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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    ABSTRACT: Bipolar disorder (BD) is a complex disorder with a number of susceptibility genes and environmental risk factors involved in its pathogenesis. In recent years, huge progress has been made in molecular techniques for genetic studies, which have enabled identification of numerous genomic regions and genetic variants implicated in BD across populations. Despite the abundance of genetic findings, the results have often been inconsistent and not replicated for many candidate genes/single nucleotide polymorphisms (SNPs). Therefore, the aim of the review presented here is to summarize the most important data reported so far in candidate gene and genome-wide association studies. Taking into account the abundance of association data, this review focuses on the most extensively studied genes and polymorphisms reported so far for BD to present the most promising genomic regions/SNPs involved in BD. The review of association data reveals evidence for several genes (SLC6A4/5-HTT [serotonin transporter gene], BDNF [brain-derived neurotrophic factor], DAOA [D-amino acid oxidase activator], DTNBP1 [dysbindin], NRG1 [neuregulin 1], DISC1 [disrupted in schizophrenia 1]) to be crucial candidates in BD, whereas numerous genome-wide association studies conducted in BD indicate polymorphisms in two genes (CACNA1C [calcium channel, voltage-dependent, L type, alpha 1C subunit], ANK3 [ankyrin 3]) replicated for association with BD in most of these studies. Nevertheless, further studies focusing on interactions between multiple candidate genes/SNPs, as well as systems biology and pathway analyses are necessary to integrate and improve the way we analyze the currently available association data.
    Neuropsychiatric Disease and Treatment 10/2013; 9:1573-1582. DOI:10.2147/NDT.S28117 · 1.74 Impact Factor
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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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    ABSTRACT: Catechol-O-methyltransferase (COMT) is an important enzyme in the metabolism of dopamine and disturbance in dopamine function is proposed to be central to the pathogenesis of schizophrenia. Clinical epidemiological studies have indicated cannabis use to confer a 2-fold increase in risk for subsequent onset of psychosis, with adolescent-onset use conveying even higher risk. There is evidence that a high activity COMT polymorphism moderates the effects of adolescent exposure to cannabis on risk for adult psychosis. In this paper we compared the effect of chronic adolescent exposure to the cannabinoid WIN 55212 on sensorimotor gating, behaviours related to the negative symptoms of schizophrenia, anxiety- and stress-related behaviours, as well as ex-vivo brain dopamine and serotonin levels, in COMT KO vs. wild-type (WT) mice. Additionally, we examined the effect of pretreatment with the COMT inhibitor tolcapone on acute effects of this cannabinoid on sensorimotor gating in C57BL/6 mice. COMT KO mice were shown to be more vulnerable than WT to the disruptive effects of adolescent cannabinoid treatment on prepulse inhibition (PPI). Acute pharmacological inhibition of COMT in C57BL/6 mice also modified acute cannabinoid effects on startle reactivity, as well as PPI, indicating that chronic and acute loss of COMT can produce dissociable effects on the behavioural effects of cannabinoids. COMT KO mice also demonstrated differential effects of adolescent cannabinoid administration on sociability and anxiety-related behaviour, both confirming and extending earlier reports of COMT×cannabinoid effects on the expression of schizophrenia-related endophenotypes.
    The International Journal of Neuropsychopharmacology 11/2011; 15(9):1331-42. DOI:10.1017/S1461145711001581 · 4.01 Impact Factor
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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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    ABSTRACT: The most common human microdeletion occurs at chromosome 22q11.2. The associated syndrome (22q11.2DS) has a complex and variable phenotype with a high risk of schizophrenia. While the role of stress in the etiopathology of schizophrenia has been under investigation for over 30 years (Walker et al. 2008), the stress-diathesis model has yet to be investigated in children with 22q11.2DS. Children with 22q11.2DS face serious medical, behavioral, and socioemotional challenges from infancy into adulthood. Chronic stress elevates glucocorticoids, decreases immunocompetence, negatively impacts brain development and function, and is associated with psychiatric illness in adulthood. Drawing knowledge from the extant and well-developed anxiety and stress literature will provide invaluable insight into the complex etiopathology of schizophrenia in people with 22q11.2DS while suggesting possible early interventions. Childhood anxiety is treatable and stress coping skills can be developed thereby improving quality of life in the short-term and potentially mitigating the risk of developing psychosis.
    Journal of Neurodevelopmental Disorders 03/2011; 3(1):68-75. DOI:10.1007/s11689-010-9069-9 · 3.27 Impact Factor
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