The catechol-O-methyl transferase (COMT) gene as a
candidate for psychiatric phenotypes: evidence and
N Craddock, MJ Owen and MC O’Donovan
Department of Psychological Medicine, The Henry Wellcome Building for Biomedical Research in Wales, Cardiff University,
School of Medicine, Heath Park, Cardiff, UK
The enzyme catechol-O-methyl transferase (COMT), identified in the 1950s, is involved in
catabolism of monoamines that are influenced by psychotropic medications, including
neuroleptics and antidepressants. The COMT gene lies in a chromosomal region of interest for
psychosis and bipolar spectrum disorder and a common polymorphism within the gene alters
the activity of the enzyme. As a consequence, COMT has been one of the most studied genes
for psychosis. On the basis of prior probabilities it would seem surprising if functional
variation at COMT did not have some influence either on susceptibility to psychiatric
phenotypes, modification of the course of illness or moderation of response to treatment.
There is now robust evidence that variation at COMT influences frontal lobe function. However,
despite considerable research effort, it has not proved straightforward to demonstrate and
characterise a clear relationship between genetic variation at COMT and psychiatric
phenotypes. It is of course, possible that COMT will turn out to be an unusually intractable
case but it seems more likely that the experiences with this gene will provide a foretaste of the
complexity of genotype–phenotype relationships that will be found for psychiatric traits. In this
review, we consider the current state of evidence and the implications both for further studies
of COMT and more generally for studies of other genes.
Molecular Psychiatry (2006) 11, 446–458. doi:10.1038/sj.mp.4001808; published online 28 February 2006
Keywords: COMT; gene; schizophrenia; bipolar disorder; psychosis; schizoaffective disorder
The enzyme catechol-O-methyl transferase (COMT),
identified in the 1950s,1is involved in catabolism of
monoamines that are influenced by psychotropic
medications, including neuroleptics and antidepres-
sants. The COMT gene lies in a chromosomal region
of interest for psychosis and mood disorder and a
common polymorphism within the gene alters the
activity of the enzyme. As a consequence, COMT has
been one of the most studied genes for psychosis. In
this review we consider the current state of evidence
and the implications both for further studies of COMT
and more generally for studies of other genes.
Catechol-O-methyl transferase: enzyme and gene
COMT degrades catecholamines including dopamine.
Two main COMT protein isoforms are known. In most
assayed tissues, a soluble cytoplasmic (S-COMT)
isoform predominates.2In brain, a longer membrane-
bound form (MB-COMT) is the major species.3
Although expressed widely, COMT appears to be a
minor player in dopamine clearance compared with
neuronal synaptic uptake by the dopamine transpor-
ter and subsequent monoamine oxidase (MAO)
(PFC) where dopamine transporter expression is
low,5the importance of COMTappears to be greater.6,7
The structure of the COMT gene, which lies on
chromosome 22q11, is shown in Figure 1. A common
G>A polymorphism is present that produces a
valine-to-methionine (Val/Met) substitution at codons
108 and 158 of S-COMTand MB-COMT, respectively,8
that results in a trimodal distribution of COMT
activity in human populations.8–10The polymorphism
is usually referred to as the Val/Met locus, but is also
known by the reference sequence identification code
rs4680 (previously rs165688). Terminology varies and
can be confusing: the Valine (Val) allele is also
referred to as the high activity (H) allele or the G
allele. We will refer to it as the Val allele.
A number of putative regulatory elements have
been discovered in the COMT gene, which may
explain the differential expression of the long
and short transcripts in different tissues.3These
include numerous oestrogen response elements11
Received 23 January 2006; accepted 23 January 2006; published
online 28 February 2006
Correspondence: Dr N Craddock, Department of Psychological
Medicine, The Henry Wellcome Building for Biomedical Research
in Wales, Cardiff University, School of Medicine, Heath Park,
Cardiff, CF14 4XN, UK.
