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The quantification of COMT mRNA in post mortem cerebellum tissue: diagnosis, genotype, methylation and expression.

ABSTRACT: BACKGROUND: The COMT gene is located on chromosome 22q11, a region strongly implicated in the aetiology of several psychiatric disorders, in particular schizophrenia. Previous research has suggested that activity and expression of COMT is altered in schizophrenia, and is mediated by one or more polymorphisms within the gene, including the functional Val158Met polymorphism. METHOD: In this study we examined the expression levels of COMT mRNA using quantitative RT-PCR in 60 post mortem cerebellum samples derived from individuals with schizophrenia, bipolar disorder, depression, and no history of psychopathology. Furthermore, we have examined the methylation status of two CpG sites in the promoter region of the gene. RESULTS: We found no evidence of altered COMT expression or methylation in any of the psychiatric diagnoses examined. We did, however, find evidence to suggest that genotype is related to COMT gene expression, replicating the findings of two previous studies. Specifically, val158met (rs165688; Val allele) rs737865 (G allele) and rs165599 (G allele) all showed reduced expression (P < 0.05). Finally, we observe a strong sexual dimorphism in COMT expression, with females exhibiting significantly greater levels of COMT mRNA. CONCLUSION: The expression of COMT does not appear to be altered in the cerebellum of individuals suffering from schizophrenia, bipolar disorder or depression, but does appear to be influenced by single nucleotide polymorphisms within the gene.

SUBMITTER: Dempster EL

PROVIDER: S-EPMC1456954 | biostudies-literature | 2006

REPOSITORIES: biostudies-literature

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The quantification of COMT mRNA in post mortem cerebellum tissue: diagnosis, genotype, methylation and expression.

Dempster Emma L EL Mill Jonathan J Craig Ian W IW Collier David A DA

BMC medical genetics 20060216

<h4>Background</h4>The COMT gene is located on chromosome 22q11, a region strongly implicated in the aetiology of several psychiatric disorders, in particular schizophrenia. Previous research has suggested that activity and expression of COMT is altered in schizophrenia, and is mediated by one or more polymorphisms within the gene, including the functional Val158Met polymorphism.<h4>Method</h4>In this study we examined the expression levels of COMT mRNA using quantitative RT-PCR in 60 post morte ...[more]

PMID: 16483362

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Project description:Schizophrenia (SCZ) is a common, disabling mental illness with high heritability but complex, poorly understood genetic etiology. As the first phase of a genomic convergence analysis of SCZ, we generated 16.7 billion nucleotides of short read, shotgun sequences of cDNA from post-mortem cerebellar cortices of 14 patients and six matched controls. A rigorous analysis pipeline was developed for analysis of digital gene expression studies. Sequences aligned to approximately 33,200 transcripts in each sample, with average coverage of 450 reads per gene. Following adjustments for confounding clinical, sample and experimental sources of variation, 215 genes differed significantly in expression between cases and controls. Golgi apparatus, vesicular transport, membrane association, Zinc binding and regulation of transcription were over-represented among differentially expressed genes. Twenty three genes with altered expression and involvement in presynaptic vesicular transport, Golgi function and GABAergic neurotransmission define a unifying molecular hypothesis for dysfunction in cerebellar cortex in SCZ. Experiment Overall Design: 16.7 billion nucleotides of shotgun, full length cDNA sequence data were generated using Illumina Genome Analyzer platforms with sequencing-by-synthesis (SBS) chemistry from 20 mRNA samples (Lister et al., 2008; Morin et al., 2008)(Mortazvi et al., 2008). mRNA samples were isolated post-mortem from the lateral hemispheres of the cerebellar cortices of 14 patients with SCZ and 6 control individuals (Paz et al., 2006; Bullock et al., In Press)(Table 1). Unrelated subjects were chosen to facilitate sampling of genetic heterogeneity (Freimer and Sabatti, 2004; McClellan et al., 2007). Cases and controls were approximately matched for age (cases, 45.2 + 11.8 years; controls 41.3 + 9.2 years), sex (all male), race, post-mortem interval (cases, 12.2 + 5.0 hours; controls 17.7 + 3.3 hours), cause of death, autopsy brain pH (cases, 6.54 + 0.19; controls 6.46 + 0.10) and RNA integrity number (cases, 8.06 + 0.53; controls, 7.87 + 0.41) (Table 1). 12.5 – 38.7 million, high quality sequences of length 32 – 36 bp were generated per sample (Table 2). Sequences were aligned to the human genome and RefSeq transcript databases using the algorithm GMAP, which allowed < 2 (< 6%) mismatches (Wu and Watanabe, 2005). There was little intra-sample variability in the number of sequences aligned to each locus from run-to-run or instrument-to-instrument (Fig. 1A; all source coefficient of variation 3.4%). 43.5 + 6.7% of sequences aligned to a transcript and 69.4 + 9.6% to the genome, evidence that annotation of mRNA isoforms in Homo sapiens is incomplete (Birney et al., 2007) (Table 2). 91% of alignments were unique (Table 2). Reads aligning to more than one location contained repetitive, paralogous, polymorphic or low complexity sequences and primarily mapped to untranslated regions or highly polymorphic gene families, such as major histocompatibility genes (Sugarbaker et al., 2008). Unmapped sequences did not align to mitochondrial or 1879 viral genomes, offering negative evidence of chronic viral etiology for SCZ in these patients.

Dataset Information

The quantification of COMT mRNA in post mortem cerebellum tissue: diagnosis, genotype, methylation and expression.

Publications

The quantification of COMT mRNA in post mortem cerebellum tissue: diagnosis, genotype, methylation and expression.

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