Transcription and Pathway Analysis of the Superior Temporal Cortex and Anterior Prefrontal Cortex in Schizophrenia

Computational Biology, Quantitative Sciences, Biopharmaceuticals, GlaxoSmithKline Medicines Research Centre, Stevenage, United Kingdom.
Journal of Neuroscience Research (Impact Factor: 2.73). 08/2011; 89(8):1218-27. DOI: 10.1002/jnr.22647
Source: PubMed

ABSTRACT The molecular basis of schizophrenia is poorly understood; however, different brain regions are believed to play distinct roles in disease symptomology. We have studied gene expression in the superior temporal cortex (Brodmann area 22; BA22), which may play a role in positive pathophysiology, and compared our results with data from the anterior prefrontal cortex (BA10), which shows evidence for a role in negative symptoms. Genome-wide mRNA expression was determined in the BA22 region in 23 schizophrenics and 19 controls and compared with a BA10 data set from the same subjects. After adjustments for confounding sources of variation, we carried out GeneGO pathway enrichment analysis in each region. Significant differences were seen in age-related transcriptional changes between the BA22 and the BA10 regions, 21.8% and 41.4% of disease-associated transcripts showing age association, respectively. After removing age associated changes from our data, we saw the highest enrichment in processes mediating cell adhesion, synaptic contact, cytoskeletal remodelling, and apoptosis in the BA22 region. For the BA10 region, we observed the strongest changes in reproductive signalling, tissue remodelling, and cell differentiation. Further exploratory analysis also identified potentially disease-relevant processes that were undetected in our more stringent primary analysis, including autophagy in the BA22 region and the amyloid process in the BA10 region. Collectively, our analysis suggests disruption of many common pathways and processes underpinning synaptic plasticity in both regions in schizophrenia, whereas individual regions emphasize changes in certain pathways that may help to highlight pathway-specific therapeutic opportunities to treat negative or positive symptoms of the disease.

