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)

Understanding how risk genes cumulatively impair brain function in schizophrenia could provide critical insights into its pathophysiology. Working memory impairment in schizophrenia has been associated with abnormal dopamine signaling in the prefrontal cortex, which is likely under complex genetic control. The catechol-O-methyltransferase (COMT) 158Val --> Met polymorphism (rs4680), which affects the availability of prefrontal dopamine signaling, consistently stratifies prefrontal activation during working memory performance. However, the low-dopamine COMT 158Val allele does not confer increased risk for schizophrenia, and its effects on prefrontal function are not specific to the disorder. In the setting of other genetic variants influencing prefrontal dopamine signaling, COMT 158Val --> Met genotype may exert disease-specific effects. A second polymorphism, methylenetetrahydrofolate reductase (MTHFR) 677C --> T (rs1801133), has been associated with overall schizophrenia risk and executive function impairment in patients, and may influence dopamine signaling through mechanisms upstream of COMT effects. We found that the hypofunctional 677T variant was associated with decreased working memory load-dependent activation in the prefrontal and insular cortices in 79 schizophrenia patients, but not in 75 demographically matched healthy controls. Further, significant MTHFR x COMT genotype interactions were observed, which differed by diagnostic group: Reduced prefrontal activation was associated with the 677T and 158Val alleles in patients, but with 677C/C and 158Met/Met genotype in controls. These findings are consistent with epistatic effects of the COMT and MTHFR polymorphisms on prefrontal dopamine signaling, and suggest that in schizophrenia patients, the MTHFR 677T allele exacerbates prefrontal dopamine deficiency. The findings also suggest the importance of weighing COMT effects on prefrontal function within the context of MTHFR genotype.
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PMID:MTHFR 677C --> T genotype disrupts prefrontal function in schizophrenia through an interaction with COMT 158Val --> Met. 1898 38

The Val(158)Met polymorphism of the catechol-O-methyltransferase (COMT) gene has been associated with aspects of schizophrenia that are possibly related to the disorder's pathogenesis. The present study investigated the Val(158)Met polymorphism in relation to anhedonia--a construct central to negative schizotypy. Anhedonia and other schizotypal characteristics were assessed in relatives of patients with schizophrenia, relatives of patients with bipolar disorder, and nonpsychiatric controls using the Chapman schizotypy scales and the Schizotypal Personality Questionnaire. Compared with controls, relatives of individuals with schizophrenia had elevated scores on Chapman scales for social anhedonia and physical anhedonia, while relatives of patients with bipolar disorder exhibited only increased scores on the Social Anhedonia Scale. As a group, relatives of patients with schizophrenia who were homozygous for the val allele of the COMT polymorphism showed the highest elevations in self-reported social and physical anhedonia. Associations with the COMT polymorphism were absent in relatives of patients with bipolar disorder and control participants. Findings suggest that anhedonia is manifest in individuals who carry genetic liability for schizophrenia and is associated with the Val(158)Met polymorphism of the COMT gene.
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PMID:Anhedonia as a phenotype for the Val158Met COMT polymorphism in relatives of patients with schizophrenia. 1902 26

The functional Val158Met polymorphism (rs4680) located at the gene that codes for the catechol-O-methyltransferase (COMT) has been extensively investigated in schizophrenia although current data are still controversial. Since COMT activity is sexually dimorphic, we carried out two independent studies in homogeneous samples of male and female Spanish schizophrenic patients. In males, we found an association between the homozygous Val genotype and the disorder, which resembled a recessive model (P = 0.022; odds ratio [OR] = 1.67). This Val homozygotes overrepresentation is produced at the expense of the heterozygous individuals decrease, whilst the Met homozygotes showed no differences when compared controls and patients. As a consequence, the heterozygous genotype in this sample had a protective effect (P = 0.03; OR = 0.65) and a strong deviation from Hardy-Weinberg equilibrium in male cases was observed (P = 0.006). In addition, a 2-SNP haplotype analysis (rs4818-Val158Met) confirmed there is an overrepresentation of the different homozygous Val genotypes in the male schizophrenic sample. Regarding females, we did not find any statistically significant association between COMT SNP and schizophrenia. In the light of this we suggest that the Val158Met SNP is involved in risk and protective genotypes for the vulnerability to schizophrenia in Spanish male population.
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PMID:Gender-specific COMT Val158Met polymorphism association in Spanish schizophrenic patients. 1936 10

