale genome-wide association studies (GWAS), the underlying genes for schizophrenia are largely unknown. Additional approaches are therefore required to identify the genetic background of this disorder. Here we report findings from a large gene expression study in peripheral blood of schizophrenia patients and controls. We applied a systems biology approach to genome-wide expression data from whole blood of 92 medicated and 29 antipsychotic-free schizophrenia patients and 118 healthy controls. We show that gene expression profiling in whole blood can identify twelve large gene co-expression modules associated with schizophrenia. Several of these disease related modules are likely to reflect expression changes due to antipsychotic medication. However, two of the disease modules could be replicated in an independent second data set involving antipsychotic-free patients and controls. One of these robustly defined disease modules is significantly enriched with brain-expressed genes and with genetic variants that were implicated in a GWAS study, which could imply a causal role in schizophrenia etiology. The most highly connected intramodular hub gene in this module (ABCF1), is located in, and regulated by the major histocompatibility (MHC) complex, which is intriguing in light of the fact that common allelic variants from the MHC region have been implicated in schizophrenia. This suggests that the MHC increases schizophrenia susceptibility via altered gene expression of regulatory genes in this network.

CX3CR1 is dysregulated in blood and brain from schizophrenia patients

“…As such, access to blood studies was limited compared to brain studies. Nevertheless, because of the simplicity of access to blood tissues, some investigators were able to recruit large cohorts of both controls and patients (de Jong et al, 2012;Gardiner et al, 2013). With inclusion of these two studies, we were able to have a balanced number of samples from our blood meta-analysis compared to our brain meta-analysis.…”

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

“…Supported by expanded basic science efforts and increasingly sophisticated animal models, a unifying concept has emerged stating that many of these disparate risk factors converge onto common dysfunctional pathways and lead to illness de Jong et al, 2012;Mirnics, 2009, 2014b;Mirnics et al, 2006). In this review, we discuss the concept that GABA system development is a major convergence point for genetic and environmental susceptibility factors for schizophrenia.…”

Gene co-expression network analysis reveals common system-level properties of genes involved in tuberculosis across independent gene expression studies

“…In addition, shared functions/pathways among genes in the modules could also be inferred via enrichment analyses. The use of module eigengene profiles as representatives of the modules has already been validated in a number of studies (de Jong et al 2012). Significance analysis of the module eigengenes in pink, green, and turquoise module reveals a strong association with TB states in all three data sets.…”

“…The Z summary score was used to evaluate module preservation, with values of 10 and above indicating strong preservation (Langfelder et al 2011). The current work also used medianRank (de Jong et al 2012) statistics which is useful for comparing relative preservation among multiple modules. A module with lower median rank tends to exhibit stronger observed preservation statistics than a module with a higher median rank.…”