Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cognitive and motor deficits have been proposed as markers of abnormal neurodevelopment in schizophrenia and have been associated with genetic liability. In a multicenter study involving 106 subjects, 56 with deficit schizophrenia and 50 with nondeficit schizophrenia, we tested the hypothesis that the catechol-O-methyltransferase (COMT) Val(158)Met polymorphism is associated with cognitive and motor deficits either in schizophrenia as a whole or in its deficit subtype. The COMT Val(158)Met polymorphism shared 6.6% of the executive/attention dysfunction variance in patients with schizophrenia and 15.6% of the motor impairment variance in patients with deficit schizophrenia. These results support the hypothesis that the COMT Val(158)Met polymorphism influences executive functions in schizophrenia and the neuromotor performance in the deficit subtype only.
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PMID:Catechol-O-methyltransferase Val158Met polymorphism in schizophrenia: associations with cognitive and motor impairment. 1603 77

This is the first study of a possible molecular genetic basis for schizophrenia with obsessive-compulsive disorder (OCD). We performed a case-control association study of the catechol-O-methyltransferase (COMT) Val158Met polymorphism in schizophrenia-OCD patients, OCD and healthy controls. One hundred and thirteen schizophrenia-OCD patients, 79 OCD patients and 171 control subjects were genotyped for the Val(158)Met polymorphism in the COMT gene. There was no significant difference in allele and genotype distribution of the COMT gene between schizophrenia-OCD patients and healthy controls. The low-activity Met allele and Met/Met genotype were more frequent in OCD men than in schizophrenia-OCD and control individuals. This difference, however, was not statistically significant following correction for multiple comparisons. These results do not support the hypothesis that the COMT Val158Met gene polymorphism is associated with liability to schizophrenia-OCD.
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PMID:COMT Val158Met polymorphism in schizophrenia with obsessive-compulsive disorder: a case-control study. 1604 83

Schizophrenic patients generally appear to have a disturbed single-carbon metabolism. Methionine and homocysteine are intermediary metabolites in this metabolic system. In a case-control study of the cerebrospinal fluid, a majority of the patients had elevated methionine and a smaller subgroup had elevated homocysteine. Elevated homocysteine is often explained by folate dependency due to mutations in the gene for methylenetetrahydrofolate reductase (MTHFR). A most encouraging feature of single-carbon metabolism is its potential modification by natural means, such as B-vitamins and antioxidants. The findings point to a new area of schizophrenia research: the role of nutrients and antioxidants for rational prevention and treatment.
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PMID:Schizophrenia and single-carbon metabolism. 1609 90

The catechol-O-methyl transferase (COMT) gene has been a promising candidate in genetic research on schizophrenia because of its function in dopamine metabolism and its location on chromosome 22q11.2, which may be implicated in both schizophrenia and velocardiofacial syndrome (VCFS). To explore the possible genetic contribution of COMT to the development of schizophrenia, we focused on the subgroup of patients with schizophrenia characterized by minor physical anomalies as a phenotype and the 158 Val/Met polymorphism as a genotype. Since some physical anomalies are found in both schizophrenia and VCFS, schizophrenia patients with minor physical anomalies could represent the putative subgroup of schizophrenia linked to a disruption in neurodevelopment. Genotyping for the 158 Val/Met (472 G>A) polymorphism in the COMT gene was done for 239 patients with schizophrenia and 248 normal controls. Our analysis did not yield any significant between-group differences in terms of either allele or genotype frequency. We also could not find any association between the COMT gene and the schizophrenia subgroup with minor physical anomalies, although there was a significant difference in Waldrop total scores between the patients with schizophrenia and the normal controls. Analyses of subgroups based on other clinical variables also did not reveal significant differences. Overall, this study does not support the hypothesis that the 158 Val/Met polymorphism in the COMT gene is associated with schizophrenia in Koreans.
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PMID:No association found between 158 Val/Met polymorphism of the COMT gene and schizophrenia with minor physical anomalies. 1610 44

