UMLS:C0036341 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0036341 (schizophrenia)
60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

New models of interaction between genetic and environmental factors have been proposed to explain the pathogenesis of schizophrenia. The Val158Met polymorphism of the COMT (Catechol-O-Methyltransferase) gene, involved in dopamine regulation and related to negative symptoms, has been previously thought to interact with cannabis use in the modulation of risk of psychosis. The aim of the study was to explore the existence of an interaction between COMT genotype and cannabis use in early stages of psychosis and its effects on the age of onset in a representative group of first-episode psychosis patients. Age of onset, DUP (Duration of Untreated Psychosis) and cannabis use (regular user versus sporadic or non-user) were assessed in 169 Caucasian patients with a first-episode schizophrenia spectrum disorder. COMT polymorphism was typed using PCR of the relevant region followed by digestion with NlaIII and electrophoresis. A multivariate ANCOVA was performed with DUP and age of onset as dependent variables, cannabis and the COMT genotype as fixed factors, and gender as a covariate. The MANCOVA was significant for age of onset and DUP. Cannabis users had a significant earlier age of onset. Age of onset was later in the Met homozygote group (non-significant). The cannabis-COMT interaction showed a significant effect on both DUP and age of onset. Post hoc analyses showed that differences between genotypes were only present in the non-users' group. Based on these results, the use of cannabis could exert a modulator effect on the genotype, suppressing the delay effect for the age of onset in the case of the Met allele patients.
...
PMID:Catechol-O-Methyltransferase (COMT) Val158Met variations and cannabis use in first-episode non-affective psychosis: clinical-onset implications. 2049 36

Catechol-O-methyl transferase (COMT) is an enzyme involved in the degradation of dopamine. The most commonly examined polymorphism within the COMT gene is Val108/158Met polymorphism, which results in three to fourfold difference in COMT enzyme activity. It is particularely important in prefrontal cortex, since COMT activity is the most important regulator of the prefrontal dopamine function. Given the association between schizophrenia and decreased dopamine activity in the prefrontal cortex, it is not surprising that Val108/158Met polymorphism is among the most extensively investigated polymorphisms in schizophrenia. According to different studies, Val allele may be a small risk factor for schizophrenia. There is also some evidence that Val108/158Met polymorphism influences the age of onset of schizophrenia, cognitive function, severity of psychotic symptoms, as well as efficacy and adverse events of antipsychotics. Heterogenity of patient population has undoubtedly influenced the results of these studies. Interaction of Val108/158Met polymorphism with other genes and environmental factors is an important avenue for future research.
...
PMID:Catechol-O-methyl transferase and schizophrenia. 2056 60

Catechol-O-methyl transferase (COMT) encodes an enzyme involved in the metabolism of dopamine and maps to a commonly deleted region that increases schizophrenia risk. A non-synonymous polymorphism (rs4680) in COMT has been previously found to be associated with schizophrenia and results in altered activity levels of COMT. Using a haplotype block-based gene-tagging approach we conducted an association study of seven COMT single nucleotide polymorphisms (SNPs) in 160 patients with a DSM-IV diagnosis of schizophrenia and 250 controls in an Australian population. Two polymorphisms including rs4680 and rs165774 were found to be significantly associated with schizophrenia. The rs4680 results in a Val/Met substitution but the strongest association was shown by the novel SNP, rs165774, which may still be functional even though it is located in intron five. Individuals with schizophrenia were more than twice as likely to carry the GG genotype compared to the AA genotype for both the rs165774 and rs4680 SNPs. This association was slightly improved when males were analysed separately possibly indicating a degree of sexual dimorphism. Our results confirm that COMT is a good candidate for schizophrenia risk, by replicating the association with rs4680 and identifying a novel SNP association.
...
PMID:HapMap tag-SNP analysis confirms a role for COMT in schizophrenia risk and reveals a novel association. 2093 10

Cognitive deficits are rate limiters on recovery in schizophrenia that respond poorly to pharmacotherapy. Cognitive remediation therapy (CRT), a novel psychological therapy, has produced promising outcomes for cognition. However, little is known about the biological mechanisms that might underlie individual differences in CRT response. Catechol-O-Methyltransferase (COMT) is associated specifically with prefrontal cognition. The COMT Val158Met polymorphism is known to have a functional effect on the rate of dopamine degradation, which may be related to cognitive treatment response. This study aimed to determine whether COMT genotype influences cognitive improvement following CRT in schizophrenia. Participants with schizophrenia were recruited from three randomised controlled trials of CRT compared to treatment as usual, and one CRT treatment only trial, each providing 40 CRT sessions. Eighty-seven participants (40%) agreed to participate in the genetic study, and provided DNA for COMT genotyping. Cognitive function and psychopathology were assessed at baseline, post-treatment and 3-6-month follow-up. People with the COMT Val/Met genotype performed more poorly on categories achieved at baseline on the Wisconsin Card Sorting Test (WCST) than those homozygous for the Val or Met allele. Cognitive function improved with CRT but there was no association between this cognitive improvement and COMT genotype, either in the CRT group or in the total sample. The COMT val158Met polymorphism does not appear to be a clinically useful biomarker of cognitive improvement following CRT in schizophrenia. A complex set of factors may influence cognitive change, however, such that the COMT genotype might still have a subtle effect on response to CRT or similar interventions.
...
PMID:No association between the Catechol-O-Methyltransferase (COMT) val158met polymorphism and cognitive improvement following cognitive remediation therapy (CRT) in schizophrenia. 2145 32

