Catechol-O-Methyltransferase Val-108/158-Met Gene Variants Associated With Performance on the Wisconsin Card Sorting Test

Joober, Ridha; Gauthier, Julie; Lal, Samarthji; Bloom, D. M.; Lalonde, Pierre; Rouleau, Guy; Benkelfat, Chawki; Labelle, Alain

doi:10.1001/archpsyc.59.7.662

Cited by 188 publications

(129 citation statements)

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“…Together, these data suggest that the Val/Met substitution affects the net enzyme activity of COMT without any change in its mRNA levels in the DLPFC. The presumed direct effect of COMT Val 108/158 Met on prefrontal dopamine metabolism is supported by previous data associating this functional polymorphism with observable dopamine-related prefrontal phenotypes, that is, working memory performance and prefrontal physiology (Bilder et al, 2002;Egan et al, 2001;Goldberg et al, in press;Joober et al, 2002;Malhotra et al, 2002;Rosa et al, 2002).…”

Section: Discussionmentioning

confidence: 67%

“…The relatively high levels of COMT and the low levels of dopamine transporters at synapses in the prefrontal cortex probably contribute to the relative functional specificity for COMT to prefrontal dopamine metabolism, in comparison to the striatum, where neuronal uptake by abundant dopamine transporters terminates the synaptic action of dopamine (Garris et al, 1993;Giros et al, 1996;Lewis et al, 2001;Mazei et al, 2002;Sesack et al, 1998;Wayment et al, 2001). Finally, we and other groups have demonstrated that a functional polymorphism of the COMT gene, a valine to methionine substitution at codon 108/158 generating a three-to fourfold less active COMT enzyme (Lachman et al, 1996;Lotta et al, 1995), affects dopamine-related prefrontal cortical function in humans (Bilder et al, 2002;Egan et al, 2001;Goldberg et al, in press;Joober et al, 2002;Malhotra et al, 2002;Mattay et al, 2003;Rosa et al, 2002).…”

Section: Introductionmentioning

confidence: 80%

“…Given that prefrontal pyramidal neurons in layer V project to the striatum and brainstem and appear to tonically inhibit striatal dopamine synthesis/release (Carlson et al, 1991;Carr and Sesack, 2000;Ferry et al, 2000;Kolachana et al, 1995;Pycock et al, 1980;Saunders et al, 1998), it is tempting to speculate that these various disease-related changes in layer V, that is, diminished dopamine innervation and increased COMT expression, synergistically contribute to a relative hypodopaminergic state at the level of prefrontal neuronal signaling and a hyperdopaminergic state at the level of striatal function, which has been implicated in the pathophysiology of schizophrenia (Bertolino et al, 2000;Grace, 2000;Laruelle et al, 1996;Meyer-Lindenberg et al, 2002;Weinberger, 1987;Weinberger et al, 1988). Finally, the combined effects of this laminar imbalance of dopamine innervation and COMT expression might explain, at least partly, recent evidence that the COMT Val 108/158 Met polymorphism has a greater impact upon working memory performance in patients with schizophrenia than in normal subjects (Joober et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

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Catechol O-Methyltransferase (COMT) mRNA Expression in the Dorsolateral Prefrontal Cortex of Patients with Schizophrenia

Matsumoto

Weickert

Beltaifa

et al. 2003

Neuropsychopharmacol

126

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Human prefrontal cortical neurons express catechol O-methyltransferase (COMT), an enzyme that inactivates the neurotransmitter dopamine. A functional polymorphism of COMT, Val 108/158 Met, affects prefrontal function, and the high-activity Val allele has been reported to be a genetic risk factor for schizophrenia. We used in situ hybridization histochemistry to measure mRNA levels of COMT in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia (N ¼ 14) and of normal controls (N ¼ 15). While the groups did not differ in terms of mean level of COMT mRNA, there was a significantly different laminar pattern of COMT mRNA expression in pyramidal neurons (F ¼ 2.68, df ¼ 4,108, Po0.04); patients with schizophrenia had relatively lower levels in the superficial (II/III) layers and higher levels in the intermediate/deep (IV/V) layers (Po0.01), while in controls, the expression was homogeneous across layers. Neither the mean level nor the laminar distribution of COMT mRNA was related to the Val 108/158 Met genotype, suggesting that the feedback regulation of mRNA level is not a compensation for the functional effect of the COMT polymorphism. The disease-related laminar difference of COMT expression may be involved in dysregulation of dopamine signaling circuits in the DLPFC of patients with schizophrenia.

