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. 2013 Dec;18(12):1308-14.
doi: 10.1038/mp.2012.146. Epub 2012 Nov 13.

Two gene co-expression modules differentiate psychotics and controls

C Chen  1 , L Cheng, K Grennan, F Pibiri, C Zhang, J A Badner; Members of the Bipolar Disorder Genome Study (BiGS) Consortium; E S Gershon, C Liu
Collaborators, Affiliations

Two gene co-expression modules differentiate psychotics and controls

C Chen et al. Mol Psychiatry. 2013 Dec.

Abstract

Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable psychiatric disorders. Associated genetic and gene expression changes have been identified, but many have not been replicated and have unknown functions. We identified groups of genes whose expressions varied together, that is co-expression modules, then tested them for association with SCZ. Using weighted gene co-expression network analysis, we show that two modules were differentially expressed in patients versus controls. One, upregulated in cerebral cortex, was enriched with neuron differentiation and neuron development genes, as well as disease genome-wide association study genetic signals; the second, altered in cerebral cortex and cerebellum, was enriched with genes involved in neuron protection functions. The findings were preserved in five expression data sets, including sets from three brain regions, from a different microarray platform, and from BD patients. From those observations, we propose neuron differentiation and development pathways may be involved in etiologies of both SCZ and BD, and neuron protection function participates in pathological process of the diseases.

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Figures

Figure 1
Figure 1. Gene network modules from PCX from schizophrenia patients and normal controls are well preserved
Zsummary is the summary preservation statistics, using the control modules as reference modules. Y-axis represents preservation statistics for the corresponding module in the case data sets, and x-axis is the gene numbers in each module. The dashed blue and green lines indicate the thresholds Z=2 and Z=10, respectively. Zsummary < 2 implies no evidence for module preservation, 2 < Zsummary < 10 implies weak to moderate evidence, and Zsummary > 10 implies strong evidence for module preservation.
Figure 2
Figure 2. Module and hub genes’ association test results
Eigengene-based test detected 24 modules in PCX (A), listed on the x-axis. The y-axis indicates the -log10 of association p value. The red line represents the p=0.05 threshold. M3A and M1A modules were significant after multiple test correction, with FDR q value<0.05 (green bars with red stars on the top). NOTCH2 in M1A (B) and MT1X in M3A (C), with disease in replicate data sets. Green bars represent the significance of association in SCZ and control networks, while red bars represent the significance of association in BD and control networks. The purple line marks the significance threshold of p=0.05.
Figure 3
Figure 3. Global gene module characterization-M1A
A. Heatmap of genes in M1A. Samples are listed in columns and genes in rows. Samples bar under the hierarchal clustering tree were marked as red indicating cases and as blue indicating controls. Normalized expression values ranged between -2 and 2, as shown in the color legend under the heatmap. B. Highly connected genes in M1A network. C. Top five enriched gene ontology categories of highly corrected genes in the M1A module.
Figure 4
Figure 4. Global gene module characterization-M3A
A. Heatmap of genes in M3A. Samples listed in column and genes in rows. Samples bar under the hierarchal clustering tree were marked as red indicating cases and as blue indicating controls. Normalized expression values ranged between -2 and 2, as shown in the color legend under the heatmap. B. Highly connected genes in M3A core network. C. Top five gene ontology categories enriched in the M3A module.
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