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)

Amino acids play a role in neurotransmitter availability in the central nervous system, in that e.g. the synthesis of brain serotonin depends on the concentration of its precursor tryptophan. Disturbances in amino acid metabolism have been implicated in the pathophysiology of schizophrenia.In the present study the effect of a 14 week treatment with atypical antipsychotics on the plasma levels of amino acids was investigated in patients with schizophrenia and compared to normal controls.Non-responders (< or =20% decrease in BPRS at endpoint) demonstrated lower baseline values of methionine as compared to good responders (> or =50% decrease in BPRS at endpoint; p<.05) and controls (p<.01). The ratio between tryptophan and the other large neutral amino acids (Trp/LNAA ratio) in poor-responders (<40%) decreased during treatment as compared to responders (> or =40%; p<.05). It is concluded that poor or non-response to atypical antipsychotics may be associated with an impaired synthesis of serotonin in the central nervous system.
...
PMID:Amino acids in schizophrenia: evidence for lower tryptophan availability during treatment with atypical antipsychotics? 1537 27

Catechol-O-methyltransferase (COMT) is a key enzyme in the elimination of dopamine in the prefrontal cortex of the human brain. Genetic variation in the COMT gene (MIM 116790) has been associated with altered prefrontal cortex function and higher risk for schizophrenia, but the specific alleles and their functional implications have been controversial. We analyzed the effects of several single-nucleotide polymorphisms (SNPs) within COMT on mRNA expression levels (using reverse-transcriptase polymerase chain reaction analysis), protein levels (using Western blot analysis), and enzyme activity (using catechol methylation) in a large sample (n = 108) of postmortem human prefrontal cortex tissue, which predominantly expresses the -membrane-bound isoform. A common coding SNP, Val158Met (rs4680), significantly affected protein abundance and enzyme activity but not mRNA expression levels, suggesting that differences in protein integrity account for the difference in enzyme activity between alleles. A SNP in intron 1 (rs737865) and a SNP in the 3' flanking region (rs165599)--both of which have been reported to contribute to allelic expression differences and to be associated with schizophrenia as part of a haplotype with Val--had no effect on mRNA expression levels, protein immunoreactivity, or enzyme activity. In lymphocytes from 47 subjects, we confirmed a similar effect on enzyme activity in samples with the Val/Met genotype but no effect in samples with the intron 1 or 3' SNPs. Separate analyses revealed that the subject's sex, as well as the presence of a SNP in the P2 promoter region (rs2097603), had small effects on COMT enzyme activity. Using site-directed mutagenesis of mouse COMT cDNA, followed by in vitro translation, we found that the conversion of Leu at the homologous position into Met or Val progressively and significantly diminished enzyme activity. Thus, although we cannot exclude a more complex genetic basis for functional effects of COMT, Val is a predominant factor that determines higher COMT activity in the prefrontal cortex, which presumably leads to lower synaptic dopamine levels and relatively deleterious prefrontal function.
...
PMID:Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. 1545 4

Several lines of evidence have implicated the catechol-O-methyltransferase (COMT) gene as a candidate for schizophrenia (SZ) susceptibility, not only because it encodes a key dopamine catabolic enzyme but also because it maps to the velocardiofacial syndrome region of chromosome 22q11 which has long been associated with SZ predisposition. The interest in COMT as a candidate SZ risk factor has led to numerous case-control and family-based studies, with the majority placing emphasis on examining a functional Val/Met polymorphism within this enzyme. Unfortunately, these studies have continually produced conflicting results. To assess the genetic contribution of other COMT variants to SZ susceptibility, we investigated three single-nucleotide polymorphisms (SNPs) (rs737865, rs4633, rs165599) in addition to the Val/Met variant (rs4680) in a highly selected sample of Australian Caucasian families containing 107 patients with SZ. The Val/Met and rs4633 variants showed nominally significant associations with SZ (P<0.05), although neither of the individual SNPs remained significant after adjusting for multiple testing (most significant P=0.1174). However, haplotype analyses showed strong evidence of an association; the most significant being the three-marker haplotype rs737865-rs4680-rs165599 (global P=0.0022), which spans more than 26 kb. Importantly, conditional analyses indicated the presence of two separate and interacting effects within this haplotype, irrespective of gender. In addition, our results indicate the Val/Met polymorphism is not disease-causing and is simply in strong linkage disequilibrium with a causative effect, which interacts with another as yet unidentified variant approximately 20 kb away. These results may help explain the inconsistent results reported on the Val/Met polymorphism and have important implications for future investigations into the role of COMT in SZ susceptibility.
...
PMID:Separate and interacting effects within the catechol-O-methyltransferase (COMT) are associated with schizophrenia. 1550 38