Dopaminergic system in the prefrontal cortex (PFC) is known to regulate the cognitive functions. Catechol-O-methyl transferase (COMT), one of the major modulators of prefrontal dopamine function, has emerged as an important determinant of schizophrenia associated cognitive dysfunction and response to antipsychotics. A common Val->Met polymorphism (rs4680) in the COMT gene, associated with increased prefrontal dopamine catabolism, impairs prefrontal cognition and might increase risk for schizophrenia. Further, the degree of cognitive improvement observed with antipsychotics in schizophrenia patients is influenced by the COMT activity, and Val/Met has been proposed as a potential pharmacogenetic marker. However, studies evaluating the role of COMT have been equivocal. The presence of other functional polymorphisms in the gene, and the observed ethnic variations in the linkage disequilibrium structure at COMT locus, suggest that COMT activity regulation might be complex. Despite these lacunae in our current understanding, the influence of COMT on PFC mediated cognitive tasks is undeniable. COMT thus represents an attractive candidate for novel therapeutic interventions for cognitive dysfunction. The COMT activity inhibiting drugs including tolcapone and entacapone, have shown promising potential as they selectively modulate dopaminergic transmission. This review is an attempt to summarize the rapidly evolving literature exploring the diverse facets of COMT biology, its functional relevance as a predictive marker and a therapeutic target for schizophrenia.
...
PMID:Diverse facets of COMT: from a plausible predictive marker to a potential drug target for schizophrenia. 2199 47

22q11.2 deletion syndrome (22q11DS) is a genetic syndrome associated with a microdeletion of the chromosome 22 band q11.2 with an estimated prevalence between 1:2,500 and 1:4,000. Studies of school-age children have shown that individuals with 22q11DS have high rates of psychiatric morbidity. In particular, by late adolescence, about 30% of patients with 22q11DS develop psychotic symptoms. One of the genes located in the microdeletion region of 22q11DS is the Catechol-O-Methyl transferase (COMT) which codes for an enzyme critically involved in the catabolic clearance of dopamine. COMT is critically involved in cognitive related disturbances, and it has often been suggested as a sensitive factor in the development of psychiatric disorders. Several studies have been conducted on the impact of COMT functional polymorphism in 22q11DS and its related cognitive/psychiatric correlates. In this review, we summarize mainly current knowledge on the correlation between schizophrenia/cognitive related symptoms and COMT genetic variations in 22q11DS. A selective literature review on this topic was undertaken. COMT might play an important role in modulating cognitive functions in 22q11DS but a clear relationship between COMT polimorphism and schizophrenia in 22q11DS need further investigation. Despite controversial results, 22q11DS represent a powerful model for studying the role of COMT and other genetic variations in schizophrenia. This is due to high risk in 22qDS patients of developing this disorder and their relative genetic homogeneity. Further research is needed to evaluate all of the polymorphic markers in the COMT gene and its nearby regulatory elements for association with schizophrenia. Identification of specific COMT-dependent molecular, cellular and circuit deficits will provide targets for the development of more efficient treatments for the cognitive and psychiatric symptoms in 22q11DS.
...
PMID:COMT implication in cognitive and psychiatric symptoms in chromosome 22q11 microdeletion syndrome: a selective review. 2248 89

Catechol-O-methyl transferase (COMT) plays a key role in the degradation of brain dopamine (DA). Specifically, low COMT activity results in higher DA levels in the prefrontal cortex (PFC), thereby reducing the vulnerability for attentional and cognitive deficits in both psychotic and healthy individuals. COMT activity is markedly reduced by a non-synonymous single-nucleotide polymorphism (SNP) that generates a valine-to-methionine substitution on the residue 108/158, by means of as-yet incompletely understood post-translational mechanisms. One post-translational modification is methionine sulfoxide, which can be reduced by the methionine sulfoxide reductase (Msr) A and B enzymes. We used recombinant COMT proteins (Val/Met108) and mice (wild-type (WT) and MsrA knockout) to determine the effect of methionine oxidation on COMT activity and COMT interaction with Msr, through a combination of enzymatic activity and Western blot assays. Recombinant COMT activity is positively regulated by MsrA, especially under oxidative conditions, whereas brains of MsrA knockout mice exhibited lower COMT activity (as compared with their WT counterparts). These results suggest that COMT activity may be reduced by methionine oxidation, and point to Msr as a key molecular determinant for the modulation of COMT activity in the brain. The role of Msr in modulating cognitive functions in healthy individuals and schizophrenia patients is yet to be determined.
...
PMID:Methionine sulfoxide reductase regulates brain catechol-O-methyl transferase activity. 2473 85

