An attractive candidate gene for schizophrenia is the catechol-O-methyltransferase (COMT) gene, which is a modulator of dorsolateral prefrontal cortical function.
The disease-related laminar difference of COMT expression may be involved in dysregulation of dopamine signaling circuits in the DLPFC of patients with schizophrenia.
Similar to our previously reported findings, a statistically significant association was found between aggressive behavior in SZ and the COMT 158 polymorphism; mean LHA scores were higher in subjects homozygous for 158Met, the low enzyme activity COMT variant (F(2,105) = 5.616, P = 0.005).
Catechol O-methyltransferase Val158Met polymorphism in schizophrenia: differential effects of Val and Met alleles on cognitive stability and flexibility.
We genotyped the valine/methionine polymorphism of codon 108/158 in the catechol-O-methyltransferase (COMT) gene, the 30-bp repeat polymorphism in the promoter of the monoamine oxidase A (MAOA) gene, and the A/G polymorphism in intron 13 of the monoamine oxidase B (MAOB) gene in 206 Japanese patients with schizophrenia.
These results support the hypothesis that the COMT Val(158)Met polymorphism influences executive functions in schizophrenia and the neuromotor performance in the deficit subtype only.
(3) The COMT genotype is related to performance on prefrontal cortex-dependent tasks and may contribute to the deficit in prefrontal-dependent memory processes in SPD as it does in schizophrenia.
These findings suggest that MB-COMT over-expression due to promoter hypomethylation and/or hyperactive allele of COMT may increase dopamine degradation in the frontal lobe providing a molecular basis for the shared symptoms of schizophrenia and bipolar disorder.
The COMT Val allele is associated with an increased risk of schizophrenia in subjects at increased familial risk, in whom it has demonstrable effects on prefrontal brain structure and function.
We were able to detect statistical interaction between COMT and polymorphisms in candidate genes for schizophrenia, many of which had no significant main effect.
The authors tested for an association between a COMT haplotype and schizophrenia-spectrum disorders and for an eventual influence of a specific COMT genotype in the clinical outcome and in the response to treatment.
These findings extend putative brain dopaminergic and glutamatergic relationships indexed by COMT and GRM3 to a systems-level interaction in human cortical circuits implicated in working memory dysfunction such as in schizophrenia.
The C957T polymorphism in the dopamine D2 receptor (DRD2) gene and the Val158Met polymorphism in the Catechol-O-Methyl-Transferase (COMT) gene affect dopamine transmission and have been found to be associated with schizophrenia.
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 present work examines evidence for the role of COMT in schizophrenia pathogenesis, and associations between COMT and cognitive and behavioral correlates of schizophrenia and related disorders.