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The met(158) allele of catechol-O-methyltransferase (COMT) is associated with obsessive-compulsive disorder in men: case-control study and meta-analysis.

Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.
Molecular Psychiatry (Impact Factor: 15.15). 06/2007; 12(6):556-61. DOI: 10.1038/sj.mp.4001951
Source: PubMed

ABSTRACT 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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    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.
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