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Association of catechol-O-methyl transferase (COMT) gene 287AG polymorphism with susceptibility to obsessiveЦcompulsive disorder in Chinese Han population.

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RESEARCH ARTICLE
Neuropsychiatric Genetics
Association of Catechol-O-Methyl Transferase
(COMT) Gene 287A/G Polymorphism With
Susceptibility to Obsessive–Compulsive Disorder
in Chinese Han Population
Shiguo Liu,1,2,3 Yanhui Liu,4,5 Haiping Wang,6 Ruiling Zhou,7 Jinbao Zong,6 Changgui Li,1,2
Xinhua Zhang,4,8* and Xu Ma9,10,11**
1
Shandong Provincial Key Laboratory of Metabolic Disease, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, China
2
Institute of Clinical Research, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, China
3
Genetic Laboratory, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, China
Department of Psychiatry, Medical College, Qingdao University, Qingdao, China
4
5
Binzhou Youfu Hospital, Shandong, China
6
The Affiliated Hospital of Medical College, Qingdao University, Qingdao, China
Rizhao People’s Hospital, Shandong, China
7
8
Psychological Clinic, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, China
9
Graduate School, Peking Union Medical College, Beijing, China
National Research Institute for Family Planning, Beijing, China
10
11
World Health Organization Collaborating Centre for Research in Human Reproduction, Beijing, China
Received 29 July 2010; Accepted 3 January 2011
How to Cite this Article:
Several studies suggested a genetic component in the etiology
of obsessive–compulsive disorder (OCD). COMT involves in
the degradation of dopamine and norepinephrin. As another
functional SNP locus, COMT 287A/G polymorphism showed
an effect on enzyme activity, suggesting that it may influence
brain dopamine levels. To identify association of COMT 287A/
G polymorphism with susceptibility to OCD in Chinese Han
population. We evaluate the genetic contribution of the COMT
287A/G polymorphism in 200 OCD patients and 403 OCD-free
control of Chinese Han population by PCR-RFLP. In addition,
we investigate whether COMT 287A/G polymorphism is associated with one or more of these symptom dimensions or
other characteristics such as sex, age of onset, and tic-relatedness
and evaluate the association of the factorial structure of OCD
symptoms from the Y-BOCS checklist with the COMT 287A/G
polymorphism. A statistical difference was found in the genotypic frequencies of COMT 287A/G between the OCD and
control groups (c2 ¼ 13.99, DF ¼ 2, P ¼ 0.00091) and in
the genotypic frequencies of GG genotype versus AA and AG
genotypes of COMT 287 (c2 ¼ 13.49, DF ¼ 1, P ¼ 0.00024,
OR ¼ 3.43, 95% CI ¼ 1.78–6.62). There was a trend for an
association in the genotypic distributions of COMT 287A/G
polymorphism of males (c2 ¼ 27.81; DF ¼ 2; P < 0.001)
and females (c2 ¼ 7.31; DF ¼ 2; P ¼ 0.026) between the OCD
patients and the controls. Using principal component analysis,
we derived 5 factors from 12 main contents of OCD symptoms
2011 Wiley-Liss, Inc.
Liu S, Liu Y, Wang H, Zhou R, Zong J, Li C,
Zhang X, Ma X. 2011. Association of
Catechol-O-Methyl Transferase (COMT)
Gene 287A/G Polymorphism With
Susceptibility to Obsessive–Compulsive
Disorder in Chinese Han Population.
Am J Med Genet Part B 156:393–400.
Grant sponsor: National Basic Research Program of China; Grant number:
2007CB511905; Grant sponsor: National Infrastructure Program of
Chinese Genetic Resources; Grant number: 2006DKA21300; Grant
sponsor: National Natural Science Foundation of China; Grant number:
30470953.
Shiguo Liu and Yanhui Liu contributed equally to this work.
*Correspondence to:
Xinhua Zhang, M.D., Department of Psychology and Psychiatry, Medical
College, Qingdao University, Qingdao 266021, China.
E-mail: xhzhang87@126.com
**Correspondence to:
Prof. Xu Ma, Center for Genetics, National Research Institute for Family
Planning, 12, Dahuisi Road, Haidian, Beijing 100081 China.
