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Catechol-O-methyltransferase and the clinical features of psychosis.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 141B:935 –938 (2006)
Brief Research Communication
Catechol-O-methyltransferase and the
Clinical Features of Psychosis
J.L. McClay,1* A. Fanous,1 E.J.C.G. van den Oord,1 B.T. Webb,1 D. Walsh,2 F.A. O’Neill,3 K.S. Kendler,1 and X. Chen1
Department of Psychiatry, Medical College of Virginia of Virginia Commonwealth University, Richmond, Virginia
The Health Research Board, Dublin, Ireland
The Department of Psychiatry, The Queens University, Belfast, Northern Ireland
A functional polymorphism (Val-158-Met) at the
Catechol-O-methyltransferase (COMT) locus has
been identified as a potential etiological factor in
schizophrenia. Yet the association has not been
convincingly replicated across independent samples. We hypothesized that phenotypic heterogeneity might be diluting the COMT effect. To
clarify the putative association, we performed
an exploratory analysis to test for association
between COMT and five psychosis symptom
scales. These were derived through factor analysis of the Operational Criteria Checklist for
Psychiatric Illness. Our sample was the Irish
Study of High Density Schizophrenia Families, a
large collection consisting of 268 multiplex
families. This sample has previously shown a
small but significant effect of the COMT Val allele
in conferring risk for schizophrenia. We tested for
preferential transmission of COMT alleles from
parent to affected offspring (n ¼ 749) for each of
the five factor-derived scales (negative symptoms,
delusions, hallucinations, mania, and depression). Significant overtransmission of the Val
allele was found for mania (P < 0.05) and depression (P ¼ 0.01) scales. Examination of odds ratios
(ORs) revealed a heterogeneous effect of COMT,
whereby it had no effect on Negative Symptoms,
but largest impact on Depression (OR ¼ 1.4). These
results suggest a modest affective vulnerability
conferred by this allele in psychosis, but will
require replication. ß 2006 Wiley-Liss, Inc.
COMT; functional polymorphism;
OPCRIT; psychiatric symptoms
Please cite this article as follows: McClay JL, Fanous A,
van den Oord EJCG, Webb BT, Walsh D, O’Neill FA,
Kendler KS, Chen X. 2006. Catechol-O-Methyltransferase and the Clinical Features of Psychosis. Am J Med
Genet Part B 141B:935–938.
The Catechol-O-methyltransferase (COMT) gene has long
been considered a candidate for psychosis. It not only encodes a
key dopamine catabolic enzyme, but also maps to the Velo-
*Correspondence to: J.L. McClay, Department of Psychiatry,
800 East Leigh St, Richmond, VA, 23298-0126.
Received 27 July 2005; Accepted 21 June 2006
DOI 10.1002/ajmg.b.30401
ß 2006 Wiley-Liss, Inc.
Cardio-Facial Syndrome (VCFS) region on chromosome 22
[O’Donovan et al., 2003]. VCFS, caused by a deletion at 22q11,
carries a greatly increased risk for psychosis, with up to 30% of
affected individuals displaying psychotic symptoms [Murphy
et al., 1999].
A nonsynonymous polymorphism (Val-158-Met) at the
COMT locus has been shown to affect the function of the
encoded enzyme, whereby the Val allele confers increased
activity and thermostability [Lotta et al., 1995; Lachman et al.,
1996]. This polymorphism has been associated with schizophrenia in several studies [e.g., Li et al., 1996; Shifman et al.,
2002; Chen et al., 2004], but the evidence is not universally in
favor of an association. Many studies, mostly employing the
case-control design, have produced negative results [e.g.,
Daniels et al., 1996; Karayiorgou et al., 1998; Norton et al.,
2002]. One meta-analysis has concluded in favor of the Val
allele, at least in populations of European ancestry, but the
associated effect size is estimated to be small [Glatt et al.,
2003]. A more recent large-scale linkage disequilibrium study
and meta-analysis found only minimal nonsignificant evidence
for an overrepresentation of the Val allele in schizophrenics
[Fan et al., 2005].
Schizophrenia can present different clinical manifestations
in different individuals, and two general approaches have
been used to describe them. The classical subtypes typify the
categorical approach, and these are well established in
the DSM and ICD classification systems. The dimensional
approach, on the other hand, describes the disorder quantitatively, usually as factors of symptoms extracted through factor
analysis. Three, four and five factor models have been
proposed, as reviewed by Peralta and Cuesta [2001]. Whilst
the dimensional and categorical models are not inconsistent,
the dimensional approach has proven to most accurately
describe the clinical characteristics of the illness [Van Os
et al., 1999].
The putative association between COMT and schizophrenia
has been described as promising but not yet persuasive
[O’Donovan et al., 2003]. We considered possible reasons for
this uncertainty, and hypothesized that the effect of this gene
may be specific to particular clinical features of psychosis. This
being the case, such specific effects could be diluted when
testing directly for association with schizophrenia, and
perhaps account for the sporadic replication thus far experienced. Therefore, in this study, we examine the association of
COMT alleles with psychosis symptom dimensions derived
from the Operational Criteria Checklist for Psychiatric Illness
(OPCRIT) [McGuffin et al., 1991].