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Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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Catechol O-Methyltransferase (COMT) mRNA Expression in the Dorsolateral Prefrontal Cortex of Patients with Schizophrenia

Matsumoto

Weickert

Beltaifa

et al. 2003

Neuropsychopharmacol

126

View full text Add to dashboard Cite

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“…Description of studies A total of 18 [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] studies published between 1996 and 2003 were identified by the search strategy, met the inclusion criteria and contributed to the meta-analysis. This included four studies not included in the original meta-analysis.…”

Section: Resultsmentioning

confidence: 99%

Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case–control studies

et al. 2005

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There is strong evidence for a genetic contribution to schizophrenia, but the contribution of individual candidate genes remains uncertain. We attempted to replicate a recent metaanalysis that reported an association of the catechol O-methyltransferase (COMT) Val allele with schizophrenia, and suggested that this effect may be moderated by ancestry. We included reports published subsequent to the original meta-analysis, and included a formal test of the moderating effect of ancestry in order to test whether the association operates differently in populations of European ancestry compared to populations of Asian ancestry. A corrected Pvalue for the 5% significance threshold was employed where appropriate, using Bonferroni's method, and studies that demonstrated departure from Hardy-Weinberg equilibrium among controls were excluded. When all studies were included in a meta-regression, there was evidence for a significant association of COMT Val allele frequency with schizophrenia case status and a significant main effect of ancestry. The interaction of COMT Val allele frequency and ancestry was also significant. However, when only studies that reported allele frequencies that did not depart significantly from Hardy-Weinberg equilibrium among controls were included, these effects were no longer significant. The results of our meta-analysis do not support an association between the COMT Val allele and schizophrenia case status, and do not support recent claims that this association may be moderated by ancestry. Twin studies provide convincing evidence that susceptibility to schizophrenia is attributable largely to genetic factors, 1,2 but progress in identifying the specific genetic variants responsible has been slow. One approach is to look at genes involved in the metabolism of dopamine, on the hypothesis that schizophrenia is primarily caused by dysregulation of dopaminergic neurotransmission in corticostriatal circuits. 3 This is one reason why the gene coding for catechol O-methyltransferase (COMT) has attracted considerable attention as a potential candidate, as it inactivates catechols at postsynaptic sites in the human brain. COMT contains a functional polymorphism, a single-nucleotide polymorphism at position 108/158 that results in a change from valine (val) to methionine (met). The amino-acid change affects function of the enzyme: val-COMT has significantly lower enzyme activity than met-COMT. 4,5 An association between the functional Val 158/108 Met polymorphism of the COMT gene and schizophrenia has been investigated in a number of studies, but with equivocal results. The small effect sizes of putative candidate genes such as COMT may, however, result in the absence of significant association in individual studies with modest sample sizes. This may explain the conflicting findings that have been reported in repeated studies of this association.A recent meta-analysis 6 of case-control and familybased studies of the association between the COMT gene Val 158/108 Met polymorphism and schizophrenia concluded...

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“…4,[7][8][9] However, other studies have failed to find an association between Met allele frequency and WCST performance. 10,11 These discrepancies may reflect differences in ethnicity or gender distribution between samples. [12][13][14] They might also reflect publication bias such as a tendency to publish positive but not negative findings from small, underpowered association studies.…”

Section: Introductionmentioning

confidence: 99%

Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls

et al. 2007

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The catechol-O-methyltransferase (COMT) Val 158 Met polymorphism is hypothesized to affect executive function in patient and control populations. Studies inconsistently report better performance on the Wisconsin Card Sort Test (WCST) in individuals with one or more Met alleles. We conducted a meta-analysis of studies published until August 2006 that reported WCST perseverative errors from healthy volunteers or patients with schizophrenia-spectrum disorders. Twelve studies met inclusion criteria (total n = 1910) providing 10 samples each of patients and controls. In healthy controls, individuals with the Met/Met genotype performed better than those with the Val/Val genotype (d = 0.29; 95% confidence interval (CI) 0.02-0.55; P = 0.03), but this was not supported in the patient sample (d = À0.07; 95% CI À0.40 to 0.26; P = 0.68). Post hoc analyses suggested that Val and Met alleles are codominant in their effects on cognition. Effect size was greater in studies published at an earlier date and may also be larger in non-Caucasian samples. Gender did not affect the results. There was no evidence of publication bias. We conclude that there is small but significant relationship between Val 158 Met genotype and executive function in healthy individuals but not in schizophrenia.

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Catechol-O-Methyltransferase Val-108/158-Met Gene Variants Associated With Performance on the Wisconsin Card Sorting Test

Cited by 188 publications

References 6 publications

Catechol O-Methyltransferase (COMT) mRNA Expression in the Dorsolateral Prefrontal Cortex of Patients with Schizophrenia

Catechol O-Methyltransferase (COMT) mRNA Expression in the Dorsolateral Prefrontal Cortex of Patients with Schizophrenia

Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case–control studies

Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls

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