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Family-based and caseтАУcontrol study of catechol-O-methyltransferase in schizophrenia among Palestinian Arabs.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 119B:35 – 39 (2003)
Family-Based and Case–Control Study
of Catechol-O-Methyltransferase in Schizophrenia
Among Palestinian Arabs
I. Kremer,1 M. Pinto,2 I. Murad,3 M. Muhaheed,4 I. Bannoura,3 D.J. Muller,5 T.G. Schulze,5 A. Reshef,1
M. Blanaru,1 S. Gathas,1 R. Goichman,1 M. Rietschel,5 M. Dobrusin,6 R. Bachner-Melman,2
L. Nemanov,2 R.H. Belmaker,6 W. Maier,5 and R.P. Ebstein2*
1
Emek Hospital, Afula, Israel
Herzog Hospital, Jerusalem, Israel
3
Dr. Kemal Psychiatric Hospital, Bethlehem, Palestine
4
The Palestinian Research Center for Genetics of Mental Disorders, Palestine
5
Department of Psychiatry, University of Bonn, Germany
6
Beersheva Mental Health Center, Beersheva, Israel
2
COMT is a ubiquitous enzyme crucial to
catechol metabolism. The molecular basis
of COMT thermolability, that leads to three
to fourfold differences in enzyme activity, is
due to a substitution of valine with methionine in the Val158/108Met polymorphism. Of
special interest is the role of this gene in
major psychoses especially since a microdeletion (22q11) containing the COMT gene
(velo-cardio-facial syndrome) also carries
with it several types of behavioral disorders,
including an increased prevalence of schizophrenia. Almost 20 genetic studies have
examined the role of COMT in schizophrenia
with ambiguous results. Towards clarifying
the role of this polymorphism in conferring
risk for psychosis, we examined a large group
of culturally and ethnically akin Palestinian
Arab schizophrenic triads (N ¼ 276) using
both a case–control and family-based study.
In 194 informative triads with at least one
heterozygote parent, no preferential transmission of either COMT allele was observed
in this sample (TDT statistic chi-square ¼
0.14 NS; 131 COMT valine alleles were transmitted and 125 alleles not transmitted).
However, using a case–control design a
Grant sponsor: Deutsche Forschungsgemeinschaft; Grant
number: Ri 908/3-1.
*Correspondence to: R.P. Ebstein, Research Laboratory, S.
Herzog Memorial Hospital, Rehov Givat Shaul, P.O. Box 35300,
Givat Shaul, Jerusalem 91351, Israel.
E-mail: ebstein@netvision.net.il
Received 14 October 2002; Accepted 9 December 2002
DOI 10.1002/ajmg.b.20008
ß 2003 Wiley-Liss, Inc.
significant increase (Likelihood ratio ¼ 3.935,
P ¼ 0.047) in the valine allele was observed in
the group of schizophrenic patients (N ¼ 276)
compared to an ethnically matched control
group (N ¼ 77). The association was stronger
in female patients (P ¼ 0.012) similar to other
studies showing that some COMT behavioral
effects are gender sensitive. In summary, by
case–control design but not by a familybased study, there is a weak effect in female
patients of the high activity COMT allele in
conferring risk for schizophrenia.
ß 2003 Wiley-Liss, Inc.
KEY WORDS: catechol-O-methyltransferase; schizophrenia; Arab;
transmission disequilibrium
test; association; linkage
INTRODUCTION
Catechol-O-methyltransferase (COMT) is a ubiquitous enzyme crucial to catechol metabolism [Mannisto
and Kaakkola, 1999]. The physiological substrates of
COMT include L-dopa, catecholamines (dopamine, norepinephrine, epinephrine), their hydroxylated metabolites, and catecholestrogens. The level of COMT enzyme
activity is genetically polymorphic in human tissues
with a trimodal distribution of low, intermediate, and
high activities [Weinshilboum and Raymond, 1977].
This polymorphism, which according to segregation
analysis of family studies is caused by autosomal codominant alleles, leads to three to fourfold differences in
COMT activity in human erythrocytes and liver. Low
COMT activity is associated with enzyme thermolability, even at 378C. The molecular basis of the thermolability is due to a substitution of valine by methionine,
(Val158/108Met) caused by transition of guanine to
36
Kremer et al.
adenine at codon 158 of the COMT gene [Lotta et al.,
1995; Lachman et al., 1996b].