Subjects came form the Irish Study of High Density
Schizophrenia Families (ISHDSF), a large collection consisting of 268 multiplex families. Details of the ISHDSF can be
found elsewhere [Kendler et al., 1996]. This sample has already
demonstrated a small, but significant, overtransmission of the
COMT Val allele to affected individuals, at the P < 0.05 level
[see Chen et al., 2004]. The odds ratio (OR) statistic gives a
McClay et al.
suitable measure of the magnitude of disease-marker association, and can be calculated for vertical transmissions analyzed
in a transmission disequilibrium test (TDT) framework
[Kazeem and Farrall, 2005]. In the ISHDSF, the COMT Val
allele is significantly overtransmitted to schizophrenics, with
an OR of 1.15.
Our previous work also examined two further single
nucleotide polymorphisms (SNPs), in addition to that conferring the Val-158-Met amino acid substitution (rs4680). From 50
to 30 , with respect to the gene, the three SNPs examined were:
rs737865-rs4680-rs165599. These had been previously shown
to constitute a highly significant risk haplotype for schizophrenia in a sample of Ashkenazi Jews, with alleles G-G-G at
the three markers being overtransmitted to affected individuals [Shifman et al., 2002]. In the ISHDSF, the haplotype
comprising of alleles A-G-A was significantly overtransmitted
to cases (OR ¼ 1.3), whereas the high-risk haplotype described
by Shifman et al. was undertransmitted. Whilst there is a lack
of consensus on the particular risk haplotype across samples,
the two studies agree on the G allele at rs4680 (conferring Val)
as a risk factor for schizophrenia. These considerations, in
addition to the well-characterized functional effect of rs4680,
led to its selection for further analysis with specific clinical
features of psychosis in this study.
The OPCRIT checklist is a phenotypic instrument, designed
for use in a best-estimate procedure, in which psychosis
symptom and course features are coded by an experienced
clinician. This allows integration of the relative prominence of
clinical features over the course of illness. For each subject with
psychosis (defined as lifetime occurrence of any psychotic
episode, n ¼ 749) the OPCRIT was completed by KSK based on
a review of typically detailed hospital records and in-depth
personal interviews. These ratings reflected both the severity
of the symptoms as well as their chronicity. OPCRIT items for
ISHDSF subjects were entered into factor analysis, carried out
as described by Fanous et al. [2005]. Five factors were
extracted, and 56 of the OPCRIT items were used to generate
corresponding factor derived scales, viz: negative symptoms,
delusions, hallucinations, mania, and depression. The symptoms included in each factor were consistent with theory and
expectation and a complete breakdown of items in each scale is
shown in Fanous et al. [2005]. The number of items per scale
ranged from 7 (hallucinations) to 16 (depression).
These ordinal data were not normally distributed, with each
scale being to a greater or lesser extent positively skewed. We
therefore chose an analysis strategy suitable to this data and
our sample type [van den Oord, 1999], whereby individuals
were classified into high and low scoring categories for each
symptom dimension. Our intention was to pick out groups of
highly affected individuals in each category without compromising power to detect association. Since the threshold for high
versus low in each category is somewhat arbitrary, multiple
thresholds were imposed on the OPCRIT symptom factors (top
20, 30, and 40% of cases, respectively).
Genotyping was carried out as described previously [Chen
et al., 2004]. We initially carried out an exploratory analysis for
all individuals in the sample with psychotic symptoms. On the
basis of this exploratory analysis, we then analyzed a selected
subgroup refined by psychiatric diagnosis. In each case, we
tested for preferential vertical transmission of COMT alleles to
individuals with high symptom counts, that is, scoring above
the relevant threshold, for each of the OPCRIT factors. For
these tests of association, we used the TDT as implemented in
TRANSMIT [Clayton, 1999], a program that improves power to
detect association by reconstructing genotype data where
information on one parent is missing. The bootstrap option in
TRANSMIT was used to generate empirical P values to
overcome bias where multiple triads were assessed within
the same family.
The results of the initial exploratory analysis are shown in
Table I. Significant associations were found with mania
(P < 0.05) and depression (P ¼ 0.012) symptoms at the 30%
TABLE I. Within-Family Transmission Tests of Association for COMT Alleles and the Five
Dimensions of the OPCRIT Scale
Transmissions (Val)
Top 20% threshold
Negative symptoms
Top 30% threshold
Negative symptoms
Top 40% threshold
Negative symptoms
w2 (1 df)
Odds ratio
Tests of association between COMT and the five OPCRIT symptom dimensions, examined at three thresholds of
decreasing stringency (20, 30, and 40%, respectively). All individuals with any lifetime occurrence of psychosis
(n ¼ 749) were included in this analysis. Sample size for each test of association is given as the number of families
with transmissions to ‘‘affected’’ offspring, that is, those individuals scoring above the relevant threshold for each
symptom dimension (second column). Tests of association using TRANSMIT are based on 50,000 bootstrap
samples, with those scoring P < 0.05 highlighted in bold.
