Application of Microarrays to Neuropsychiatry Disorders

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Neuropsychiatric disorders such as schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) are complex diseases, whose exact etiology is unknown. Evidence suggests genetic, developmental, and environmental factors combine to create each disorder, with susceptibility loci for SZ, BD, and MDD identified throughout the genome. With an absence of clearly defined genetic factors on which cellular and animal models can be generated, to further the understanding of this spectrum of disorders, gene expression analysis of postmortem material has been utilized to distinguish particular clinical phenotypes, to determine specific gene signatures [138], and to identify novel genes implicated in the disorder [139].

6.1. Schizophrenia and Bipolar Disorder

SZ is a common psychiatric disorder affecting 1% of the population. Onset usually occurs in late adolescence or early adulthood, coinciding with a developmental reduction in brain synapse density, and symptoms include delusions, hallucinations, impaired motivation, and changes in cognitive responses such as attention span and working memory. Pathologically, the hippocampus, superior temporal gyrus, and thalamus are affected, with predominant pathology occurring in the prefrontal cortex, which is thought to underlie the cognitive impairment symptoms. Gene expression studies have identified the involvement of presynaptic secretion, mitochondrial dysfunction, and oligodendrocyte impairment in the molecular pathogeneis of SZ.

BD occurs in 1% of the population and affects an individual's emotional response, with symptoms cycling between depression and mania. It is a complex genetic disease thought to require additional environmental factors for onset. Gene expression studies in BD have identified many changes in common with SZ, including oligodendrocyte abnormalities [140] and mitochondrial dysfunction [141].

6.1.1. Expression Profiling in SZ and BD

In the first microarray study to sample gene expression of the prefrontal cortex in 10 SZ patients compared to matched controls, the major group of transcripts differentially expressed belonged to those involved in the presyn-aptic secretory machinery [142]. This was also seen in a further five SZ cases and in subsequent microarray studies conducted by Vawter et al. [143] and Hemby et al. [144]. Interestingly, two of the SZ cases in the initial study were not taking medication, suggesting that these changes were specific to SZ, and were not produced in response to drug treatment. Additional array and in situ hybridization studies were performed on prefrontal cortex from monkeys treated with haloperidol, an antipsychotic drug [142]. These studies failed to detect any decreases in the presynaptic genes that were altered in the SZ cases, supporting the hypothesis that these changes are SZ specific.

Subsequent studies demonstrated the involvement of dysfunctional mito-chondrial energy metabolism in SZ, with decreases in the mitochondrial malate shuttle system and the tricarboxylic acid (TCA) cycle [145]. In this study, comparison of these gene expression changes with those occurring in haloperidol treated monkeys identified malate dehydrogenase as increased following treatment, suggesting a direct therapeutic effect of the drug on mitochondrial metabolism.

Mitochondrial involvement was further analyzed by Iwamoto, whose study included both Sz and BD cases [141]. Focusing on the expression of 676 mitochondrial-related genes, global downregulation was seen in genes, including those involved in mitochondrial cell respiration, the TCA cycle, and mitochondrial transcription and translation. A previous study demonstrated that decreases in energy metabolism genes correlated with brain tissue of low pH (correlating with prolonged agonal state), rather than with the psychiatric disorders BD and MDD [146]. However, the study by Iwamoto reanalyzed the data using only high-pH samples. Although there were some changes to the genes identified as differentially expressed, the global down-regulation of the mitochondrial-related genes was still evident. Fifty-seven transcripts were found to be in common between Sz and BD, while Sz exhibited 25 specific changes, and 19 changes were specific for BD. However, rather than using monkeys to assess the effect of the drug treatments, two non-medicated Sz cases and four non-medicated BD cases were analyzed for gene expression changes. Interestingly, these cases did not demonstrate a global downregulation of mitochondrial genes, but a tendency for upregula-tion, particularly in those genes involved in the respiratory chain components. Thus, the drug treatments in these patients are suggested to have a repressive effect on mitochondrial genes in the brain.

Early studies on prefrontal cortex of Sz cases also identified decreases in myelination-related genes, implicating oligodendrocyte dysfunction in the pathogenesis of SZ [147]. This hypothesis was supported and extended by Tkachev, who demonstrated oligodendrocyte and myelination genes, and the transcription factors controlling the expression of these genes, were down-regulated not only in SZ but also in BD [140]. In addition, the changes in myelination-related genes are not specific for the prefrontal cortex, as they have also been identified in the temporal cortex of SZ cases [148]. A further study investigated whether these oligodendrocyte-related gene changes were due to drug treatments in SZ patients [149]. Although a few gene changes were found in common with monkeys treated with haloperidol for 3 months, unlike the mitochondrial gene changes, the majority of the data supported a role for oligodendrocyte impairment in SZ.