In a multicenter study involving 217 subjects of European ancestry [106 patients with schizophrenia and 111 healthy subjects], we tested the hypothesis that the catechol-O-methyl transferase (COMT) Val(158)Met and/or the brain-derived neurotrophic factor (BDNF) C(270)T gene polymorphisms are associated with schizophrenia. The COMT and BDNF genotype and their allele distribution did not differ between patients with schizophrenia and healthy comparison subjects. These results do not support the hypothesis that the COMT Val(158)Met or BDNF C(270)T gene polymorphisms are associated with liability to schizophrenia.
...
PMID:COMT Val(158)Met and BDNF C(270)T polymorphisms in schizophrenia: a case-control study. 1766 28

Schizophrenia is a severe psychiatric disease with a strong genetic component. Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of schizophrenia and bipolar (BP) disorders. The present study has examined two polymorphisms in linkage disequilibrium in the BDNF gene, which have been variously reported as associated with schizophrenia and BP. In our study, 321 probands with a primary diagnosis of schizophrenia or schizoaffective disorder, and 263 with a diagnosis of bipolar affective disorder, were examined together with 350 controls drawn from the same geographical region of Scotland. The val66met single-nucleotide polymorphism (SNP) showed significant (P = 0.005) association for valine (allele G) with schizophrenia but not bipolar disorder. Haplotype analysis of val/met SNP and a dinucleotide repeat polymorphism in the putative promoter region revealed highly significant (P < 1 x 10(-8)) under-representation of the methionine or met-1 haplotype in the schizophrenic but not the BP population. We conclude that, although the val66met polymorphism has been reported to alter gene function, the risk may depend upon the haplotypic background on which the val/met variant is carried.
...
PMID:BDNF gene is a risk factor for schizophrenia in a Scottish population. 1563 Apr 10

The catechol-o-methyltransferase (COMT) gene on chromosome 22q11 has been considered a strong candidate gene for schizophrenia (SZ) susceptibility. A functional Val/Met polymorphism in exon 4, with potential to affect COMT activity has been implicated in SZ, but the results remain inconclusive. We hypothesized that the association of COMT gene with SZ is not strictly a genetic alteration but could involve DNA methylation, as an epigenetic alteration. Thus, we chose to examine the cytosine DNA methylation profile of the human COMT promoter regions, which partially overlaps with the MB-COMT coding region and covers a total of 56 cytosines. Our analysis of 31 brain regions and 51 individual blood samples suggests that the cytosine methylation in his region is restricted to the CpG dinucleotides only. Also, the methylation pattern is nearly identical in the brain and blood with few exceptions. One cytosine (#27) is partially methylated in 5 brain regions and another cytosine (#23) is partially methylated in 81 of 82 samples studied. The exception being the blood DNA from a single SZ patient with prominent extreme negative symptoms, which was completely methylated. Interestingly, there was no difference in methylation at these sites in the blood DNA from three pairs of monozygotic twins discordant for SZ. The results support the use of blood DNA in methylation studies and rule out S-COMT promoter methylation as a common cause of SZ. The unique observation of a completely methylated cytosine 23 in one patient with SZ may have the potential to affect COMT mRNA transcription and gene activity, but remains to be evaluated.
...
PMID:Site-specific cytosine methylation in S-COMT promoter in 31 brain regions with implications for studies involving schizophrenia. 1563 61

Catechol-O-methyltransferase (COMT) inactivates circulating catechol hormones, catechol neurotransmitters, and xenobiotic catecholamines by methylating their catechol moieties. The COMT gene has been suggested as a candidate gene for schizophrenia through linkage analyses and molecular studies of velo-cardio-facial syndrome. A coding polymorphism of the COMT gene at codon 108/158 (soluble/membrane-bound form) causing a valine to methionine substitution has been shown to influence enzyme activity, but its association with schizophrenia is inconclusive. We have screened 17 known polymorphisms of the COMT gene in 320 Korean schizophrenic patients and 379 controls to determine whether there is a positive association with a nonsynonymous single-nucleotide polymorphism (rs6267) at codon 22/72 (soluble/membrane-bound form) causing an alanine-to-serine (Ala/Ser) substitution. With the Ala/Ala genotype as a reference group, the combined genotype (Ala/Ser and Ser/Ser)-specific adjusted odds ratio was 1.82 (95% CI = 1.19-2.76; P = 0.005), suggesting the Ser allele as a risk allele for schizophrenia. However, the Val/Met polymorphism was not associated with an increased risk of schizophrenia in Koreans (OR = 0.88, 95% CI = 0.64-1.21; P = 0.43). The Ala72Ser substitution was correlated with reduced COMT enzyme activity. Our results support previous reports that the COMT haplotype implicated in schizophrenia is associated with low COMT expression.
...
PMID:Association of Ala72Ser polymorphism with COMT enzyme activity and the risk of schizophrenia in Koreans. 1564 82