*The Hallucinations scale yielded the same integer cut-off value for both the 20 and 30% thresholds, so that an
identical single test accounts for both levels.
COMT and Psychosis Dimensions
TABLE II. Tests of Association for the Five OPCRIT Symptom Dimensions, at the 30% Threshold
Only, After Exclusion of Patients With Affective Disorders
Transmissions (Val)
Top 30% threshold
Negative symptoms
w2 (1 df)
Odds ratio
Individuals with a primary diagnosis of schizoaffective or affective disorder were omitted from this analysis, to
examine if the COMT association remained consistent. This reduced sample comprised of 606 psychotic cases.
Sample size for each test of association is given as the number of families with transmissions to ‘‘affected’’ offspring,
that is, those individuals scoring above the 30% threshold for each symptom dimension (second column). Tests of
association using TRANSMIT are based on 50,000 bootstrap samples, with those scoring P < 0.05 are highlighted
in bold.
threshold. Depression remained significant at the 40% threshold (P ¼ 0.022), whereas mania displayed merely a trend
approaching significance. At the most stringent 20% threshold,
no symptom scales were significantly associated, but this is
most likely a result of small numbers and resulting low power
offsetting any gains afforded by increased selection. A broad
pattern of overtransmission of the Val allele was observed.
When complete triads only were examined, the results were
consistent in terms of direction and ORs with the results shown
in Table I, but did not achieve statistical significance due to
reduced power, relative to the complete analysis.
To correct for multiple testing we first used the ‘‘lowest slope’’
method, known to be conservatively biased towards one
[Hsueh et al., 2003]. This estimated the number of true null
hypotheses to be as low as p0 ¼ 0.64. Another way to look at the
significant results is to compute the positive false discovery
rate pFDR [Storey, 2002, 2003], which was 0.33. This means
that the estimated proportion of false discoveries among the
three significant tests was 33%. Both of these correction
methods are valid for correlated tests [Van den Oord, 2005].
The ORs for the tests of association shown in Table I
highlight a consistent heterogeneity in the COMT effect,
apparent at all three thresholds, with the largest effects seen
with depression symptoms. Delusions, hallucinations, and
mania symptoms all exhibit ORs broadly in line with that
observed in the sample for diagnosis of schizophrenia (1.15).
Negative symptoms show no effect at all with a consistent OR of
1.0 for all thresholds.
This initial exploratory analysis included all individuals
displaying psychotic symptoms, but the total phenotyped
group of 749 individuals included 109 with schizoaffective
disorder and 29 with a primary diagnosis of an affective
disorder, mostly bipolar. To prevent the possibility that the
observed association with affective symptoms was coming
solely from these individuals, we re-examined the threshold
yielding the clearest results (30%) for all symptom factors, with
these individuals excluded. The results are presented in
Table II. The association with depression symptoms remained
intact, whilst mania symptoms exhibited a borderline trend
towards significance. However, the estimated ORs were highly
consistent with those observed for all cases with psychosis
(Table I). It therefore appears that the putative association is
not solely attributable to those in the sample with diagnosis of
schizoaffective or affective disorder.
This study yields initial tentative evidence that the COMT
Val allele acts as a modest risk factor for affective symptoms,
particularly depression, in patients with psychosis. Previous
work on the ISHDSF sample [Kendler et al., 1997] has shown
affective symptoms to be significantly correlated in sib pairs
concordant for schizophrenia. This observation could, in part,
be explained by allele sharing at the COMT locus in siblings.
Considering molecular evidence, the COMT Val allele may
increase liability for affective disorders, such as early-onset
major depressive disorder [Massat et al., 2005], irrespective of
psychosis. Further recent evidence has led to the suggestion
that COMT is a common risk factor for both schizophrenia and
bipolar disorder [Shifman et al., 2004]. However, taken as a
whole, evidence relating COMT and affective disorders can
appear confusing and contradictory. Many studies have found
no association between COMT and bipolar or major depression
[e.g., Kunugi et al., 1997], whilst others have reported
associations, but with the low activity Met allele, both for
bipolar [Li et al., 1997; Kirov et al., 1998] and unipolar
depression [Ohara et al., 1998]. However, many of these early
studies suffered from very small sample sizes, and may have
capitalized on chance or other factors.
The relationship between the COMT gene and psychiatric
disorders is considered to be complex, with possible pleiotropic
effects [Kunugi et al., 1997; Shifman et al., 2004; Massat et al.,
2005]. As evidence, several different etiological pathways are
influenced by this important gene, such as prefrontal cognition
in schizophrenia [Goldberg et al., 2003] or emotional processing in the amygdala and prefrontal cortex [Smolka et al.,
2005]. To add further complexity, putative environmental
risks for adult psychosis, such as adolescent cannabis use,
appear to be moderated by COMT genotype [Caspi et al., 2005].
Further analysis of the effects of COMT alleles in large,
extensively phenotyped samples may provide answers. The
results presented here, whereby the COMT Val allele is
associated with affective symptoms in psychosis, could provide
a starting point for future replication studies.
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catechol, features, methyltransferases, clinical, psychosis
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