E-mail: genetics@263.net.cn
Published online 22 February 2011 in Wiley Online Library
(wileyonlinelibrary.com).
DOI 10.1002/ajmg.b.31173
393
394
from the Y-BOCS checklist and found no association with COMT
287A/G polymorphism. Our study supports the involvement of
the COMT 287A/G polymorphism in the genetic susceptibility
to OCD in Chinese Han population. 2011 Wiley-Liss, Inc.
Key words: COMT 287A/G polymorphism; OCD; principal
component analysis; genotype and phenotype
INTRODUCTION
Obsessive–compulsive disorder (OCD) is a common and severe
neuropsychiatric illness characterized by anxiety-producing intrusive thoughts and performance of anxiety-reducing rituals and
affects an estimated 1% of the Chinese mainland population. With
rapid development of science and technology and changes of life
style, the prevalence and epidemiology of this disorder is experiencing a dramatically increase in China. Furthermore, OCD is ranked 1
of the 10 most disabling medical conditions by the World Health
Organization (WHO). Despite controlled family studies [Bellodi
et al., 1992; Pauls et al., 1995] and twin studies [Inouye, 1965; The
Clomipramine Collaborative Study Group, 1991; Chouinard,
1992] in OCD suggest a genetic component in the etiology of
OCD, the exact disease etiology remains poorly understood. It is
believed that susceptibility to OCD is determined by the interactions of multiple genetic loci with unknown environmental factors
[Fontenelle and Hasler, 2008]. As a result, a great deal of research
has been focused on identifying OCD susceptibility genes. Thus far,
two strong linkage loci for OCD including 9p24 [Hanna et al., 2002]
and 3q27-28 [Shugart et al., 2006] have been suggested by genomewide screenings. Candidate gene approach has suggested evidence
for several genes relevant to neuronal signaling susceptibility to
OCD, such as dopamine neurotransmission (including Dopamine
transporter gene DAT1, dopamine receptor genes DRD2-4) [Frisch
et al., 2000; Hemmings et al., 2003] and serotonin neurotransmission (serotonin transporter gene 5-HTT [McDougle et al., 1998;
Hu et al., 2006], serotonin receptor genes 5-HT2A [Nicolini
et al., 1996; Walitza et al., 2002], tryptophan hydroxylase (TPH)
[Frisch et al., 2000; Han et al., 1999]), metabolism of neurotransmitters cathecholamine-O-methyl transferase (COMT) [Schindler
et al., 2000; Pooley et al., 2007], monoamineoxidase A (MAO-A)
[Karayiorgou et al., 1999; Camarena et al., 2001].
COMT, located at chromosome 22q11 [Grossman et al., 1992], is
a key enzyme which metabolizes monoamine neurotransmitters
and involves in the degradation of dopamine and norepinephrin,
and is of particular importance for the clearance of dopamine in the
prefrontal cortex. It has been previously described that patients with
22q11 microdeletions manifest a number of psychiatric phenotypes, including schizophrenia and OCD, which suggest that
COMT may be one of the candidate genes of OCD [Karayiorgou
et al., 1999]. A more recent follow-up study on phenotypes observed
in patients with the 22q11 deletion reported OCD symptoms in the
majority of these patients, thus providing even stronger evidence
that the 22q11 locus harbors gene(s) predisposing to OCD
[Hemmings and Stein, 2006]. COMT c.472 G>A polymorphism
resulting in a valine (Val) to methionine (Met) amino acid substitution, is of particular interest functional SNP of COMT, which
affects dopamine regulation in the prefrontal cortex by reducing the
AMERICAN JOURNAL OF MEDICAL GENETICS PART B
activity of the enzyme to one quarter of that encoded by the Val
allele to alter the stability of the enzyme activity [Lachman et al.,
1996]. However, investigations of a possible role for a COMT
V158M polymorphism in OCD pathogenesis have generated conflicting results [Hemmings and Stein, 2006]. Some studies have
identified positive associations between the COMT and OCD
[Karayiorgou et al., 1997; Niehaus et al., 2001; Denys et al.,
2006; Pooley et al., 2007], while others have negative results
[Ohara et al., 1998; Erdal et al., 2003; Meira-Lima et al., 2004].
To clarify the global relevance of other functional variants of
COMT and OCD development, the possible association needs to
be confirmed by independent studies in different ethnic groups.
