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Catechol-O-methyltransferase polymorphisms and some implications for cognitive therapeutics.

ABSTRACT: Catechol-O-methyltransferase (COMT) is a gene involved in the degradation of dopamine and may both increase susceptibility to develop schizophrenia and affect neuronal functions involved in working memory. A common variant of the COMT gene (val(108/158)met) has been widely reported to affect pre-frontally mediated working memory function, with the high-activity val allele associated with poorest performance across a number of tests sensitive to updating and target detection. Pharmacological manipulations of COMT val(108/158)met also have reliably produced alterations in cognitive function, in line with an inverted U function of prefrontal dopamine signaling. Furthermore, there is accumulating evidence that COMT val(108/158)met genotype may influence the cognitive response to antipsychotic treatment in schizophrenia patients, with met allele load predicting the greatest improvement with medication. Recently, other single-nucleotide polymorphisms (SNPs) across the COMT gene have emerged as possible risk alleles for schizophrenia, although little is known about whether they affect prefrontal cognition in a manner similar to COMT val(108/158)met. Preliminary evidence suggests a modest role for a SNP in the 5' region of the gene on select tests of attention and target detection. Haplotype effects also may account for a modest percentage of the variance in test performance, and are an important area for future study.

SUBMITTER: Diaz-Asper CM

PROVIDER: S-EPMC3593358 | biostudies-other | 2006 Jan

REPOSITORIES: biostudies-other

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Catechol-O-methyltransferase polymorphisms and some implications for cognitive therapeutics.

Diaz-Asper Catherine M CM Weinberger Daniel R DR Goldberg Terry E TE

NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics 20060101 1

Catechol-O-methyltransferase (COMT) is a gene involved in the degradation of dopamine and may both increase susceptibility to develop schizophrenia and affect neuronal functions involved in working memory. A common variant of the COMT gene (val(108/158)met) has been widely reported to affect pre-frontally mediated working memory function, with the high-activity val allele associated with poorest performance across a number of tests sensitive to updating and target detection. Pharmacological mani ...[more]

PMID: 16490416

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Project description:Catechol-O-methyltransferase (COMT), a key enzyme in catecholamine metabolism, is implicated in cardiovascular, sympathetic, and endocrine pathways. This study aimed to confirm preliminary association of COMT genetic variation with incident cardiovascular disease (CVD). It further aimed to evaluate whether aspirin, a commonly used CVD prevention agent, modified the potential association of COMT with incident CVD.We examined COMT polymorphism rs4680 (MAF [minor allele frequency], 0.47), encoding a nonsynonymous methionine-to-valine substitution, in the Women's Genome Health Study (WGHS), a large population-based cohort of women with randomized allocation to aspirin or vitamin E when compared with placebo and 10-year follow-up. Rs4680 effects were confirmed with COMT polymorphism rs4818 and also examined in Coronary ARtery DIsease Genome-wide Replication and Meta-analysis/The Coronary Artery Disease Genetics Consortium, consortia for genome-wide association studies of coronary artery disease. Among WGHS women allocated to placebo (135 events/n=5811), the rs4680 valine allele was protective against incident CVD relative to the methionine (hazard ratio [HR; 95% confidence interval {CI}], 0.66 [0.51-0.84]; P=0.0007); an association also observed in Coronary ARtery DIsease Genome-wide Replication and Meta-analysis and The Coronary Artery Disease Genetics Consortium (combined P=2.4×10(-5)). In the WGHS, the rs4680 association was abolished by randomized allocation to aspirin, such that valine/valine women experienced higher CVD rates with aspirin allocation when compared with placebo (HR [95% CI], 1.85 [1.05-3.25]; P=0.033), whereas methionine/methionine women experienced lower rates (HR [95% CI], 0.60 [0.39-0.93]; P=0.023). Allocation to vitamin E also conferred higher but nonsignificant CVD rates on valine/valine (HR [95% CI], 1.50 [0.83-2.70]; P=0.180) when compared with significantly lower rates on methionine/methionine (HR [95% CI], 0.53 [0.34-0.84]; P=0.006) women. Rs4818 results were similar.Common COMT polymorphisms were associated with incident CVD, and this association was modified by randomized allocation to aspirin or vitamin E. Replication of these findings is required.

Dataset Information

Catechol-O-methyltransferase polymorphisms and some implications for cognitive therapeutics.

Publications

Catechol-O-methyltransferase polymorphisms and some implications for cognitive therapeutics.

Similar Datasets

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