Putative psychosis genes in the prefrontal cortex: combined analysis of gene expression microarrays

Abstract

Background: Recent studies have shown similarities between schizophrenia and bipolar disorder in phenotypes and in genotypes, and those studies have contributed to an ongoing re-evaluation of the traditional dichotomy between schizophrenia and bipolar disorder. Bipolar disorder with psychotic features may be closely related to schizophrenia and therefore, psychosis may be an alternative phenotype compared to the traditional diagnosis categories.

Methods: We performed a cross-study analysis of 7 gene expression microarrays that include both psychosis and non-psychosis subjects. These studies include over 400 microarray samples (163 individual subjects) on 3 different Affymetrix microarray platforms.

Results: We found that 110 transcripts are differentially regulated (p < 0.001) in psychosis after adjusting for confounding variables with a multiple regression model. Using a quantitative PCR, we validated a set of genes such as up-regulated metallothioneins (MT1E, MT1F, MT1H, MT1K, MT1X, MT2A and MT3) and down-regulated neuropeptides (SST, TAC1 and NPY) in the dorsolateral prefrontal cortex of psychosis patients.

Conclusion: This study demonstrates the advantages of cross-study analysis in detecting consensus changes in gene expression across multiple microarray studies. Differential gene expression between individuals with and without psychosis suggests that psychosis may be a useful phenotypic variable to complement the traditional diagnosis categories.

Figure 1

Increased gene expression of metallothioneins in the cross-study analysis of psychosis. A: metallothionein 1E, B: metallothionein 1F, C: metallothionein 1K, D: metallothionein 1X. The plots with fold changes and 95% confidence intervals show consistent up-regulation of metallothioneins across individual studies as shown on the Y-axis. Combined analysis shown on the bottom of each panel represents the weighted fold change and 95% confidence intervals for each gene.

Figure 2

Decreased gene expression of neuropeptides in the cross-study analysis of psychosis. A: somatostatin, B: tachykinin, precursor 1, C: neuropeptide Y, D: NR4A2. The plots with fold change and 95% confidence intervals show consistent down-regulation across multiple individual studies. Combined analysis shown on the bottom of each panel represents the weighted fold change and 95% confidence intervals for each gene.

Figure 3

Consistent up-regulation of metallothionein genes among metal ion binding genes in the Gene Ontology (GO) term. Seven metallothionein genes including MT1E, MT1F, MT1H, MT1K, MT1X, MT2A and MT3 are significantly up-regulated in this category.

Figure 4

Quantitative PCR validation of metallothionein and neuropeptide genes. The gene plots with fold changes and 95% confidence intervals show that metallothionein genes including MT1X, MT2A, MT1E, MT1K, MT1H, MT3, AND MT1F are significantly up-regulated and four genes including NPY, NR4A2, SST and TAC1 are significantly down-regulated in psychosis (p < 0.05).