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Is COMT a susceptibility gene for schizophrenia?

ABSTRACT: Catechol-O-methyl transferase (COMT) is a catabolic enzyme involved in the degradation of a number of bioactive molecules; of principal interest to psychiatry, these include dopamine. The enzyme is encoded by the COMT gene. COMT is located (along with 47 other genes) in a fragment of chromosome 22q11 which when deleted results in a complex syndrome, the psychiatric manifestations of which include schizophrenia and other psychoses. These 2 observations have placed COMT near the top of a rather long list of plausible candidate genes for schizophrenia. The ability to test the hypothesis that COMT might be a susceptibility gene for schizophrenia has been simplified in principle by the existence of a valine-to-methionine (Val/Met) polymorphism which results respectively in high and low activity forms of the enzyme. Given the unequivocal effect of this polymorphism on the function of COMT, and the evidence for a critical role for dopamine in the pathophysiology and treatment of psychosis, there are strong prior expectations that Val/Met influences susceptibility to schizophrenia as well as other psychiatric phenotypes. Indeed the Val/Met polymorphism has become the most widely studied polymorphism in psychiatry. In this review, we consider the evidence for and against the involvement of COMT in schizophrenia. The current data allow us to virtually exclude a simple relationship between schizophrenia and the Val/Met variant previously thought to dominate COMT function. However, recent data suggest a more complex pattern of genetic regulation of COMT function beyond that attributable to the Val/Met locus. Moreover, it is also clear that there is a complex nonlinear relationship between dopamine availability and brain function. These 2 factors, allied to phenotypic complexity within schizophrenia, make it difficult to draw strong conclusions regarding COMT in schizophrenia. Nevertheless, emerging research that takes greater account of all these levels of complexity is beginning to provide tantalizing, but far from definitive, support for the view that COMT influences susceptibility to at least some forms of psychosis.

SUBMITTER: Williams HJ

PROVIDER: S-EPMC2526139 | biostudies-literature | 2007 May

REPOSITORIES: biostudies-literature

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Is COMT a susceptibility gene for schizophrenia?

Williams Hywel J HJ Owen Michael J MJ O'Donovan Michael C MC

Schizophrenia bulletin 20070404 3

Catechol-O-methyl transferase (COMT) is a catabolic enzyme involved in the degradation of a number of bioactive molecules; of principal interest to psychiatry, these include dopamine. The enzyme is encoded by the COMT gene. COMT is located (along with 47 other genes) in a fragment of chromosome 22q11 which when deleted results in a complex syndrome, the psychiatric manifestations of which include schizophrenia and other psychoses. These 2 observations have placed COMT near the top of a rather lo ...[more]

PMID: 17412710

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Project description:Abstract Background Schizophrenia spectrum disorders (SSD) are often characterised by a plateau or decline in cognitive abilities early in the prodrome. The cause of developmental alteration remains unknown, and investigation of genetic involvement in cognitive function in these disorders may assist the understanding of the underlying neurobiological mechanisms involved. Variation at two single nucleotide polymorphisms (SNPs) of the catechol-O-methyltransferase (COMT) gene have previously shown an influence on COMT protein levels and cognition; rs4680 and rs4818. Here we investigate the influence of the nonsynonymous “Val/Met” SNP rs4680 and a second functional SNP, rs4818, on tasks of cognitive flexibility and attention. Methods The sample comprised 48 healthy controls (HC; age = 31.95 ± 12.80; 25 males, 23 females), and 43 with a diagnosis of SSD (age = 41.64 ± 10.36; 26 males, 17 females). Measures of cognitive flexibility and attention included the Wisconsin Card Sorting Test (WCST), Continuous Performance Test-Identical Pairs version (CPT-IP), Trail Making Test (TMT), and the D-KEFS Colour Word Interference Test (CWIT). Due to small cohort sizes, in our preliminary analyses we chose to compare people who should be most severely affected because of inheriting COMT haplotypes associated with poor cognitive functioning (GG rs4818 / GG rs4680: G-G haplotype) to those with haplotypes associated with better cognitive functioning (CC rs4818 / AA rs4680: C-A haplotype). Multivariate analysis of variance factors included COMT haplotype, diagnosis (HC and SSD), and gender, with Bonferroni correction for multiple comparisons; age was included as a covariate. Analyses were also conducted based on a non-functional SNP of the COMT gene; rs165599, as a negative control. Results SSD exhibited reduced cognitive performance compared to HC; F(4, 75) = 8.810, p < .001. Investigation of C-A haplotype revealed an interaction with diagnosis on cognitive performance; F(8, 154) = 2.075, p = .041; SSD had reduced performance compared to HC for the WCST, CPT-IP, and TMT in C-A haplotypes (all p < .05). COMT haplotype also interacted with gender on cognitive performance (C-A haplotype; F(8, 154) = 2.315, p = .023, G-G haplotype; F(8, 154) = 2.706, p = .008). Males who were C-A non-carriers and /or G-G haplotype (high COMT activity groups) performed better on CPT-IP (both p < .05) and worse on CWIT (both p < .05) compared to females. Control SNP rs165599 revealed no main effects or significant interactions (all p > .05). Discussion The role of the COMT gene in the cognitive abilities of SSD remains contentious as gene expression does not differ from a healthy population. This preliminary analysis revealed an interaction between diagnosis and COMT haplotype, however, this only reached statistical significance for the C-A haplotype, where SSD with C-A haplotype and C-A non-carriers had reduced performance compared to HC on most tasks except TMT. The different effects found across the tasks, which probed various elements of cognitive flexibility and attention, supports a nuanced role of COMT in cognitive function. Further, high COMT activity was beneficial for males on CPT-IP but not CWIT compared to females. Gender interaction remains a significant consideration in studies of the COMT gene, likely involving the catechol-estrogens which are substrates of COMT. As expected there was no significant results with control SNP rs165599, indicating that findings were due to the influence of SNPs rs4680 and rs4818 on COMT activity.

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Is COMT a susceptibility gene for schizophrenia?

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Is COMT a susceptibility gene for schizophrenia?

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