The objective of this present research was as follows: (1) to assess the
genetic association of 287A/G (rs2097063) polymorphism in
the promoter of COMT with OCD in Chinese Han population.
(2) To investigate whether the COMT 287A/G polymorphism is
associated with one or more of these symptom dimensions or
other characteristics such as sex, age of onset, and tic-relatedness.
And (3) to evaluate the association of the factorial structure of OCD
symptoms from the Y-BOCS checklist with the COMT 287A/G
polymorphism.
MATERIALS AND METHODS
Patient Population
Two hundred unrelated patients with OCD [mean age (SD) ¼ 28.9
(18.7) years; 35.5% females; 64.5% males] were recruited from the
Affiliated Hospital of Medical College, Qingdao University over a
period of 10 years (Table I). All OCD patients met the DSM-IV
criteria and clinical records for OCD. In addition, the MiniInternational Neuropsychiatric Interview (MINI, DSM-IV criteria)
was used as a diagnostic interview in the groups of patients, as well
as in the healthy control group. Subjects were excluded if they
presented with a movement disorder other than a tic, schizophrenia, recurrent major depression, bipolar disorder, mental retardation, alcohol or other substance abuses within the last 6 months, or a
history of psychosurgery, encephalitis, or significant head trauma.
Of the 200 subjects, 177 were taking medications (mainly selective
serotonin reuptake inhibitors (SSRIs), chlorimipramine, and lowdose benzodiazepines) and/or exposure/response-prevention behavioral therapy. The remaining 23 patients had not received any
TABLE I. Demographic Characteristics of OCD Patients and
Controls
Age, mean (SD)
Gender
Female
Male
a
OCD patients
28.9 (18.7)
Controls
30.2 (11.9)
71 (35.5%)
129 (64.5%)
155 (38.5%)
248 (61.5%)
t-Test.
Chi-square test (c2 ¼ 0.50, DF ¼ 1).
b
P-value
0.40a
0.48b
LIU ET AL.
treatment for their OCD symptoms at least within the previous
1–2 years. Four hundred three unrelated control individuals [mean
age (SD) ¼ 30.2 (11.9) years; 38.5%females; 61.5% males], were
recruited from at the students and volunteers at Qingdao University. All controls were included after being interviewed with the
Diagnostic Interview for Genetic Studies (DIGS) [Nurnberger
et al., 1994] and with the Family Interview for Genetic Studies to
confirm the absence of both personal and familial history of OCD
and other psychiatric disorders. The protocol was approved by the
Ethics Committees of the Affiliated Hospital of Medical College,
Qingdao University, and all subjects provided written informed
consent. In 200 cases, obsessions and compulsions were recorded
according to the Y-BOCS checklist, including more than 60 items
organized in seven categories of obsessions and seven categories of
compulsions.
Genotyping
The primers of COMT 287A/G used for PCR were as fellows:
forwards: 50 -TAGTAACAGACTGGCACGAA-30 and rewards: 50 GTTCAAAGGGCATTTATCATG-30 . The PCR reactions (25 ml)
contained 2 ng of genomic DNA, 2.5 ml of 10 PCR buffer, 3 ml
of 200 mM dNTPs, 1 ml of 10 pM of sense and antisense primers,
1.2 ml of 2.25 mM MgCl2, 0.4 U of Taq DNA polymerase, and 14.4 ml
of ddH2O. PCR were performed using a Thermocycler under the
following conditions: enzyme activation step at 94.0 C for 5 min,
and 35 alternating cycles of denaturation at 94.0 C for 30 sec
and reannealing at 60 C for 1 min and extension at 72.0 C for
1 min, and a final extension step at 72 C for 10 min. The
products (4 ml) were digested with HindIII (2.5 U) (New England
Biolabs, Beijing, China) in a reaction volume of 10 ml. There is
no cut with A allele, while the G allele resulted in digestion of the
350 bp fragment into 276 and 74 bp fragments. The restriction
fragment products were separated on 2% agarose gels stained
with ethidium bromide and viewed under UV light. More than
30 subjects were selected to confirm the genotype by DNA sequencing techniques.
