The met158allele of catechol-O-methyltransferase (COMT)
is associated with obsessive-compulsive disorder in men:
case–control study and meta-analysis
EC Pooley1, N Fineberg2and PJ Harrison1
1Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK and2OCD Specialist Service, Department of
Psychiatry, Queen Elizabeth II Hospital, Hertfordshire Partnership NHS Trust, Welwyn Garden City, UK
Existing data suggest a genetic association between the met158allele 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 met158allele
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 met158with 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 met158and 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
val158met 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.
Molecular Psychiatry (2007) 12, 556–561; doi:10.1038/sj.mp.4001951; published online 30 January 2007
Keywords: COMT; OCD; gender; dopamine; polymorphism
COMT metabolizes catechols, including dopamine,
norepinephrine and catecholestrogens.1,2The human
COMT gene contains a common single nucleotide
polymorphism (SNP), a G to A missense variant, which
encodes either valine (val) or methionine (met) at
codon 158.3The val158met SNP has been associated
with a range of psychiatric phenotypes, as well as with
the performance and efficiency of cortical information
processing in domains including working memory,
emotional reactivity and pain responses.4–6These
effects are thought to reflect the impact of COMT upon
dopamine metabolism and signalling,7,8and its mod-
ulation by the val158met SNP.6,9–11Importantly, the SNP
is functional,3with met-COMT having a 30% lower
enzyme activity in human brain compared to val-
COMT.12Thus, genetic associations with the val158met
allele are likely to be direct, and can be interpreted with
regard to the known biology of COMT.
Obsessive-compulsive disorder (OCD) is a familial
disorder with a heritable component.13The genetic
architecture, chromosomal loci and susceptibility
genes are unclear, but the postulated pathophysiolo-
gical involvement of monoamines14,15has led to
association studies with serotonergic and dopaminer-
gic candidate genes. Positive findings have been
reported for several genes, particularly the serotonin
2A receptor (HTR2A), monoamine oxidase A (MAOA)
One complicating factor is that gender differences
are relatively common in genetic studies of OCD,
perhaps contributing to the differing clinical pheno-
type between the sexes, whereby males have an
earlier age of onset, more comorbid tics and poorer
outcome.16For example, HTR2A shows association
with OCD primarily in women,17whereas MAOA18
and COMT19–21have been associated with OCD
in men, albeit one study found association with
COMT in women.22However, it is always the COMT
met158allele that is associated with OCD. Here we
report an additional case–control study of COMT
val158met in OCD and provide a meta-analysis of the
literature. The results provide support for the associa-
tion of the met158allele of COMT with OCD, but only
Received 1 September 2006; revised 12 November 2006; accepted
13 November 2006; published online 30 January 2007
Correspondence: Dr PJ Harrison, Department of Psychiatry,
Universityof Oxford, Neurosciences
Hospital, Oxford OX3 7JX, UK.
Molecular Psychiatry (2007) 12, 556–561
& 2007 Nature Publishing Group All rights reserved 1359-4184/07 $30.00
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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)
COMT polymorphism in OCD
EC Pooley et al