Human catechol O-methyltransferase (COMT) contains three common polymorphisms (A22S, A52T, and V108M), two of which (A22S and V108M) render the protein susceptible to deactivation by temperature or oxidation. We have performed multiple molecular dynamics simulations of the wild-type, A22S, A52T, and V108M COMT proteins to explore the structural consequences of these mutations. In total, we have amassed more than 1.4 micros of simulation time, representing the largest set of simulations detailing the effects of polymorphisms on a protein system to date. The A52T mutation had no significant effect on COMT structure in accord with experiment, thereby serving as a good negative control for the simulation set. Residues 22 (alpha2) and 108 (alpha5) interact with each other throughout the simulations and are located in a polymorphic hotspot approximately 20 A from the active site. Introduction of either the larger Ser (22) or Met (108) tightens this interaction, pulling alpha2 and alpha5 toward each other and away from the protein core. The V108M polymorphism rearranges active-site residues in alpha5, beta3, and alpha6, increasing the S-adenosylmethionine site solvent exposure. The A22S mutation reorients alpha2, moving critical catechol-binding residues away from the substrate-binding pocket. The A22S and V108M polymorphisms evolved independently in Northern European and Asian populations. While the decreased activities of both A22S and V108M COMT are associated with an increased risk for schizophrenia, the V108M-induced destabilization is also linked with improved cognitive function. These results suggest that polymorphisms within this hotspot may have evolved to regulate COMT activity and that heterozygosity for either mutation may be advantageous.
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PMID:A hotspot of inactivation: The A22S and V108M polymorphisms individually destabilize the active site structure of catechol O-methyltransferase. 1943 24

Dopamine has a crucial role in the modulation of neurocognitive function, and synaptic dopamine activity is normally regulated by the dopamine transporter (DAT) and catechol-O-methyltransferase (COMT). Perturbed dopamine function is a key pathophysiological feature of schizophrenia. Our objectives were (i) to examine epistasis between the DAT 3' UTR variable number of tandem repeats (VNTR) and COMT Val158Met polymorphisms on brain activation during executive function, and (ii) to then determine the extent to which such interaction is altered in schizophrenia. Regional brain response was measured by using blood-oxygen-level-dependent fMRI during an overt verbal fluency task in 85 subjects (44 healthy volunteers and 41 patients with DSM-IV schizophrenia), and inferences were estimated by using an ANOVA in SPM5. There was a significant COMT x DAT nonadditive interaction effect on activation in the left supramarginal gyrus, irrespective of diagnostic group (Z-score = 4.3; family-wise error (FWE) p = 0.03), and in healthy volunteers alone (Z-score = 4.7; FWEp = 0.006). In this region, relatively increased activation was detected only when COMT Met-158/Met-158 subjects also carried the 9-repeat DAT allele, or when, reversely, Val-158/Val-158 subjects carried the 10/10-repeat genotype. Also, there was a significant diagnosis x COMT x DAT nonadditive interaction in the right orbital gyrus (Z-score = 4.3; FWEp = 0.04), where, only within patients, greater activation was only associated with a 9-repeat allele and Val-158 conjunction, and with a 10-repeat and Met-158 conjunction (Z-score = 4.3; FWE p = 0.04). These data demonstrate that COMT and DAT genes interact nonadditively to modulate cortical function during executive processing, and also, that this effect is significantly altered in schizophrenia, which may reflect abnormal dopamine function in the disorder.
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PMID:Epistasis between the DAT 3' UTR VNTR and the COMT Val158Met SNP on cortical function in healthy subjects and patients with schizophrenia. 1966 77

Decreased levels of N-acetylaspartate (NAA) and brain-derived neurotrophic factor (BDNF) in the anterior cingulate cortex (ACC) have been linked to neuronal loss and psychiatric disorders like schizophrenia and bipolar disorder. We previously found that BDNF serum concentration was predicted by the concentration of NAA in the ACC, indicating that neuronal integrity and vitality of a cortical region like the ACC, as reflected by a high concentration of NAA, might be related to high concentrations of BDNF in serum. Moreover, our recent finding that Val66Met genotype appears to predict the BDNF serum level in healthy human volunteers suggests the Met allele to be connected to higher concentrations of BDNF in serum. We examined absolute NAA concentrations in the ACC and hippocampus of 40 male and 42 female healthy volunteers (age: 33.3+/-9 years). We found NAA in the ACC to be significantly increased in Met carriers (F=5.2, df=1, p=0.025). On the other hand, the concentration of creatine+phosphocreatine in the hippocampus was significantly decreased in Met carriers. We hypothesize that higher NAA levels in the ACC might contribute to the protection of Met allele carriers against major psychiatric disorders as schizophrenia and bipolar disorder.
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PMID:Met carriers of BDNF Val66Met genotype show increased N-acetylaspartate concentration in the anterior cingulate cortex. 1968 59