Statistical Analysis
First, the genotypic and allelic frequency of patients and controls
were analyzed by chi-square test. Power analysis was performed
with the Genetic Power Calculator program, considering 0.05, twotailed [Purcell et al., 2003]. Second, to determine the number and
structural definition of specific dimensions, principal component
analysis applying a varimax rotation with the data from the Y-BOCS
checklist was performed following the methodology of Leckman
et al. [1997]. Briefly, a score of 0 or 1 was assigned to each of the
seven major obsessive symptom categories and to each of the seven
major compulsion categories of the Y-BOCS checklist as follows:
taking into account items noted as current, Responses on each of the
14 symptom categories of the Y-BOCS were scored 1 if at least one
item in the category had a check mark-indicating that the subject
presented with that symptom, 0 if none of the items was checked
[Feinstein et al., 2003]. Note that miscellaneous obsessions
and compulsions were excluded because each contained many
heterogeneous symptoms.
395
RESULTS
Case–Control Study
There were no differences in the age and gender distributions
between the OCD and control groups (Table I), and control groups
were in Hardy–Weinberg equilibrium (c2 ¼ 2.68, P ¼ 0.10). A
statistical difference was found in the genotypic frequencies of
COMT 287A/G polymorphism between the OCD and control
groups (c2 ¼ 13.99, DF ¼ 2, P ¼ 0.00091) and in the genotypic
frequencies of GG genotype versus AA and AG genotypes of COMT
287A/G (c2 ¼ 13.49, DF ¼ 1, P ¼ 0.00024, OR ¼ 3.43, 95% ¼
1.78–6.62). However, no statistical difference was observed in allelic
frequencies between the OCD and control groups (c2 ¼ 3.22,
DF ¼ 1, P ¼ 0.07, OR ¼ 1.29, 95% CI ¼ 0.82–2.04). There were also
no association between heterozygous AG genotype and homozygous for AA and GG genotype (c2 ¼ 1.91, DF ¼ 1, P ¼ 0.17,
OR ¼ 0.78, 95% CI ¼ 0.55–1.11) or AA genotypes versus AG and
GG (c2 ¼ 0.18, DF ¼ 1, P ¼ 0.67, OR ¼ 0.93, 95% CI ¼ 0.67–1.30)
(Table II).
There was a trend for an association in the genotypic distributions of COMT 287A/G polymorphism of males (c2 ¼ 27.81;
DF ¼ 2; P < 0.001) and females (c2 ¼ 7.31; DF ¼ 2; P ¼ 0.026)
between the OCD patients and the controls, while no association
was found in the allele frequencies of female (c2 ¼ 2.72, DF ¼ 1;
P ¼ 0.099) or male (c2 ¼ 0.64, DF ¼ 1; P ¼ 0.42). There was no
statistical in genotypic (c2 ¼ 2.12, DF ¼ 2; P ¼ 0.35) and allelic
(c2 ¼ 2.03, DF ¼ 1; P ¼ 0.16) frequencies on set age subgroups
<18 and 18, and between subgroups OCD with tic and without
tic in the observed genotypic (c2 ¼ 2.87, DF ¼ 2; P ¼ 0.24) and
allelic (c2 ¼ 0.19, DF ¼ 1; P ¼ 0.66) frequencies of 287A/G polymorphism (Table III).
Factor Analysis
In the category level factor analysis, we revealed five symptom
dimensions in the Y-BOCS checklist using principal component
analysis. Our factor solution shows a wide degree of consistency
with the data published previously, confirming the potential multidimensional structure of OCD [Baer, 1994]. The principal component analysis on OC contents from the Y-BOCS checklist yielded
the following five-factor solution (Table IV) that accounted for
71.80% of the total variance. The first factor accounted for 17.22%
of the variance and included hoarding obsessions and compulsions.
The second factor accounted for 15.89% and included contamination obsessions and cleaning compulsion. The third factor accounted for 14.95% and included symmetry obsessions and
ordering compulsions. The fourth factor accounted for 14.60%
and included aggressive obsession and checking compulsion. The
fifth factor accounted for 9.15% and included somatic obsession
and repeating compulsion.
Association Between Obsessive–Compulsion
Contents and Genotypes of COMT 287A/G
Polymorphism
We estimated the association between obsessive–compulsion contents and genetic distributions of COMT 287A/G polymorphism.