The identification of oligodendrocyte abnormalities and mitochondrial dysfunctional in both SZ and BD provide targets for symptomatic relief, and the similarity in pathways affected may reflect those genes involved in psychosis, and may explain why particular drugs developed for SZ are used successfully to treat BD. However, genes specifically altered in BD have been identified such as decreases in distinct mitochondrial genes [141] and increases in procaspase-8 and transforming growth factor (31 (TGF^1) [150]. Since TGF,31 is neuroprotective, the decrease in expression may contribute to the neurotoxicity seen in the disorder.

6.1.2. Identifying Susceptibility Genes in SZ

While the above studies have demonstrated how the molecular pathogen-esis of SZ has been revealed using gene expression assays, they also provide an example of how novel susceptibility genes for SZ are identified. Regulator of G-signaling 4 (RGS4) was originally identified as the only consistently downregulated gene out of 7800 transcripts interrogated in 6 SZ cases, compared to 6 controls [139]. Analysis of 5 further SZ and 10 MDD cases confirmed the decrease as specific to SZ. Furthermore, the decrease was also evident in two SZ cases not on medication. Since RGS4 is also localized close to a region previously identified as an SZ susceptibility locus, chr 1q21-22 [151], sequencing of the coding regions in the SZ cases was carried out to determine if there were any mutations or functional polymorphisms. None were found. However, subsequent studies have focused on four single nucleotide polymorphisms (SNPs) located upstream and in intron 1 of the RGS4 gene.

The first study screened 13 SNPs from the RGS4 region in 3 cohorts of SZ cases and found 4 SNPs which showed distorted transmission [152]. However, the haplotypes differed between two American cohorts from Pittsburgh and the NIMH. Further studies by Morris et al. [153], Williams et al. [154], and Chen et al. [155] confirmed an association of SZ with RGS4, while Sobell et al. [156] and Brzustowicz et al. [157] have failed to find supporting data. To try to clarify the results, a meta-analysis of 13,807 samples were used from 13 cohorts to evaluate RGS4 as a susceptibility gene [158]. Although no individual risk factor was identified, at least two common haplotypes conferred a risk of SZ, and it is suggested this is due to the presence of an undetected risk factor which is only localized on these two haplotypes. Thus, the location of this susceptibility gene was enhanced by gene expression analysis.

6.1.3. Identifying Biomarkers in SZ and BD

As with HD, following gene expression assays to further the basic molecular pathology of the disease, identification of biomarkers in biological samples that can be taken while patients are alive, such as blood, presents the next goal. The first study of this kind in psychiatric cases describes the identification of a unique gene signature in blood samples which allows the SZ, BD, and control samples to be distinguished [138]. Following validation of key markers by RT-PCR, eight potential biomarkers were used to discriminate between SZ, BD, and control samples with an accuracy of 95-97%. Blood-derived biomarkers have potential benefits for diagnosis of these disorders, as early diagnosis and correct drug treatment can provide those affected with the disorders with a better quality of life.

6.2. Major Depressive Disorder

MDD describes individuals who experience a depression event of more than 2 weeks duration, though this may be a single or recurrent event. Unlike BD, there is no mania associated with the depression. Due to the complex interaction of genetic and environmental factors, gene expression arrays have been used to provide an overall view of the disorder and identify disease mechanisms. Although pathological studies implicate prefrontal and temporal cortices, as well as limbic structure, the temporal cortex is thought to be important in regulating emotional states, and functional magnetic resonance imaging (fMRI) and low-resolution electromagnetic tomography demonstrate differential responses in MDD cases compared to controls. Therefore, gene expression profiling of the temporal cortex (Brodmann area 21) in 12 MDD cases, including 7 under treatment, was performed and compared against control samples [159]. The study identified 225 changes in gene expression, including genes involved in neurogenesis, cell communication, chromatin and gene expression, and the cell cycle. To clarify that these changes were specific for the disease, rather than an effect of the drug treatments, the five samples from unmedicated individuals were used for analysis. All 225 changes identified initially were also found in this subsequent analysis. Therefore, these changes were due to MDD. The decreases in neurogenesis genes, specifically the myelin-related changes, correlate with the reduced density of oligodendrocytes seen in Brodmann area 9 [160] and amygdala of MDD cases [161], and may underlie the white matter changes seen by imaging techniques [162].

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