A functional polymorphism of the brain-derived neurotrophic factor (BDNF) gene (Val66Met) has been associated with the risk for schizophrenia and volume differences in the hippocampus. However, little is known about the association between progressive brain volume change in schizophrenia and BDNF genotype. The aim of this study was to investigate the relationship between hippocampal volume change in patients with schizophrenia and healthy control subjects and BDNF genotype. Two structural magnetic resonance imaging brain scans were acquired of 68 patients with schizophrenia and 83 healthy subjects with an interval of approximately 5 yrs. Hippocampal volume change was measured and related to BDNF genotype in patients and healthy controls. BDNF genotype was not associated with hippocampal volume change over time in patients or healthy controls, nor could we replicate earlier findings on smaller hippocampal volume in Met-carriers. However, we did find a genotype-by-diagnosis interaction at baseline demonstrating smaller hippocampal volumes in patients homozygous for the Val-allele relative to healthy Val-homozygotes. In addition, irrespective of genotype, patients showed smaller hippocampal volumes compared with healthy controls at baseline. In summary, our results suggest that the BDNF Val66Met polymorphism is not associated with hippocampal volume change over time. Nevertheless, our findings may support the possibility that BDNF affects brain morphology differently in schizophrenia patients and healthy subjects.
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PMID:Effects of brain-derived neurotrophic factor Val66Met polymorphism on hippocampal volume change in schizophrenia. 1971 65

Velo-cardio-facial syndrome (VCFS) is caused by a micro-deletion of over 40 genes at the q11.2 locus of chromosome 22 and is a risk factor for the development of schizophrenia and other psychiatric disorders. COMT, one of the genes located in the deleted region, has been considered as a major candidate gene for genetic susceptibility in psychiatric diseases. Its functional polymorphism Val108/158Met has been shown to affect prefrontal function and working memory and has been associated with emotional dysregulation. We utilized a functional magnetic resonance imaging (fMRI) event-related paradigm to asses COMT genotype and gender-moderated effects on the neural activation that are elicited by viewing emotionally salient images charged with pleasant, unpleasant, and neutral content. Since estrogen down-regulates COMT activity resulting in lower COMT activity in women than men, we hypothesized an allele-by-gender interaction effect on neural activation. Participants included 43 VCFS individuals (Val/male=9, Val/female=17, Met/male=9, Met/female=8). We observed a gender effect on processing positive emotions, in that girls activated the cingulate gyrus more than boys did. We further observed a significant gender-by-allele interaction effect on neural function specific to the frontal lobe during the processing of pleasant stimuli, and specific to limbic regions during the processing of unpleasant stimuli. Our results suggest that in VCFS, the effect of the COMT Val108/158Met polymorphism is moderated by gender during the processing of emotional stimuli and could contribute to the understanding of the way in which this COMT polymorphism affects vulnerability to neuropsychiatric disorders.
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PMID:The effects of gender and catechol O-methyltransferase (COMT) Val108/158Met polymorphism on emotion regulation in velo-cardio-facial syndrome (22q11.2 deletion syndrome): An fMRI study. 2012 31

Several studies have reported associations between catechol-O-methyltransferase (COMT) gene Val158Met polymorphism and P300 event-related potentials in schizophrenic patients. But there has been no research to study the association between the P300 component and the Val158Met polymorphism in Chinese Han schizophrenia patients. Therefore, the present article was aimed at investigating the relationship of the Val158Met polymorphism with P300 in Chinese schizophrenic patients. The Val158Met polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 287 schizophrenia patients and 84 healthy control subjects. P300 recordings were obtained in a subsample. A significant difference was not observed between the patients and control subjects in the genotype distributions and allele frequencies. P300 amplitude in schizophrenia patients was significantly lower than that of controls. The P300 latency in schizophrenia patients was also significantly longer than that of controls. The P300 latency of Met homozygotes was significantly shorter than that of Val/Met and of Val/Val carriers at Cz and Pz. The latency of Val/Met carriers was significantly shorter than that of Val/Val carriers at Pz. The results did not suggest an association between the polymorphism in the COMT gene and susceptibility to schizophrenia in the Chinese Han population. However, the COMT Val158Met polymorphism might be a susceptibility variant for P300 abnormality in Chinese Han schizophrenia.
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PMID:Association study of catechol-O-methyltransferase (COMT) gene Val158Met polymorphism with auditory P300 in Chinese Han patients with schizophrenia. 2048 73

Negative symptoms commonly seen in chronic schizophrenia are related to prefrontal hypodopaminergia. Dysfunction of the catechol-O-methyltransferase (COMT) gene has long been thought to confer susceptibility to schizophrenia because of its catalytic activity for dopamine degradation. The present study is an attempt to perform a quantitative trait test for genetic association between the COMT gene and negative symptoms in a Chinese population. A total of 290 unrelated individuals with schizophrenia patients were recruited and their symptoms were assessed through the Positive and Negative Syndrome Scale (PANSS). The quantitative trait test was performed by the UNPHASED programme to examine the correlation between the scored negative symptoms and the coding single nucleotide polymorphisms (SNPs) present in the COMT gene. The rs4633-rs4680 haplotype showed significant association with the overall score of negative symptoms, and four individual negative symptoms, including blunted affect, emotional withdrawal, poor rapport and passive/apathetic social withdrawal. SNP rs4680 (Val/Met) showed significant association with blunted affect. The present finding suggests that the COMT gene may a etiologically contribute to the severity of negative symptoms in schizophrenia, but its precise mechanism needs further investigating.
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PMID:Analysis of association between the catechol-O-methyltransferase (COMT) gene and negative symptoms in chronic schizophrenia. 2048 79


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