396
AMERICAN JOURNAL OF MEDICAL GENETICS PART B
TABLE II. Genotype and Allele Frequency of the COMT Gene Polymorphism in OCD Patients and Controls
Genotype
Total
AA
AG
GG
AG
AA þ GG
AA
AG þ GG
GG
AA þ AG
Allele
Total
G
A
OCD patients
Controls
200
115 (57.5%)
63 (31.5%)
22 (11.0%)
63 (31.5%)
137 (68.5%)
115 (57.5%)
85 (42.5%)
22 (11.0%)
178 (89.0%)
403
239 (59.3%)
150 (37.2%)
14 (3.5%)
150 (37.2%)
253 (62.8%)
239 (59.3%)
164 (40.7%)
14 (3.5%)
389 (96.5%)
400
107 (26.8%)
293 (73.3%)
806
178 (22.1%)
628 (77.9%)
x2
DF
P-value
13.99
2
0.00091*
1.91
1
0.18
OR
95% CI
0.17
0.78
0.55–1.11
1
0.67
0.93
0.67–1.30
13.49
1
0.00024*
3.43
1.78–6.62
3.22
1
0.07
1.29
0.82–2.04
P < 0.001.
a
Our findings suggest that there is no association between the
category-based factor of obsession–compulsion and genotypic
(Table V) and allelic frequencies (data of allele frequency not
shown). We also evaluate the association between five factors score
followed by principal component analysis and genetic distributions
of COMT 287A/G polymorphism, and no association was found
in genotypic (Table VI) and allelic frequencies (data of allele
frequency not shown).
DISCUSSION
Many studies indicate that catecholamine plays a major function in
the pathophysiology of OCD [Karayiorgou et al., 1997; Poyurovsky
et al., 2005; Denys et al., 2006; Pooley et al., 2007; Katerberg et al.,
2010]. COMT, as one of major genes that modulate CA neurotransmission, has become as a candidate gene for OCD for many
years. However, previous investigations in different population on
the role of the COMT polymorphism in the development of OCD
have produced inconsistent results [Ohara et al., 1998; Erdal
et al., 2003; Meira-Lima et al., 2004]. Some research groups
reported that COMT V158M polymorphism was associated with
OCD [Karayiorgou et al., 1997; Poyurovsky et al., 2005; Denys et al.,
2006; Pooley et al., 2007; Katerberg et al., 2010], while many others
found no association with susceptibility to OCD [Ohara et al., 1998;
Erdal et al., 2003; Meira-Lima et al., 2004]. Thus, it is necessary to
reevaluate the global relevance of other functional variants of
COMT and OCD development in different ethnic groups.
As another functional SNP locus, COMT 287A/G polymorphism showed an effect on enzyme activity, suggesting that it may
indeed influence brain dopamine levels [Chen et al., 2004; Funke
et al., 2005]. Several studies suggested that variations in the COMT
287A/G played a significant role in the development of some
diseases, such as habituation and other psychiatries [Cao et al.,
2003].
TABLE III. Difference in Sex, Age of Onset and Presence of Tics of Case–Control Association Study
Genotype
Group
Male OCD
Male control
Female OCD
Female control
Onset age <18
Onset age 18
OCD with tic
OCD without tic
*P < 0.001.
**P < 0.05.
N
129
248
71
155
108
92
11
189
AA
74 (57.4%)
140 (56.5%)
41 (57.7%)
99 (63.9%)
66 (61.1%)
49 (53.3%)
8 (72.7%)
107 (56.6%)
AG
41 (31.8%)
98 (39.5%)
22 (31.0%)
52 (33.5%)
33 (30.6%)
30 (32.6%)
1 (9.1%)
62 (32.8%)
Allele
GG
14 (10.9%)
10 (4.0%)
8 (11.3%)
4 (2.6%)
9 (8.3%)
13 (14.1%)
2 (18.2%)
20 (10.6%)
x2
27.81
P-value
0.00*
7.31
0.026**
2.12
0.35
2.87
0.24
G
69 (26.7%)
118 (23.8%)
38 (26.8%)
60 (19.4%)
51 (23.6%)
56 (30.4%)
5 (22.7%)
102 (27.0%)
A
189 (73.3%)
378 (76.2%)
104 (73.2%)
250 (80.6%)
165 (76.4%)
128 (69.6%)
17 (77.3%)
276 (73.0%)
x2
P-value
OR
95% CI
0.64
0.42
1.17
0.80–1.72
2.72
0.099
1.52
0.92–2.50
2.03
0.16
0.71
0.44–1.14
0.19
0.66
0.80
0.29–2.18
LIU ET AL.
