Meta‐analysis of the association between the catecholamine‐<i>O</i>‐methyl‐transferase gene and obsessive‐compulsive disorder

Azzam, Amin; Mathews, Carol A.

doi:10.1002/ajmg.b.20013

Cited by 71 publications

(42 citation statements)

References 23 publications

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“…It has also been strongly associated with one anxiety disorder in particularFpanic disorder ( (Ohara et al, 1998;Samochowiec et al, 2004) and, according to a recent meta-analysis, not with obsessive-compulsive disorder (Azzam and Mathews, 2003). There was therefore ample a priori reason to hypothesize that we would find an effect of the val158met polymorphism on neuroticism and extraversion in this study.…”

Section: Discussionmentioning

confidence: 57%

COMT Polymorphisms and Anxiety-Related Personality Traits

Stein

Fallin

Schork

2005

Neuropsychopharmacol

196

128

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High neuroticism and low extraversion are characteristic of anxiety-prone individuals. A functional variant in the catechol-Omethyltransferase (COMT) gene, the Val158Met ('val/met') polymorphism, has been associated in some prior studies with several phenotypes, including neuroticism. We tested the hypothesis that the val158met polymorphism would be associated with both high neuroticism and low extraversion, making it a plausible candidate locus for anxiety susceptibility. To determine whether val158met is responsible for these effects, we also evaluated the association with haplotypes that included two other SNPs within the COMT gene. We collected a sample of 497 undergraduate college students who were phenotyped on a personality inventory (the NEO-Personality Inventory-Raised (NEO-PI-R)). Subjects were genotyped for three COMT polymorphisms: the well-studied nonsynonymous SNP rs4680 that generates a valine-to-methionine substitution (val158met), rs737865 (near exon #1), and rs165599 (also functional, near the 3 0 -UTR). Together, these three SNPs define a haplotype that is associated with reduced COMT expression in human brain. Logistic regression analyses were used to examine the effects of individual SNPs on extraversion and neuroticism scores. Score tests for association between these traits (quantitatively and dichotomously considered) and haplotypes were also conducted. We evaluated potential for population stratification artifact by genotyping a set of 36 unlinked highly polymorphic markers previously demonstrated to distinguish sufficiently ancestry of major American populations. Two of the SNPs (rs4680 ('val/met') and rs737865) were significantly associated with (low) extraversion and, less consistently, with (high) neuroticism, with effects confined to women. A significant association between COMT haplotype and (low) extraversion and (high) neuroticism was also observed. Formal testing showed that population structure did not explain the findings. These data suggest that involvement of the COMT locus in susceptibility to anxiety-related traits (ie low extraversion and high neuroticism) is unlikely to be wholly accounted for by the well-studied rs4680 ('val/met') polymorphism. Other functional variants may exist that contribute to this relationship. Possible sex-specific effects remain to be further studied and explained.

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Section: Discussionmentioning

confidence: 57%

COMT Polymorphisms and Anxiety-Related Personality Traits

Stein

Fallin

Schork

2005

Neuropsychopharmacol

196

128

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“…[31][32][33] As such, the candidacy of COMT as a susceptibility gene for OCD is relatively, perhaps unexpectedly, strong, and has substantially advanced since the equivocal positive result of the earlier meta-analysis, which was based on 144 OCD cases and 337 controls. 34 In terms of mechanism, an involvement of COMT in OCD likely reflects its role in modulation of cortical dopamine metabolism, although its role in methylation of other substrates, including catecholestrogens, should be noted. 2 We assume that the association of the met 158 allele with OCD reflects the lower enzyme activity of met-COMT 12 and the consequent enhancement of cortical dopamine signalling, relative to val-COMT.…”

Section: Discussionmentioning

confidence: 99%

The met158 allele of catechol-O-methyltransferase (COMT) is associated with obsessive-compulsive disorder in men: case–control study and meta-analysis

2007

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Existing data suggest a genetic association between the met 158 allele of catechol-Omethyltransferase (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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“…For example, whereas some studies have reported a link between the COMT met allele and increased predisposition to clinical anxiety and heightened subclinical anxiety levels, others have failed to do so (Azzam & Mathews, 2003;Ohara, Nagai, Suzuki, Ochiai, & Ohara, 1998). This is likely to reflect the complexity of the mechanisms and associated genetic influences involved.…”

Section: Discussionmentioning

confidence: 99%

COMT genotype influences prefrontal response to emotional distraction

Bishop

Cohen

Fossella

et al. 2006

Cognitive, Affective, & Behavioral Neuroscience

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Early studies of genetic effects on brain activity have been conducted to investigate primarily either the influence of polymorphisms in dopaminergic genes, especially the catechol-O-methyltransferase (COMT) gene, on prefrontal cognitive processes such as working memory, or that of polymorphisms in the serotonin transporter gene on the amygdala response to threatening stimuli. Here, we address genetic influences on the neural systems underlying cognitive-affective interactions. Specifically, we assess the effect of the COMT val 158 met polymorphism on frontal regulation of attention under emotional distraction. Healthy volunteers were scanned while performing a house-matching task with affectively negative versus neutral distractors. Effects of val allele load were examined on frontal regions associated with attentional control and emotion regulation, and on parahippocampal regions associated with perception of houses. As we predicted, val load correlated positively with activity in control-and task-related regions during performance under emotional distraction. These findings provide an initial step toward identifying genetic contributions to interindividual variability in recruitment of mechanisms that regulate affective processing.

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Meta‐analysis of the association between the catecholamine‐O‐methyl‐transferase gene and obsessive‐compulsive disorder

Cited by 71 publications

References 23 publications

COMT Polymorphisms and Anxiety-Related Personality Traits

COMT Polymorphisms and Anxiety-Related Personality Traits

The met158 allele of catechol-O-methyltransferase (COMT) is associated with obsessive-compulsive disorder in men: case–control study and meta-analysis

COMT genotype influences prefrontal response to emotional distraction

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