Schizophrenia is a complex neuropsychiatric disorder strongly associated with dopamine dysregulation. Catechol-O-methyl-transferase (COMT) is a candidate gene for schizophrenia that encodes an enzyme involved in the metabolic inactivation of dopamine. The COMT Val(158)Met polymorphism has been associated with schizophrenia and has significant inter- and intra-ethnic variations. We examined a possible association between the COMT Val(158)Met polymorphism and schizophrenia in Saudis, taking into account gender and functional symptoms. Saudi subjects including 172 unrelated schizophrenia patients and 177 matched controls were analyzed for allele and genotype distribution of the COMT Val(158)Met polymorphism. We found significant differences in allele and genotype frequencies between patients and controls. The frequencies of Met(158) allele (A) and genotype Val(158)Met (GA) were significantly higher in patients compared to those in controls. On the other hand, the frequencies of Val(158) allele (G) and genotype Val(158)Val (GG) were significantly higher in controls than those in patients. We found a significant association of the COMT Val(158)Met polymorphism with schizophrenia. Moreover, male patients with the COMT Val(158)Met polymorphism had increased risk for schizophrenia compared to female subjects. However, no association was noticed with the COMT Val(158)Met polymorphism and negative or positive symptoms of schizophrenia. These results provide evidence for a role of the COMT Val(158)Met polymorphism in the etiopathophysiology of schizophrenia in Saudi population. It appears that the association of the COMT Val(158)Met polymorphism with schizophrenia is mediated by gender.
...
PMID:Genetic association of catechol-O-methyltransferase val(158)met polymorphism in Saudi schizophrenia patients. 2478 65

Mismatch negativity (MMN) is a component of auditory event-related potentials that reflects automatic change detection in the brain, showing qualities of endophenotypes in schizophrenia. MMN deficiency is one of the robust findings in patients, and it reflects both cognitive and functional decline. Catechol-o-methyltransferase (COMT) is a key enzyme involved in regulating dopamine transmission within the prefrontal cortex. A preliminary study suggested that the COMTVal108/158Met genotype (rs4680) is related to cognitive function in schizophrenia. Both the COMTVal108/158Met genotype and MMN are related to cognitive function, but no studies have reported on the relationship between MMN and the COMTVal108/158Met genotype in schizophrenia. This study therefore examined the relationship between COMTVal108/158Met genotype and MMN. The duration of MMN was measured, and the COMTVal108/158Met polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism in 49 Japanese schizophrenia patients (Val/Val, n = 21; Met carriers, n = 28). Amplitude and latency of MMN were compared between Val/Val and Met carriers.
...
PMID:The Relationship between Mismatch Negativity and the COMTVal108/158Met Genotype in Schizophrenia. 3032 66

Prepulse inhibition (PPI) can be modulated by both the Val158Met (rs4680) polymorphism of the Catechol-O-Methyltransferase (COMT) gene and the menstrual-cycle-related hormone fluctuations, each of which affects the subcortical/cortical dopamine metabolism. PPI can also be modulated by attention. The attentional modulation of PPI (AMPPI) is sensitive to psychoses. Whether the Val158Met polymorphism affects the AMPPI in female adults at different menstrual-cycle phases is unknown. This study examined whether AMPPI and/or PPI are affected by the Val158Met polymorphism in 177 younger-adult females whose menstrual cycles were mutually different across the menstruation, proliferative, or secretory phases. The AMPPI was evaluated by comparing PPI under the condition of the auditory precedence-effect-induced perceptual spatial separation between the prepulse stimulus and a masking noise (PPI_PSS) against that under the condition of the precedence-effect-induced perceptual spatial co-location (PPI_PSC). The results showed that both the menstrual cycle and the COMT Val158Met polymorphism affected both PPI_PSC and PPI_PSS, but not the AMPPI (difference between PPI_PSS and PPI_PSC). Moreover, throughout the menstrual cycle, both PPI_PSC and PPI_PSS decreased monotonously in Val/Val-carrier participants. However, the decreasing pattern was not overserved in either Met/Met-carrier or Met/Val-carrier participants. Thus, in healthy younger-adult females, PPI_PSC and PPI_PSS, but not the AMPPI, is vulnerable to changes of ovarian hormones, and the COMT Val158Met polymorphism also has a modulating effect on this menstrual-cycle-dependent PPI variation. In contrast, the AMPPI seems to be more steadily trait-based, less vulnerable to ovarian hormone fluctuations, and may be useful in assisting the diagnosis of schizophrenia in female adults.
...
PMID:Both Val158Met Polymorphism of Catechol-O-Methyltransferase Gene and Menstrual Cycle Affect Prepulse Inhibition but Not Attentional Modulation of Prepulse Inhibition in Younger-Adult Females. 3074 58

<< Previous 1 2 3 Next >>