397
TABLE IV. Varimax Ratated Factor Structure of the Yale-Brown Obsessive–Compulsive Scale Symptom Checklist in a Sample of 200
Patients With OCD
Obsession
Aggressive
Contamination
Sexual
Hoarding
Symmetry
Somatic
Compulsion
Cleaning
Checking
Repeating
Counting
Ordering
Hoarding
Variance explained, %
Factor1
hoarding
Factor2
contamination/cleaning
Factor3
symmetry/ordering
Factor4
aggressive/checking
Factor5
somatic/repeating
0.147
0.042
0.010
0.987
0.037
0.255
0.102
0.925
0.121
0.045
0.101
0.206
0.093
0.125
0.099
0.032
0.919
0.114
0.851
0.141
0.033
0.022
0.052
0.093
0.040
0.060
0.406
0.026
0.055
0.575
0.044
0.096
0.127
0.027
0.018
0.987
17.22
0.939
0.092
0.243
0.127
0.045
0.045
15.89
0.040
0.022
0.160
0.095
0.929
0.032
14.95
0.049
0.884
0.408
0.204
0.048
0.022
14.60
0.037
0.150
0.624
0.423
0.010
0.026
9.15
Factor loadings >0.5; principal component analysis; total variance explained >71.80; Eigenvalues over >1.
In our present case–control study, there is a trend for an
association between OCD patients and controls in genotypic
frequencies, whereas, lack of association between OCD patients
and controls in allelic frequencies or between homozygote genotype
and heterozygote genotype or between AA genotype versus AG and
GG genotypes of the COMT 287A/G polymorphism in Chinese
mainland Han population. But there is significant difference in
genotypic frequencies of GG versus AA and AG. As significant risk
between 287GG genotype and OCD (OR ¼ 3.43; 95% CI ¼ 1.78–6.62), It suggested that GG genotype have a susceptibility to OCD
and may operate a much stronger effect on the vulnerability to
OCD.
Although our studies found that there was remarkable difference
in genotypic frequencies of COMT 287A/G polymorphism between the OCD patients and the controls in both agenda, there was
no difference in allelic frequencies between female and male. In
several study on association between OCD and COMT V158M
polymorphism, Karayiorgou et al. [1997, 1999] reported that the
COMT L allele conferred a risk for the development of OCD,
particularly in L/L homozygous males. However, in a subsequent
study, conducted in a Japanese population, no association between
the functional variants of COMT and anxiety disorders, including
OCD, was detected [Ohara et al., 1998]. It is speculated that
susceptibility genes can operate in unison with one another such
that a particular combination of alleles has a much stronger effect
on the vulnerability to OCD than each separate allele. Our study
also found that there was no difference between OCD with tic and
without tic, or between onset age subgroups, <18 years versus 18
years. In the sample power of study, considering genotypic frequencies in our sample, our sample size had a high power (0.706) to
detect a small effect size, which suggested the sample size would be
sufficient.
Distinction between obsessions and compulsions is comfortably
established in clinical usage, there is mounting evidence to support
a more multidimensional view of OCD. Our principal component
analysis revealed five symptom dimensions in the Y-BOCS checklist. Our factor solution showed a wide degree of consistency with
the data published previously, confirming the potential multidimensional structure of OCD [Baer, 1994]. Some minor discrepancies between the studies might be attributable to the differences in
sample sizes, in some environmental factors and in the ethnicity of
the populations. The principal component analysis on OC contents
from the Y-BOCS checklist yielded the following five-factor solution that accounted for 71.80% of the total variance. The first factor
accounted for 17.22% of the variance and included hoarding
obsessions and compulsions. Hoarding has emerged as an independent factor in most previous factorial studies [Mataix-Cols
et al., 2005]. The familiality of hoarding has been previously
demonstrated using data from the OCD Collaborative Genetics
Study (OCGS) and the Johns Hopkins OCD Family Study, which
predated the OCGS. Samuels et al. [2002] reported that the firstdegree relatives of hoarding probands had a greater prevalence of
hoarding behavior than the relatives of non-hoarding probands,
and both Hasler et al. [2007] and Cullen et al. [2007] noted a
significant intrafamiliar sib–sib correlation for the hoarding factor.