Reduction of prefrontal cortex glutamic acid decarboxylase (GAD67) and reelin (mRNAs and proteins) expression is the most consistent finding reported by several studies of postmortem schizophrenia (SZ) brains. Converging evidence suggests that the reduced GAD67 and reelin expression in cortical GABAergic interneurons of SZ brains is the consequence of an epigenetic hypermethylation of RELN and GAD67 promoters very likely mediated by the overexpression of DNA methyltransferase 1 in cortical GABAergic interneurons. Studies of the molecular mechanisms (DNA methylation plus related chromatin remodeling factors) that cause the down-regulation of reelin and GAD67 in SZ brains have important implications not only to understand the disease pathogenesis but also to improve present pharmacological interventions to treat SZ. The mouse treated with l-methionine models some of the molecular neuropathologies detected in SZ, including the hypermethylation of RELN promoter CpG islands and the down-regulation of reelin and GAD67 expression. We now report that in these mice, RELN and GAD67 promoters express an increased recruitment of methyl-CpG binding domain proteins. In these mice the histone deacetylase inhibitor valproate, which increases acetylated histone content in cortical GABAergic interneurons, also prevents MET-induced RELN promoter hypermethylation and reduces the methyl-CpG binding domain protein binding to RELN and GAD67 promoters. These findings suggest that DNA hypermethylation and the associated chromatin remodeling may be critically important in mediating the epigenetic down-regulation of reelin and GAD67 expression detected in cortical GABAergic interneurons of SZ patients.
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PMID:Reelin and glutamic acid decarboxylase67 promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia. 1611 80

The catechol-O-methyl transferase (COMT) gene is considered to be a promising schizophrenia susceptibility gene. A common functional polymorphism (Val158Met) in the COMT gene affects dopamine regulation in the prefrontal cortex (PFC). Recent studies suggest that this polymorphism contributes to poor prefrontal functions, particularly working memory, in both normal individuals and patients with schizophrenia. However, possible morphological changes underlying such functional impairments remain to be clarified. The aim of this study was to examine whether the Val158Met polymorphism of the COMT gene has an impact on brain morphology in normal individuals and patients with schizophrenia. The Val158Met COMT genotype was obtained for 76 healthy controls and 47 schizophrenics. The diagnostic effects, the effects of COMT genotype and the genotype-diagnosis interaction on brain morphology were evaluated by using a voxel-by-voxel statistical analysis for high-resolution MRI, a tensor-based morphometry. Patients with schizophrenia demonstrated a significant reduction of volumes in the limbic and paralimbic systems, neocortical areas and the subcortical regions. Individuals homozygous for the Val-COMT allele demonstrated significant reduction of volumes in the left anterior cingulate cortex (ACC) and the right middle temporal gyrus (MTG) compared to Met-COMT carriers. Significant genotype-diagnosis interaction effects on brain morphology were noted in the left ACC, the left parahippocampal gyrus and the left amygdala-uncus. No significant genotype effects or genotype-diagnosis interaction effects on morphology in the dorsolateral PFC (DLPFC) were found. In the control group, no significant genotype effects on brain morphology were found. Schizophrenics homozygous for the Val-COMT showed a significant reduction of volumes in the bilateral ACC, left amygdala-uncus, right MTG and left thalamus compared to Met-COMT schizophrenics. Our findings suggest that the Val158Met polymorphism of the COMT gene might contribute to morphological abnormalities in schizophrenia.
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PMID:The association between the Val158Met polymorphism of the catechol-O-methyl transferase gene and morphological abnormalities of the brain in chronic schizophrenia. 1633 May

Catechol-O-methyltransferase (COMT) is thought to functionally modulate dopamine neurons, thus likely influencing frontal-executive functioning. High enzyme activity (COMT Val) and low enzyme activity (COMT Met) are functional polymorphisms resulting from a G to A transition in exon 4 (codon 158) of the human COMT gene. Decreased cortical dopamine should result in poorer executive functioning. Therefore, the authors hypothesized that individuals with traumatic brain injury (TBI) and the low enzyme activity polymorphism would perform better on tests of executive functioning than individuals with the high enzyme activity polymorphism. One hundred thirteen individuals referred to the Defense and Veterans Brain Injury Center underwent a comprehensive TBI evaluation and were genotyped for the COMT polymorphism. Comparison of mean differences among the COMT genotype groups for several measures of aspects of executive functioning was conducted using analysis of variance (ANOVA) with adjustment for multiple comparisons. Homozygotes for the higher activity allele made more perseverative responses on the Wisconsin Card Sorting Test, while homozygotes for the lower activity allele had the least number of perseverative responses. While it cannot be determined whether TBI influenced the association of COMT Val158Met to executive functioning, these data extend the known relationship of genotype to executive performance seen in healthy comparison subjects and individuals with schizophrenia to individuals with TBI.
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PMID:Association of COMT Val158Met genotype with executive functioning following traumatic brain injury. 1638 84