Many genetic studies have focused on the possible
clinical relevancy of the COMT polymorphism in psychiatric disorders. Although some of these yielded
uncertain results there are several disorders in which
some relationship has been observed. First, obsessivecompulsive disorder (OCD) has been correlated in some
[Karayiorgou et al., 1997, 1999; Alsobrook et al., 2002]
but not all studies [Ohara et al., 1998] to low COMT
activity alleles. Second, low COMT activity allele appears to be associated with aggressive and highly
antisocial impulsive schizophrenia [Strous et al., 1997a;
Lachman et al., 1998; Kotler et al., 1999]. The high
enzyme activity COMT valine allele has also been shown
to confer risk for polysubstance abuse and heroin
addiction [Vandenbergh et al., 1997; Horowitz et al.,
2000].
Of special interest is the role of this gene in major
psychoses especially since a microdeletion (22q11) containing the COMT gene (velo-cardio-facial syndrome)
also carries with it several types of behavioral disorders,
including a higher prevalence of schizophrenia than in
the general population [Pulver et al., 1994; Lachman
et al., 1996a; Murphy et al., 1998, 1999]. Almost 20
genetic studies have examined the role of COMT in
schizophrenia with ambiguous results [Chen et al.,
1996; Li et al., 1996; Karayiorgou et al., 1997, 1999;
Kunugi et al., 1997; Strous et al., 1997a,b; Ohmori et al.,
1998; Wei and Hemmings, 1999; Nolan et al., 2000; de
Chaldee et al., 2001; Egan et al., 2001; Liou et al., 2001;
Semwal et al., 2001]. Six of these studies were based on a
family-based design [Kunugi et al., 1997; de Chaldee
et al., 1999, 2001; Wei and Hemmings, 1999; Egan et al.,
2001; Semwal et al., 2001]. The most recent familybased study in a Chinese population examined the
transmission of five SNP markers in the COMT gene
from parents to schizophrenic offspring in 166 trios
and found no evidence for preferential transmission
of any allele or haplotype [Fan et al., 2002]. A recent
case–control study of a large number of non-related
Ashkenazi Jews showed a highly significant association
between haplotypes at the COMT locus and schizophrenia [Shifman et al., 2002]. On the other hand, a British
study also with a substantial number of patients failed
to find an association using a case–control design when
two polymorphisms (Val158/108Met and a promoter
region variant) in the COMT gene were examined
[Norton et al., 2002].
A recent article by Egan et al. [2001] rekindled
interest regarding the role of COMT in schizophrenia.
These authors found that the COMT genotype was
related in allele dosage fashion to performance on the
Wisconsin Card Sorting Test of executive cognition.
Consistent with other evidence that dopamine enhances
prefrontal neuronal function the low-activity methionine allele predicted enhanced cognitive performance.
The effect of COMT genotype on prefrontal physiology
during a working memory task assayed with functional
MRI was then examined. Subjects with the methionine
allele showed a more efficient physiological response in
prefrontal cortex. Finally, in a family-based association
analysis of 104 trios, Egan et al. [2001] found a
significant increase in transmission of the valine allele
to the schizophrenic offspring. The authors interpreted
their results to suggest that the COMT valine allele,
because it increases prefrontal dopamine catabolism,
impairs prefrontal cognition and physiology, and by this
mechanism slightly increases risk for schizophrenia.
The intriguing finding of Egan et al. [2001] prompted
us to examine the COMT polymorphism and schizophrenia in the largest group of nuclear families (parents
and proband) so far examined for this gene. The robust
transmission disequilibrium test design [Spielman et al.,
1993; Ewens and Spielman, 1995] that is not sensitive to
population admixture, a common cause of type I errors
in case–control studies, was employed in the analysis.
Schizophrenic subjects were recruited from a culturally
and ethnically akin Palestinian Arab population that we
are studying in schizophrenia [Dobrusin et al., 2001;
Murad et al., 2001] and bipolar disorder [Mujaheed
et al., 2000]. In addition to the TDT design we also
examined the association between COMT and schizophrenia using a case–control strategy.