Molecular Psychiatry (2006) 11, 446–458
& 2006 Nature Publishing Group All rights reserved 1359-4184/06 $30.00
and oestradiol has been shown to downregulate
COMT expression in cell culture.12A recent report
suggests that MB-COMT exists in two forms which
may be differentially affected by the Val/Met geno-
type.13Thus, it is to be expected that there will be a
level of genetic complexity including possible gender-
Polymorphism and haplotype frequencies at COMT
have been shown to vary substantially across popula-
tions.14,15For example, the Val allele has been
reported at frequencies varying between 0.99 and
0.48.14Moreover, in certain Asian populations, a
second functional variant, Ala72Ser, (MB COMT
nomenclature) has been reported16Hence, population
origin of samples is a potentially important variable
for interpreting genetic studies of COMT.
Positional studies of psychiatric phenotypes
The 22q11 chromosomal region in which COMT is
located is involved in microdeletions that are present
in most individuals with velocardiofacial syndrome
(VCFS) and related clinical syndromes which we will
collectively refer to as chromosome 22q11 deletion
syndrome (22q11DS). In addition to characteristic
core features of dysmorphology, abnormalities of the
palate and congenital heart disease, cognitive impair-
ments are common, and range in severity from
minimal to severe.17An increase in a broad spectrum
of psychiatric disorders in children with 22q11DS has
been reported including anxiety, mood disorders,
obsessive-compulsive disorder (OCD), and attention
deficit disorder.17–21In adults with 22q11DS, high
rates of psychosis have been reported,20,22–24with the
majority of cases satisfying diagnostic criteria for
schizophrenia25and an estimated risk of around 25%.
Linkage studies have provided evidence for one or
more loci in the 22q11 region in which COMT is
located that influence susceptibility to several psy-
the two published meta-analyses of bipolar disorder.26
The region is supported by one of
use families selected on the basis of having at least
one member with schizoaffective disorder, bipolar
type provided genome-side suggestive evidence for
linkage at 22q11.28
The only linkage study to
been undertaken for other psychiatric phenotypes so
there have not been the same opportunities for this
chromosomal region to be implicated for these
phenotypes. The region has not been implicated in
genome scans of unipolar depression.29Lod scores
close to 3 have been reported at the 22q11 locus close
to COMT in a study of 70 panic disorder pedigrees.30
This is of particular interest given that evidence has
been reported to support a genetic contribution to the
In summary, on the basis of position, COMT must
be considered as a strong candidate for involvement
in psychiatric phenotypes, particularly psychosis and
bipolar mood disorder.
Many fewer linkage studies have
in some bipolar
Association studies of COMT and frontal lobe
Several studies suggest that the COMT Val/Met locus
influences performance on tests of frontal lobe
function, with the Val allele and/or Val/Val genotype
being associated with poorer performance. The Val
allele was initially associated with poorer function as
indexed by the Wisconsin Card Sorting Test and
fMRI32in patients with schizophrenia and controls.
Subsequently, a fairly strong body of evidence has
been reported for association between the Val allele
and poorer performance in controls,33–35patients with
(although not the schizophrenics themselves),38and
a small sample of subjects with 22q11DS.39One study
of individuals with schizophrenia demonstrated a
biphasic effect, with the Val allele being associated
with poorer performance in some tests, but better
performance in others.37However, not all studies,40,41
including the largest study comprising 543 Greek
army conscripts,42have supported association be-
tween frontal cognitive measures and COMT. Re-
cently, the low activity Met allele has been reported as
a risk factor for cognitive decline in 22q11DS.43
Most work to date has focussed on the Val/Met
polymorphism and other variants reported to be
associated with altered mRNA expression44,45have
not been widely studied. However, on the current
evidence, the mechanism for the cognitive effects at
COMT is unlikely to be simple. Weinberger and
COMT - Genomic Structure
2 3 4 56
exons of COMT are shown together with the and indication
of the structure of the two transcripts, S-COMT and MB-
COMT. The three polymorphisms that have been most
widely studied are shown.
Schematic representation of COMT gene. The six
COMT gene and psychiatric phenotypes
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