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 prefrontally 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.

DRD3, but not COMT or DRD2, genotype affects executive functions in healthy and first‐episode psychosis adolescents

“…Our lack of associations do not seem to depend on gender or diagnostic status, although a trend toward an interaction between these two factors with COMT Val158Met SNP was found for the memory domain. Other authors have reported associations between the presence of the Val allele and poorer performance in tasks of working memory Goldberg et al, 2003;Diamond et al, 2004], executive functioning [Egan et al, 2001;Goldberg et al, 2003;Tsai et al, 2003;Rosa et al, 2004], attention [Bilder et al, 2002;Blasi et al, 2005;Diaz-Asper et al, 2006], and memory [de Frias et al, 2004]. However, several studies have reported the absence of COMT-cognition associations Eisenberg et al, 1999;Tsai et al, 2003;Mills et al, 2004;Stefanis et al, 2004;Taerk et al, 2004], and a recent metaanalysis reported that the subtle effect (d ¼ 0.29; 95% CI ¼ 0.02-0.55; P ¼ 0.03) of the COMT on executive functioning was exclusive of healthy subjects, and was not significant for patients with schizophrenia-spectrum disorders [Barnett et al, 2007b].…”

Noradrenergic modulation of working memory and emotional memory in humans

“…see Fletcher et al 1998). With the advent of pharmacogenetics, future work should also investigate effects of functional polymorphisms in genes known to modulate NA actions (Diaz-Asper et al 2006;Neumeister et al 2006).…”

Genetic Influences on Outcome Following Traumatic Brain Injury

“…These three functional polymorphisms differentially affect DA levels [66], which have an effect on DA associated cognitive functions [67][68][69]. Lipsky et al [70] reported an association between COMT Val158Met genotype and executive functioning following TBI.…”