MATERIALS AND METHODS
Clinical Sample
All patients were interviewed by an experienced psychiatrist using the SCID interview. Diagnosis of schizophrenia was assigned on the basis of the interview and
medical records according to DSM IV criteria [American
Psychiatric Association, 1994]. The sample was constituted of 248 nuclear families (276 probands) from
3 different centers: 136 families from Bethlehem,
62 families from Afula, and 50 families from Beersheba.
Twenty-four families contained more than one affected
child. The mean age of the schizophrenic probands was
34.8 13.6 years and included 31% men and 69%
women. The average age of onset was 21.0 4.8.
The control sample consisted of Palestinian Arabs
recruited from the Northern area of Israel. Their
average age was 39.5 15.5 years and consisted of 31%
men and 69% women. The control group was randomly
recruited from subjects visiting a family medicine (not
psychiatric) national health care clinic (Kupat Holim) or
minor medical ailments.
The protocol for recruiting both control and schizophrenic families was approved by the local IRB
committees and all subjects or their legal representative
gave informed consent.
Genotyping
Genomic DNA containing the COMT polymorphism
was amplified as previously described in our laboratory
[Eisenberg et al., 1999] using the following primers:
F 50 ACT GTG GCT ACT CAG CTG TG 30
R 50 CCT TTT TCC AGG TCT GAC AA 30 .
The PCR product was purified using exonuclease 1 and
SAP (shrimp alkaline phosphatase) for 15 min at 808C.
Following purification the Val158/108Met polymorphism was genotyped using a ABI PRISM1 SNaPshotTM Multiplex System for SNP Analysis (Applied
COMT and Schizophrenia
Biosystems, Foster City, CA). The primer used in the
sequencing/extension reaction was 50 TGC ACA CCT
TGT CCT TCA 30 . The polymorphism extension products were identified using an ABI Prism 310 Genetic
Analyzer.
TABLE II. COMT Allele Frequency Tabulated by
Diagnosis Sex
Male
Val
Met
Statistical Procedures
All statistical analyses were carried out using SPSS
for Windows. Power calculations were carried out
courtesy of a convenient web site (http://statgen.iop.
kcl.ac.uk/gpc/) kindly maintained by S. Purcell and P.
Sham at the Social, Genetic & Developmental Research
Centre, London. The TDT test was carried out as
described in the article by Daly and his colleagues [Daly
et al., 1999]. All significance levels were two-sided. No
correction was made for Type I error rate.
37
Female
Val
Met
Control
Patients
Total
22
91.67
2
8.33
24
31
58.49
22
41.51
53
124
77.02
37
22.98
161
73
77.66
21
22.34
94
146
Count
%
Count
%
Total count
Count
%
Count
%
Total count
39
185
104
43
147
statistic ¼ 1.64, P ¼ 0.2; female probands TDT statistic ¼
0.576, P ¼ 0.45).
RESULTS
Genotype and allele frequency of the COMT Val158/
108Met polymorphism in schizophrenic patients and an
ethnically matched control group is shown in Table I.
There is an insignificant excess of the valine/valine
genotype (Likelihood ratio ¼ 4.02, P ¼ 0.134, 2df) in the
schizophrenic subjects. However, when allele frequencies are compared excess of the valine allele in schizophrenia attains significance (Likelihood ratio ¼ 3.935,
P ¼ 0.047, 1df). The odds ratio indicated a minor effect of
the valine allele in this population (OR ¼ 1.19; 95% CI
1.01–1.402) as observed in some [Egan et al., 2001] but
not all previous studies of schizophrenia. Interestingly,
when subjects are examined by gender diagnosis
(Table II) the association between the valine allele and
schizophrenia is significant in female patients (Likelihood ratio ¼ 5.89, P ¼ 0.015) but not in male subjects
(Likelihood ratio ¼ 3.21, P ¼ 0.073). Indeed in male
subjects, the trend is in the opposite direction for
decreased prevalence of the valine allele in the schizophrenic group.
