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. 2008 Jul 15;64(2):89-97.
doi: 10.1016/j.biopsych.2007.11.010. Epub 2008 Jan 11.

Shared gene expression alterations in schizophrenia and bipolar disorder

Ling Shao  1 , Marquis P Vawter
Affiliations

Shared gene expression alterations in schizophrenia and bipolar disorder

Ling Shao et al. Biol Psychiatry. .

Abstract

Background: Schizophrenia and bipolar disorder together affect approximately 2.5% of the world population, and their etiologies are thought to involve multiple genetic variants and environmental influences. The analysis of gene expression patterns in brain may provide a characteristic signature for each disorder.

Methods: RNA samples from the dorsolateral prefrontal cortex (Brodmann area 46) consisting of individuals with schizophrenia (SZ), bipolar disorder (BPD), and control subjects were tested on the Codelink Human 20K Bioarray platform. Selected transcripts were validated by quantitative real-time polymerase chain reaction (PCR). The strong effects of age, gender, and pH in the analysis of differential gene expression were controlled by analysis of covariance (ANCOVA). Criteria for differential gene expression were 1) a gene was significantly dysregulated in both BPD and SZ compared with control subjects and 2) significant in ANCOVA analysis with samples that have a pH above the median of the sample.

Results: A list of 78 candidate genes passed these two criteria in BPD and SZ and was overrepresented for functional categories of nervous system development, immune system development and response, and cell death. Five dysregulated genes were confirmed with quantitative Q-PCR in both BPD and SZ. Three genes were highly enriched in brain expression (AGXT2L1, SLC1A2, and TU3A). The distribution of AGXT2L1 expression in control subjects versus BPD and SZ was highly significant (Fisher's Exact Test, p < 10(-06)).

Conclusions: These results suggest a partially shared molecular profile for both disorders and offer a window into discovery of common pathophysiology that might lead to core treatments.

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Figures

Figure 1
Figure 1
The Venn diagram for analysis of 88 dorsolateral prefrontal cortex RNA samples (bipolar disorder [BPD], shizophrenic [SZ], and control subjects) showing the overlap between the number of differentially expressed genes. (A) In schizophrenia (left circle, 627 genes) and bipolar disorder (right circle, 1166 genes). The intersection of two circles produces a set of 327 genes. (B) The same analysis was repeated on a restricted set of samples (brain pH > 6.57) and yielded 280 genes that were shared between both disorders. (C) The overlap of both analyses (intersection of Venn diagrams, A and B) shows differentially expressed genes that are robust to pH differences and shared between schizophrenia and bipolar disorder. Of 82 probes shared in the final analysis (C), 78 genes mapped unambigously to these probes. The details of list of 78 genes are shown in Table 3 in Supplement 1.
Figure 2
Figure 2
The distribution of gene expression values for AGXT2L1 for schizophrenia subjects (top red circles, A), control subjects (middle blue circle, B), and bipolar disorder subjects (bottom green circle, C). The distribution for the 88 samples combined suggests that individuals with a high AGXT2L1 value are at a higher risk of developing a psychiatric disorder. Individuals with psychiatric disorder (48) showed above the mode of control AGXT2L1 expression levels. The distribution of control subjects versus subjects with a psychiatric disorder was highly significant for the (Fisher’s Exact Test, p = .000001), with an odds ratio of 11.4 for developing a psychiatric disorder on the basis of the above control mode expression of AGXT2L1.
Figure 3
Figure 3
Genes from two categories, nervous system development (labeled 1–9) and cell death (labeled 10), were subsets of cellular growth and proliferation. The most significant functional category for genes shared in schizophrenia and bipolar disorder was cell cycle, cell stage process (p = 9.18 × 10−06) that contained the following genes: ERBB2, FGF2, JARID2, LGALS3, NFATC1, PPARA, PVR, SOX9, and TXNIP. Genes from two categories, nervous system development and function including quantity of neuroglia process (p = 8.31 × 10−05; ERBB2, FGF2, SOX9), and cell death (p = 8.31 × 10−05; FGF2, SMUG1, UNG) were also significant following Bonferroni correction for 546 processes.
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