Suicidal behavior in patients with schizophrenia is related to COMT polymorphism

Nolan, Karen; Volavka, Jan; Czobor, Pál; Cseh, Ágnes; Lachman, Herbert M.; Saito, Takuya; Tiihonen, Jari; Putkonen, Anu; Hallikainen, Tero; Kotilainen, Irma; Räsänen, Pirkko; Isohanni, Matti; Järvelin, Marjo‐Riitta; Karvonen, Matti K.

doi:10.1097/00041444-200010030-00003

Cited by 97 publications

(72 citation statements)

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“…The low activity of COMT mutant may associate with its poor thermostability at physiological temperature and not with its differ- ent kinetic properties. Because the endogenous substrates of COMT include catecholamine neurotransmitters and catechol estrogens, it has been suggested that the COMT V108M polymorphism is related to increased risk of psychotic disorders and breast cancer (43,44). This SNP in the COMT gene has also been readily associated with an increased risk of lung cancer (45,46).…”

Section: Discussionmentioning

confidence: 99%

Detoxication of Structurally Diverse Polycyclic Aromatic Hydrocarbon (PAH) o-Quinones by Human Recombinant Catechol-O-methyltransferase (COMT) via O-Methylation of PAH Catechols

Zhang

Jin

Chen

et al. 2011

Journal of Biological Chemistry

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Polycyclic aromatic hydrocarbons (PAH)2 are ubiquitous environmental pollutants that are products of fossil fuel combustion and found in tobacco smoke and are suspect lung carcinogens (1, 2). PAH are considered to be procarcinogens and require metabolic activation to elicit their deleterious effects. Benzo[a]pyrene (B[a]P) is a representative PAH and widely used to study the metabolic activation of PAH (3, 4).There are three major pathways for the activation of B[a]P. In the first pathway, P450 peroxidases catalyze the generation of radical cations (5) PAH o-quinones, produced by AKRs are electrophilic and highly reactive to endogenous nucleophiles. PAH o-quinones can readily form conjugates with cellular thiols to yield and GSH conjugates, leading to their elimination (12,13). PAH o-quinones can also react with DNA to form both stable and depurinating adducts, which may result in mutagenesis (14 -16). PAH o-quinones are also able to undergo nonenzymatic/enzymatic reduction to reform catechols at the expense of NADPH and establish futile redox cycles that amplify the generation of reactive oxygen species (ROS). ROS can cause DNA damage resulting in the formation of 7,8-dihydro-8-oxo-2Ј-deoxyguanosine (8-oxo-dGuo) lesions and can contribute to G to T transversions in ras and p53 (17,18). PAH o-quinones were found to be more mutagenic than diol-epoxides in an in vitro p53 mutagenesis assay provided they redox-cycled and a linear correlation was observed

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Section: Discussionmentioning

confidence: 99%

Detoxication of Structurally Diverse Polycyclic Aromatic Hydrocarbon (PAH) o-Quinones by Human Recombinant Catechol-O-methyltransferase (COMT) via O-Methylation of PAH Catechols

Zhang

Jin

Chen

et al. 2011

Journal of Biological Chemistry

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“…The methionine allele has been associated with aggression, suicide, worse prognosis and greater positive symptom severity in schizophrenia. 91,[96][97][98][99][100] Egan et al's finding of an association between the valine allele and poor WCST performance has generated renewed interest in this area of investigation, especially with regard to the effects of COMT in mediating cognition in schizophrenia. 52 This finding has been replicated in part by Joober et al, who found that genotype effects on WCST performance among schizophrenia patients was at a trend level of significance, and was nonsignificant in healthy volunteers.…”

Section: Discussionmentioning

confidence: 99%

Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow

et al. 2005

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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.

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“…Few have been statistically convincing, eg by demonstrating a sex-by-genotype interaction (eg Kates et al, 2006;Lang et al, 2007). Many studies simply found an association that reached significance in one sex but not in the other, without demonstrating an interaction between sex and genotype (eg Enoch et al, 2006), an approach further compromised by the fact that the nonsignificant sex often had a smaller sample size and less power than did the significant one (eg Nolan et al, 2000;Ono et al, 2004;Stein et al, 2005). Other studies discuss sex-related effects despite reporting a nonsignificant sex-by-genotype interaction (eg Olsson et al, 2005;Zinkstok et al, 2006), while a final category of studies, not included in the table, provide only trend-level findings of sex-related effects of COMT genotype (eg Eley et al, 2003;Sazci et al, 2004;Woo et al, 2004).…”

Section: Comt and Sexual Dimorphismsmentioning

confidence: 99%

Catechol-O-Methyltransferase (COMT): A Gene Contributing to Sex Differences in Brain Function, and to Sexual Dimorphism in the Predisposition to Psychiatric Disorders

Harrison

Tunbridge

2007

Neuropsychopharmacol

275

217

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Sex differences in the genetic epidemiology and clinical features of psychiatric disorders are well recognized, but the individual genes contributing to these effects have rarely been identified. Catechol-O-methyltransferase (COMT), which metabolizes catechol compounds, notably dopamine, is a leading candidate. COMT enzyme activity, and the neurochemistry and behavior of COMT null mice, are both markedly sexually dimorphic. Genetic associations between COMT and various psychiatric phenotypes frequently show differences between men and women. Many of these differences are unconfirmed or minor, but some appear to be of reasonable robustness and magnitude; eg the functional Val 158 Met polymorphism in COMT is associated with obsessive-compulsive disorder in men, with anxiety phenotypes in women, and has a greater impact on cognitive function in boys than girls. Sex-specific effects of COMT are usually attributed to transcriptional regulation by estrogens; however, additional mechanisms are likely to be at least as important. Here we review the evidence for a sexually dimorphic influence of COMT upon psychiatric phenotypes, and discuss its potential basis. We conclude that despite the evidence being incomplete, and lacking a unifying explanation, there are accumulating and in places compelling data showing that COMT differentially impacts on brain function and dysfunction in men and women. Since sex differences in the genetic architecture of quantitative traits are the rule not the exception, we anticipate that additional evidence will emerge for sexual dimorphisms, not only in COMT but also in many other autosomal genes.

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Suicidal behavior in patients with schizophrenia is related to COMT polymorphism

Cited by 97 publications

References 0 publications

Detoxication of Structurally Diverse Polycyclic Aromatic Hydrocarbon (PAH) o-Quinones by Human Recombinant Catechol-O-methyltransferase (COMT) via O-Methylation of PAH Catechols

Detoxication of Structurally Diverse Polycyclic Aromatic Hydrocarbon (PAH) o-Quinones by Human Recombinant Catechol-O-methyltransferase (COMT) via O-Methylation of PAH Catechols

Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow

Catechol-O-Methyltransferase (COMT): A Gene Contributing to Sex Differences in Brain Function, and to Sexual Dimorphism in the Predisposition to Psychiatric Disorders

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