Possible preferential transmission of alleles was also
examined in informative families using the TDT design
that examines transmission of either the valine or
methionine allele from a heterozygote parent to the
proband. As shown in Table III, no preferential transmission of either allele was observed (TDT statistic ¼
0.14, NS) in the entire sample and when each geographical recruitment center was separately examined. Nor
was any preferential transmission observed when
probands were sorted by gender (male probands TDT
DISCUSSION
By case–control analysis the current study offers
weak support to some findings showing an excess of the
COMT high enzyme valine allele in schizophrenia. Interestingly, these results are only significant in female
subjects. This tendency may be related to consistent
gender effects in schizophrenia; male patients having an
earlier age of onset, poorer functional outcome, greater
negative symptoms and cognitive impairment, and less
severe positive symptoms [Leung and Chue, 2000;
Moriarty et al., 2001; Roy et al., 2001]. Regarding
cognitive function the direction of the gender difference is unclear and two recent articles suggest that
female patients show more cognitive impairment
[Faraone et al., 2000; Weiser et al., 2000]. In a recent
case–control study of a large number of Ashkenazi Jews
the association with schizophrenia was also stronger for
some haploytpes in female patients [Shifman et al.,
2002].
When we attempted to validate our case–control
findings using a family based design, no evidence for
preferential transmission of the valine allele from
heterozygous parent to proband was observed overall
as well as when families with male and female probands
were examined separately. Failure to observe a significant association using the TDT design suggests that
the results obtained using the case–control approach is
a false positive, perhaps related to undetected population stratification in our sample of Palestinian Arabs
[Hamer and Sirota, 2000]. However, an alternative
TABLE I. COMT Genotype and Allele Frequency of Schizophrenic Patients and Ethnically
Matched Control Subjects
Genotype
Control
SCZ
Count
%
Count
%
Total
Allele
Val/val
Val/met
Met/met
Total
Val
Met
Total
14
18.18
77
27.90
91
39
50.65
136
49.28
175
24
31.17
63
22.83
87
77
100
276
100
353
67
43.51
290
52.54
357
87
56.49
262
47.46
349
154
100
552
100
706
38
Kremer et al.
TABLE III. TDT Analysis of Val108/Met108 Allele Transmission
From a Heterozygote Parent to Schizophrenic Proband
All locations
Val
Met
Bethlehem
Val
Met
Afula
Val
Met
Beersheva
Val108
Met108
Transmitted
Not transmitted
de Chaldee M, Laurent C, Thibaut F, Martinez M, Samolyk D, Petit M,
Campion D, Mallet J. 1999. Linkage disequilibrium on the COMT gene
in French schizophrenics and controls. Am J Med Genet 88(5):452–
457.
131
125
125
131
de Chaldee M, Corbex M, Campion D, Jay M, Samolyk D, Petit M, Thibaut F,
Laurent C, Mallet J. 2001. No evidence for linkage between COMT and
schizophrenia in a French population. Psychiatry Res 102(1):87–90.
77
72
72
77
32
33
33
32
22
20
20
22
explanation related to power considerations also needs
to be addressed. For example, the minor risk conferred
by the valine allele for schizophrenia calculated from the
current case–control design suggests that our sample of
276 triads is unlikely to provide sufficient power to
detect preferential transmission of the valine allele
using the TDT design. Indeed, a sample size of several
thousand (3,792 triads, 80% power) would be required
for detecting preferential transmission of the valine
allele assuming a genotype relative risk (valine/valine)
of 1.2 for the valine/valine homozygotes.
The COMT Val158/108Met allele in schizophrenia
should be evaluated in light of a recent article by
Ioannidis et al. [2001] who evaluated by meta-analysis
370 studies addressing 36 genetic associations for
various outcomes of disease. Significant between-study
heterogeneity (diversity) is frequent, and that the
results of the first study correlate only modestly with
subsequent research on the same association. The first
study often suggests a stronger genetic effect than is
found by subsequent studies. Both bias and genuine
population diversity might explain why early association studies tend to overestimate the disease protection
or predisposition conferred by a genetic polymorphism.
The authors conclude that a systematic meta-analytic
approach may assist in estimating population-wide effects of genetic risk factors in human disease. Undoubtedly, a meta-analysis including case–control and
family-based studies of the role of COMT in schizophrenia is required to resolve the role of this polymorphism in
schizophrenia.
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base, catechol, methyltransferases, family, stud, arab, among, schizophrenia, palestinians, caseтауcontrol
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