Craddock, N., Owen, M. J. & O'Donovan, M. C. The catechol-O-methyl transferase (COMT) gene as a candidate for psychiatric phenotypes: evidence and lessons. Mol. Psychiatry 11, 446-458

Department of Psychological Medicine, The Henry Wellcome Building for Biomedical Research in Wales, Cardiff University, School of Medicine, Heath Park, Cardiff, UK.
Molecular Psychiatry (Impact Factor: 14.5). 06/2006; 11(5):446-58. DOI: 10.1038/
Source: PubMed


The enzyme catechol-O-methyl transferase (COMT), identified in the 1950s, is involved in catabolism of monoamines that are influenced by psychotropic medications, including neuroleptics and antidepressants. The COMT gene lies in a chromosomal region of interest for psychosis and bipolar spectrum disorder and a common polymorphism within the gene alters the activity of the enzyme. As a consequence, COMT has been one of the most studied genes for psychosis. On the basis of prior probabilities it would seem surprising if functional variation at COMT did not have some influence either on susceptibility to psychiatric phenotypes, modification of the course of illness or moderation of response to treatment. There is now robust evidence that variation at COMT influences frontal lobe function. However, despite considerable research effort, it has not proved straightforward to demonstrate and characterise a clear relationship between genetic variation at COMT and psychiatric phenotypes. It is of course, possible that COMT will turn out to be an unusually intractable case but it seems more likely that the experiences with this gene will provide a foretaste of the complexity of genotype-phenotype relationships that will be found for psychiatric traits. In this review, we consider the current state of evidence and the implications both for further studies of COMT and more generally for studies of other genes.

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    • "COMT is an enzyme involved in monoamine degradation and its gene has been suggested as a candidate for BD.28 The most studied polymorphism, Val/Met substitution, which has been shown to influence enzyme activity, has not been confirmed to be associated with BD29–35 except in some studies.36,37 "
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    • "The human COMT gene contains a common functional polymorphism [valine (Val) substitution for methionine (Met)] at the 158/108 locus, with the Met allele resulting in a 4-fold reduction in enzymatic activity (Tunbridge et al. 2006). Its regional and functional specificity, together with the COMT gene lying within a chromosomal region of interest for psychosis (22q11), has made COMT the subject of extensive study in schizophrenia (Craddock et al. 2006). Although clinical data have not confirmed a direct link between COMT gene variation and schizophrenia (Allen et al. 2008 ; Okochi, 2009), functional polymorphisms of the COMT gene are associated with performance on frontal cortical tasks such as the Wisconsin card sort task in patients with schizophrenia and controls (Barnett et al. 2008). "
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    • "Lower enzymatic action on DA may increase the likelihood of psychosis due to an overabundance of synaptic DA (Carlsson 1988; Dunham et al. 1992) and the low-activity allele has been correlated with ADHD, OCD, and schizophrenia incidence in some studies of 22q11.2DS (Bassett et al. 2007; Gothelf et al. 2007; Michaelovsky et al. 2008) and the general population (Shifman et al. 2002) but not in others (Murphy et al. 1999; Fan et al. 2005; Murphy and Scambler 2005) likely because of additional genetic and experiential variation (Craddock et al. 2006; Michaelovsky et al. 2008). Furthermore, while DA activity is enhanced by GCs in the prefrontal cortex (Mizoguchi et al. 2004), understanding of the complex relationship between CG and DA is still developing (Craenenbroeck et al. 2005). "
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