Neurocognitive correlates of the COMT Val158Met polymorphism in chronic schizophrenia

Bilder, Robert M.; Volavka, Jan; Czobor, Pál; Malhotra, Anil K.; Kennedy, James L.; Ni, Xingqun; Goldman, Robert; Hoptman, Matthew J.; Sheitman, Brian; Lindenmayer, Jean Pierre; Citrome, Leslie; McEvoy, Joseph P.; Kunz, Michal; Chakos, Miranda; Cooper, Thomas B.; Lieberman, Jeffrey A.

doi:10.1016/s0006-3223(02)01416-6

Cited by 312 publications

(241 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: 72%

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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: 72%

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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“…To test this hypothesis, future studies might use tasks that enable more precise segregation of cognitive processes. However, positive associations with COMT genotype have now been reported across a very broad range of cognitive phenotypes 13,30,31,[38][39][40] as well as with structural 41,42 and functional 34,[43][44][45] brain measures. These wide-ranging reports suggest that COMT's effects on cognition may be relatively widespread.…”

Section: Discussionmentioning

confidence: 99%

“…8,30,31 The effect of genotype on WCST errors appeared larger in the non-Caucasian samples (d = 0.34; 95%CI 0.05, 0.63; P = 0.02) than in the Caucasian samples (d = 0.05, 95% CI -0.21, 0.31; P = 0.70); however, the between-groups comparison was underpowered owing to the small number of non-Caucasian samples, and failed to reach significance (Q = 2.14, d.f. = 1, P = 0.14).…”

Section: Effects Of Moderatorsmentioning

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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“…In schizophrenia patients, a diplotype that includes the Val allele was associated with greater global, positive, and negative symptoms and worse response to neuroleptic treatment, though the Val158Met single nucleotide polymorphism failed to independently show the association (Molero et al, 2007). In contrast, the Met allele has been associated with greater negative symptoms (Bilder et al, 2002), delusions (Han et al, 2006), depression (Herken and Erdal, 2001), frequency of hospitalizations (Herken and Erdal, 2001), and higher dosage of neuroleptic medication (Inada et al, 2003) in schizophrenia. Other studies have found no association between COMT and clinical phenotypes in schizophrenia patients (Numata et al, 2007;Strous et al, 2006;Tsai et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Differential association of the COMT Val158Met polymorphism with clinical phenotypes in schizophrenia and bipolar disorder

Goghari

Sponheim

2008

Schizophrenia Research

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Schizophrenia and bipolar disorder, although diagnostically separate, likely share elements of their genetic etiology. This study assessed whether COMT Val158Met polymorphism has shared or specific associations with clinical phenotypes evident in schizophrenia and bipolar disorder. Schizophrenia and bipolar patients completed a clinical assessment encompassing premorbid functioning and current and lifetime symptomatology. Multivariate analyses yielded a three-way interaction of diagnosis, COMT genotype, and lifetime symptomatology. The COMT Val allele was associated with greater positive symptomatology in schizophrenia, whereas Met homozygosity was associated with greater positive symptomatology in bipolar disorder. Findings support the COMT Val158Met polymorphism conferring vulnerability for different clinical phenotypes in schizophrenia and bipolar disorder. Lifetime symptomatology may be particularly useful in determining the relationship between genes and clinical phenotypes across mental disorders.

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Neurocognitive correlates of the COMT Val158Met polymorphism in chronic schizophrenia

Cited by 312 publications

References 21 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

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

Differential association of the COMT Val158Met polymorphism with clinical phenotypes in schizophrenia and bipolar disorder

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