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    • "Overall, we identified 49 differentially regulated genes in these cohorts that clustered into a relatively small number of functional groups that are associated with synaptic function via synaptic vesicle regulation, signal transduction or cytoskeletal dynamics. Subsequently, we compared the data from frontal and superior temporal cortex using GeneGo maps and GeneGo processes and showed over-representation of genes involved in cytoskeletal remodelling, neurodevelopment, cell adhesion, cellular signalling, and neurotransmission in both regions, consistent with a disruption of processes underpinning synaptic plasticity [4]. "
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    ABSTRACT: Previous microarray analysis of gene expression in frontal cortex showed differential expression of genes associated with synaptic function in schizophrenia compared to matched-controls in two independent cohorts. One of these genes validated in both cohorts, SLC30A3, which encodes the Zinc Transporter 3 (ZNT3), is localised to synaptic vesicles in glutamate synapses and known to be involved in cognitive function. In view of the robust depletion of SLC30A3 mRNA in two independent studies and the importance of this gene in cognitive function, we investigated whether single nucleotide polymorphism (SNP) associations with schizophrenia could be detected in a UK case controlled schizophrenia cohort. Four SNPs were selected across this gene and genotyped in a cohort of cases and controls from East UK. We found significant associations with schizophrenia at the allelic (ORs: 1.51 to 1.57), genotype (ORs: 1.46 to 1.53) and haplotype level (P=2.15×10(-4)). These associations proved to be gender-specific with significant effects of allele (ORs: 1.74 to 2.11), genotype (ORs: 1.78 to 2.14) and haplotype (P=3.51×10(-5)) observed in female schizophrenia cases but not males, when split by gender. In conclusion, SNPs in SLC30A3 showed a gender-specific association with schizophrenia in this East UK cohort, which merits further investigation in other population samples.
    European Psychiatry 07/2013; DOI:10.1016/j.eurpsy.2013.05.007 · 3.21 Impact Factor
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    • "protein encoded by the overexpressed ATP1B1 gene is a member of the family of Na+/K+ and H+/K+ ATPases, as well as a member of the subfamily of responsible proteins for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membranes [29]. PLA2G5 gene encodes an enzyme that belongs to PLA family. "
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    ABSTRACT: Schizophrenia affecting almost 1% and bipolar disorder affecting almost 3%-5% of the global population constitute two severe mental disorders. The catecholaminergic and the serotonergic pathways have been proved to play an important role in the development of schizophrenia, bipolar disorder, and other related psychiatric disorders. The aim of the study was to perform and interpret the results of a comparative genomic profiling study in schizophrenic patients as well as in healthy controls and in patients with bipolar disorder and try to relate and integrate our results with an aberrant amino acid transport through cell membranes. In particular we have focused on genes and mechanisms involved in amino acid transport through cell membranes from whole genome expression profiling data. We performed bioinformatic analysis on raw data derived from four different published studies. In two studies postmortem samples from prefrontal cortices, derived from patients with bipolar disorder, schizophrenia, and control subjects, have been used. In another study we used samples from postmortem orbitofrontal cortex of bipolar subjects while the final study was performed based on raw data from a gene expression profiling dataset in the postmortem superior temporal cortex of schizophrenics. The data were downloaded from NCBI's GEO datasets.
    The Scientific World Journal 03/2013; 2013:685917. DOI:10.1155/2013/685917 · 1.73 Impact Factor
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    • "Consistent with its involvement in schizophrenia pathogenesis, blood TCF4 levels were found to be reduced during psychotic states [Kurian et al., 2011], and a small study of post-mortem cerebellar cortices of 14 schizophrenia patients and six controls also highlighted TCF4, but found up-regulation of expression in patients [Mudge et al., 2008]. However, post-mortem brain mRNA-level analyses of three brain regions, the dorsolateral prefrontal cortex (DLPFC; Brodmann area BA46) [Narayan et al., 2008], the lateral and caudal superior temporal gyrus (BA22) [Barnes et al., 2011] and the frontopolar prefrontal cortex (BA10) [Maycox et al., 2009], found no association between schizophrenia and TCF4. These discrepancies may well be explained by differences in expression patterns among tissues and cell type. "
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    ABSTRACT: Common SNPs in the transcription factor 4 (TCF4; ITF2, E2-2, SEF-2) gene, which encodes a basic Helix-Loop-Helix (bHLH) transcription factor, are associated with schizophrenia, conferring a small increase in risk. Other common SNPs in the gene are associated with the common eye disorder Fuch's corneal dystrophy, while rare, mostly de novo inactivating mutations cause Pitt-Hopkins syndrome. In this review, we present a systematic bioinformatics and literature review of the genomics, biological function and interactome of TCF4 in the context of schizophrenia. The TCF4 gene is present in all vertebrates, and although protein length varies, there is high conservation of primary sequence, including the DNA binding domain. Humans have a unique leucine-rich nuclear export signal. There are two main isoforms (A and B), as well as complex splicing generating many possible N-terminal amino acid sequences. TCF4 is highly expressed in the brain, where plays a role in neurodevelopment, interacting with class II bHLH transcription factors Math1, HASH1, and neuroD2. The Ca(2+) sensor protein calmodulin interacts with the DNA binding domain of TCF4, inhibiting transcriptional activation. It is also the target of microRNAs, including mir137, which is implicated in schizophrenia. The schizophrenia-associated SNPs are in linkage disequilibrium with common variants within putative DNA regulatory elements, suggesting that regulation of expression may underlie association with schizophrenia. Combined gene co-expression analyses and curated protein-protein interaction data provide a network involving TCF4 and other putative schizophrenia susceptibility genes. These findings suggest new opportunities for understanding the molecular basis of schizophrenia and other mental disorders. © 2012 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 01/2013; 162(1). DOI:10.1002/ajmg.b.32109 · 3.27 Impact Factor
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