The catechol-O-methyl transferase (COMT) gene is considered a leading schizophrenia candidate gene. Although its role in increasing schizophrenia susceptibility has been conflicting, recent studies suggest the valine allele may contribute to poor cognitive function in schizophrenia. V(158)M COMT genotype was obtained on 159 schizophrenia patients and 84 healthy controls. The effects of COMT genotype on four measures of working memory/executive functions (Wisconsin Card Sorting, digit span backward, Trail Making and N-back tests) and on MRI frontal brain volumes were examined. Genotype distributions were not significantly different between patients and controls. There were no significant genotype or genotype-by-group effects on any working memory/executive function measures. No genotype or genotype-by-diagnosis interaction effects were found with MRI frontal lobe volumes. Randomization analyses using [(15)O]H(2)O positron emission tomography (PET) cerebral blood flow data found Val/Val patients had higher frontal lobe activation than Met/Met patients while performing the one-back task. Overall, these findings do not support a major role for COMT in increasing susceptibility for schizophrenia or in mediating frontal lobe function. Age-related changes and phenotypic heterogeneity of schizophrenia may influence the complex relationships between COMT genotype and cognition.
...
PMID:Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow. 1566 20

The polygenic nature of complex psychiatric disorders suggests a common pathway that may be involved in the down-regulation of multiple genes through an epigenetic mechanism. To investigate the role of methylation in down-regulating the expression of mRNAs that may be associated with the schizophrenia phenotype, we have adopted a cell-culture model amenable to this line of investigation. We have administered methionine (2 mM) to primary cultures of cortical neurons prepared from embryonic day 16 mice and show that this treatment down-regulated reelin and glutamic acid decarboxylase 67 (GAD67) mRNA expression but not that corresponding to neuron-specific enolase mRNA. Moreover, methionine increased methylation of the reelin promoter, suggesting a possible mechanism for the observed change. These cultures contain a mixed population of neurons and glia. Approximately 83% of the neurons are GABAergic based on GAD immunoreactivity, and these neurons coexpress high levels of reelin and DNA methyltransferase (Dnmt) 1 immunoreactivity. To examine whether Dnmt1 regulates reelin gene expression, we used an antisense approach to reduce (knock down) Dnmt1 expression. The reduced Dnmt1 mRNA and protein were accompanied by increased reelin mRNA expression. More importantly, the Dnmt1 knockdown blocked the methionine-induced reelin and GAD67 mRNA down-regulation. These data support the hypothesis that the reduced amounts of reelin and GAD67 mRNAs documented in postmortem schizophrenia brain may be the consequence of a Dnmt1-mediated hypermethylation of the corresponding promoters.
...
PMID:DNA methyltransferase 1 regulates reelin mRNA expression in mouse primary cortical cultures. 1567 Nov 76

Psychotic symptoms in subjects with Alzheimer disease (AD with psychosis, AD+P) define a phenotype characterized by greater cognitive burden than in AD without psychosis. We have proposed that genes of small effect may contribute to the risk for expression of psychosis in multiple disorders, including AD. Recently, sex-differential association of a three-locus haplotype, including a G-->A transition at codon 108/158 of catechol-O-methyltransferase (COMT) resulting in a Val-->Met substitution, has been reported to confer an increased risk for schizophrenia. The main objective of the study was to determine if COMT genetic variation is associated with risk of psychosis in AD, and included a case-control study of 373 individuals diagnosed with AD with, or without, psychosis. All subjects were characterized for alleles at the three loci associated with schizophrenia, RS737865, COMT G-->A 108/158 (RS4680), and RS165599, and for a C/T transition adjacent to an estrogen response element (ERE6) in the COMT P2 promoter region. Both single locus and haplotype tests of association were conducted. Logit models were used to examine independent and interacting effects of alleles at the associated loci. All analyses were stratified by sex. In female subjects, RS4680 demonstrated a modest association with AD+P; RS737865 demonstrated a trend towards an association. There was a highly significant association of AD+P with the four-locus haplotype, which resulted from additive effects of alleles at RS4680 and ERE6 (or RS737865, as this locus was in almost absolute linkage disequilibrium (LD) with ERE6). In male subjects, no single locus test was significant, but there remained a strong association between AD+P and the four-locus haplotype. This association appeared to result from interaction of the ERE6/RS737865, RS4680, and RS165599 loci. Genetic variation in COMT is associated with AD+P, and thus appears to contribute to psychosis risk across disorders. Sex-differential associations of COMT with psychosis may result from variation at, or in LD with, ERE6. Examination of variation at ERE6 in subjects with schizophrenia, and further examination of the independent and additive effects of variations in COMT on gene expression, is warranted.
...
PMID:Catechol-O-methyltransferase haplotypes are associated with psychosis in Alzheimer disease. 1602 41

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>