The human gene for catechol O-methyltransferase (COMT) contains a common polymorphism that results in substitution of methionine (M) for valine (V) at residue 108 of the soluble form of the protein. While the two proteins have similar kinetic properties, 108M COMT loses activity more rapidly than 108V COMT at 37 degrees C. The cosubstrate S-adenosylmethionine (SAM) stabilizes the activity of 108M COMT at 40 degrees C. The 108M allele has been associated with increased risk for breast cancer, obsessive-compulsive disorder, and aggressive and highly antisocial manifestations of schizophrenia. In the current work, we have constructed homology models for both human COMT polymorphs and performed molecular dynamics simulations of these models at 25, 37, and 50 degrees C to explore the structural consequences of the 108V/M polymorphism. The simulations indicated that replacing valine with the larger methionine residue led to greater solvent exposure of residue 108 and heightened packing interactions between M108 and helices alpha2, alpha4 (especially with R78), and alpha5. These altered packing interactions propagated subtle changes between the polymorphic site and the active site 16 A away, leading to a loosening of the active site. At physiological temperature, 108M COMT sampled a larger distribution of conformations than 108V. 108M COMT was more prone to active-site distortion and had greater overall, and SAM binding site, solvent accessibility than 108V COMT at 37 degrees C. Similar structural perturbations were observed in the 108V protein only at 50 degrees C. Addition of SAM tightened up the cosubstrate pocket in both proteins and prevented the altered packing at the polymorphic site in 108M COMT.
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PMID:The 108M polymorph of human catechol O-methyltransferase is prone to deformation at physiological temperatures. 1647 6

Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor that promotes several functions of neurons and modulates neurotransmissions. It has been reported that there are alterations of BDNF levels in schizophrenic brains and that BDNF gene expressional changes would be responsible for the etiology of schizophrenia. Recent studies have shown that a variation of BDNF gene (Val66Met polymorphism) affects the function of neurons, and is associated with several neurological and psychiatrical disorders. We investigated the relationship between BDNF Val66Met polymorphism and the onset age as well as levels of clinical symptoms in 159 of chronic schizophrenia in-patients diagnosed by DSM-IV. The mean onset ages were 27.5+/-9.5 for BDNF Val/Val, 25.5+/-7.4 for BDNF Val/Met and 22.9+/-6.0 for BDNF Met/Met and this polymorphism was significantly associated with age at onset (P=0.023). The mean Brief Psychiatric Rating Scale scores (BPRS) were significantly different among those three groups (P=0.003). No significant differences were demonstrated comparing the BDNF genotype distributions of positive and negative family history (P=0.21). Our investigation indicates that the BDNF gene Val66Met polymorphism is related to the onset age of schizophrenia and the levels of clinical symptoms that remain after long-term antipsychotic treatment.
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PMID:Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism in schizophrenia is associated with age at onset and symptoms. 1653 63

Chromosome 22q11.2 deletion syndrome (22q11DS) is a common microdeletion syndrome associated with a markedly elevated risk of schizophrenia in adulthood. Cognitive impairments such as a low IQ and deficits in attention and executive function are common in childhood. The catechol O-methyltransferase (COMT) gene maps within the deleted region and is involved in the degradation of dopamine, a neurotransmitter thought to be important in cognition and the development of schizophrenia. Thus, we examined the correlation between neurocognitive deficits and a common polymorphism Val(158)Met in the COMT gene in a cohort of children with 22q11DS. Our results show that children with 22q11DS who have the Met allele have higher IQ and achievement scores and perform better on measures of prefrontal cognition, such as the Continuous Performance Task, as compared with those with the Val allele. These results confirm that the hemizygous COMT Val(158)Met genotype impacts upon cognition in children with 22q11DS.
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PMID:Cognitive correlates of a functional COMT polymorphism in children with 22q11.2 deletion syndrome. 1654 88


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