Pooley EC, Fineberg N, Harrison PJ. The met158 allele of catechol-O-methyltransferase (COMT) is associated with obsessive-compulsive disorder in men: case-control study and meta-analysis. Mol Psychiatry 12: 556-561

Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.
Molecular Psychiatry (Impact Factor: 14.5). 06/2007; 12(6):556-61. DOI: 10.1038/
Source: PubMed


Existing data suggest a genetic association between the met(158) allele of catechol-O-methyltransferase (COMT) and obsessive-compulsive disorder (OCD). However, the results are inconclusive and complicated by possible gender differences. We sought to resolve the question in two ways. First, we carried out a new case-control study in 87 adults with OCD and 327 healthy comparison subjects. The study replicated reports of an increased met(158) allele frequency in men with OCD (odds ratio (OR)=1.91, 95% confidence interval (CI) 1.07-3.40, P=0.026), with no effect in women (OR=1.13, 95% CI 0.74-1.72, P=0.56). Second, we performed a meta-analysis of all published case-control data (n=1908 subjects). This revealed an association of COMT met(158) with OCD (OR=1.23, 95% CI 1.06-1.42, P=0.005) and an interaction with gender (z=4.27, P<0.0001). The association between COMT met(158) and OCD was present in men (OR=1.88, 95% CI 1.45-2.44, P<0.001) but not in women (OR=0.98, 95% CI 0.78-1.22, P=0.83). We conclude that COMT may play a role in the genetic aetiology of OCD in men. The biological plausibility of the association is increased by the functionality of the val(158)met polymorphism in terms of its effect on COMT enzyme activity, and by the role of COMT in cortical dopamine signalling and information processing. The finding also extends the evidence for sexual dimorphism in COMT and in OCD.

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    • "First, we did not find a significant association between the Met allele and OCD using Japanese subjects, which is consistent with the results of previous studies, including recent genome-wide association studies (Ohara et al. 1998; Erdal et al. 2003; Meira-Lima et al. 2004; Poyurovsky et al. 2005; Denys et al. 2006; Tükel et al. 2013, Stewart et al., 2013; Mattheisen et al., 2014). However, the meta-analysis of previous genetic association studies demonstrated that the COMT Val158Met polymorphism was a risk factor for developing OCD (Taylor, 2012; Pooley et al. 2007). This discrepancy might be caused by a lack of adequate statistical power to detect the relatively small genetic effect of this polymorphism on OCD or ethnic differences. "
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    ABSTRACT: Catechol-O-methyltransferase (COMT) is an enzyme that participates in the metabolic inactivation of dopamine and norepinephrine, and the Met allele of the COMT Val158Met polymorphism is associated with lower enzymatic activity. The purpose of the present study was to investigate whether this functional variant is associated with obsessive-compulsive disorder (OCD) and the clinical responses in OCD. We first performed a case-control association study between the COMT Val158Met polymorphism and OCD (171 cases and 944 controls). Then, we examined the association between this polymorphism and the clinical responses in 91 of the OCD patients. Our study did not find a significant association between the Met allele and OCD risk or between the Met allele and clinical responses (p > 0.05). The present case-control/pharmacogenetic study did not provide clear evidence that the COMT Val158Met polymorphism is a predictor of OCD or of OCD patients' clinical responses. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
    Human Psychopharmacology Clinical and Experimental 05/2015; 30(5). DOI:10.1002/hup.2485 · 2.19 Impact Factor
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    • "However, this effect was conflicted with a null finding from the same study when considering family association studies, and not case-controls (Azzam and Mathews, 2003) (Supplementary Table 3). This effect was also not apparent when considering females alone (Pooley et al., 2007) (Supplementary Table 2). The COMT Met allele was also implicated in Panic Disorder (PD) in Asian females (Domschke et al., 2007), but not in mixed or Asian males and females combined (Zintzaras and Sakelaridis, 2007). "
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    ABSTRACT: Major efforts have been directed at family-based association and case-control studies to identify the involvement of candidate genes in the major disorders of mental health. What remains unknown is whether candidate genes are associated with multiple disorders via pleiotropic mechanisms, and/or if other genes are specific to susceptibility for individual disorders. Here we undertook a review of genes that have been identified in prior meta-analyses examining specific genes and specific mental disorders that have core disruptions to emotional and cognitive function and contribute most to burden of illness- major depressive disorder (MDD), anxiety disorders (AD, including panic disorder and obsessive compulsive disorder), schizophrenia (SZ) and bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD). A literature review was conducted up to end-March 2013 which included a total of 1519 meta-analyses across 157 studies reporting multiple genes implicated in one or more of the five disorders studied. A total of 134 genes (206 variants) were identified as significantly associated risk variants for MDD, AD, ADHD, SZ or BD. Null genetic effects were also reported for 195 genes (426 variants). 13 genetic variants were shared in common between two or more disorders (APOE e4, ACE Ins/Del, BDNF Val66Met, COMT Val158Met, DAOA G72/G30 rs3918342, DAT1 40-bp, DRD4 48-bp, SLC6A4 5-HTTLPR, HTR1A C1019G, MTHR C677T, MTHR A1298C, SLC6A4 VNTR and TPH1 218A/C) demonstrating evidence for pleiotrophy. Another 12 meta-analyses of GWAS studies of the same disorders were identified, with no overlap in genetic variants reported. This review highlights the progress that is being made in identifying shared and unique genetic mechanisms that contribute to the risk of developing several major psychiatric disorders, and identifies further steps for progress.
    Journal of Psychiatric Research 09/2014; 60. DOI:10.1016/j.jpsychires.2014.09.014 · 3.96 Impact Factor
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    • "Possibly contributing to this variation are the sexually dimorphic effects of COMT genotype, which have been observed on both neurochemical and behavioural measures (Gogos et al., 1998), and on associations with psychopathology (Harrison and Tunbridge, 2008). For example, the Met allele is associated with obsessive-compulsive disorder in males but not females (Pooley et al., 2007). The basis of the sexual dimorphism of COMT effects is not well understood, but may in part be explained by the regulation of COMT expression by oestrogen, and sex differences in baseline dopamine levels, among other mechanisms (Gogos et al., 1998; Harrison and Tunbridge, 2008). "
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    ABSTRACT: The catechol-O-methyltransferase (COMT) enzyme is a major determinant of prefrontal dopamine levels. The Val158Met polymorphism affects COMT enzymatic activity and has been associated with variation in executive function and affective processing. This study investigated the effect of COMT genotype on the flexible modulation of the balance between processing self-generated and processing stimulus-oriented information, in the presence or absence of affective distractors. Analyses included 124 healthy adult participants, who were also assessed on standard working memory (WM) tasks. Relative to Val carriers, Met homozygotes made fewer errors when selecting and manipulating self-generated thoughts. This effect was partly accounted for by an association between COMT genotype and visuospatial WM performance. We also observed a complex interaction between the influence of affective distractors, COMT genotype and sex on task accuracy: male, but not female, participants showed a sensitivity to the affective distractors that was dependent on COMT genotype. This was not accounted for by WM performance. This study provides novel evidence of the role of dopaminergic genetic variation on the ability to select and manipulate self-generated thoughts. The results also suggest sexually dimorphic effects of COMT genotype on the influence of affective distractors on executive function.
    Social Cognitive and Affective Neuroscience 09/2014; 10(6). DOI:10.1093/scan/nsu118 · 7.37 Impact Factor
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