When used as a predictor in treatment studies, the hoarding factor
also stands out as being associated with poorer response to SSRIs
[Black et al., 1998; Saxena et al., 2002] and greater likelihood of drop
out from cognitive behavior therapy [Pinto et al., 2007], although a
recent study found that hoarding and non-hoarding OCD patients
responded equally well to paroxetine [Saxena et al., 2007]. In
addition, hoarding is the only subphenotype for which genetic
linkage results have been reported. Further support for this subphenotype comes from studies of treatment response. The second
factor accounted for 15.89% of the variance and included contamination obsessions and cleaning compulsions. The combination of
these two categories is commonly supported not only by clinical
evidence but also by evidence from other studies [Nothen et al.,
398
AMERICAN JOURNAL OF MEDICAL GENETICS PART B
TABLE V. Association Between Obsessive–Compulsion Contents (Present/Absent) and COMT 287 Genotypes
Obsession
Aggressive
Present
Absent
Contamination
Present
Absent
Sexual
Present
Absent
Hoarding/saving
Present
Absent
Symmetry/exactness
Present
Absent
Miscellaneous
Present
Absent
Somatic
Present
Absent
Compulsion
Cleaning/washing
Present
Absent
Checking
Present
Absent
Repeating
Present
Absent
Counting
Present
Absent
Ordering/arranging
Present
Absent
Hoarding/collecting
Present
Absent
Miscellaneous
Present
Absent
AA (115)
AG (63)
GG (22)
x2 (DF ¼ 2)
P-value
68 (62.96%)
47 (51.09%)
27 (25.00%)
36 (39.13%)
13 (12.04%)
9 (9.78%)
4.60
0.10
27 (57.45%)
88 (57.52%)
15 (31.91%)
48 (31.37%)
5 (10.64%)
17 (11.11%)
0.01
0.99
1 (50.00%)
114 (57.58%)
1 (50.00%)
62 (31.31%)
0 (0.00%)
22 (11.11%)
0.46
0.79
0 (0.00%)
115 (58.08%)
2 (100%)
61 (30.81%)
0 (0.00%)
22 (11.11%)
4.39
0.11
14 (48.28%)
101 (59.06%)
14 (48.28%)
49 (28.65%)
1 (3.45%)
21 (12.28%)
5.29
0.07
53 (54.08%)
62 (60.78%)
33 (33.67%)
30 (29.41%)
12 (12.24)
10 (9.80%)
0.95
0.62
10 (62.50%)
105 (57.07%)
4 (25.00%)
59 (32.07%)
2 (12.50%)
20 (10.87%)
0.34
0.84
27 (56.25%)
88 (57.89%)
15 (31.25%)
48 (31.58%)
6 (12.50%)
16 (10.53%)
0.15
0.93
76 (59.84%)
39 (53.42%)
34 (26.77%)
29 (39.73%)
17 (13.39%)
5 (6.85%)
4.60
0.10
8 (50.00%)
107 (58.15%)
4 (25.00%)
59 (32.07%)
4 (25.00%)
18 (9.78%)
3.5
0.17
2 (100%)
113 (57.07%)
0 (0.00%)
63 (31.82%)
0 (0.00%)
22 (11.11%)
1.49
0.47
9 (50.00%)
106 (58.24%)
9 (50.00%)
54 (29.67%)
0 (0.00%)
22 (12.09%)
4.52
0.10
0 (0.00%)
115 (58.08%)
2 (100%)
61 (30.81%)
0 (0.00%)
22 (11.11%)
4.39
0.11
42 (62.69%)
73 (54.89%)
18 (26.87)
45 (33.83)
7 (10.45%)
15 (11.29%)
1.19
0.55
Percentages of each content characterized by a specific genotype in (parentheses): Bonferroni correction for multiple testing P ¼ a/14 ¼ 0.0036.
1993; Baer, 1994; Leckman et al., 1997; Mataix-Cols et al., 1999].
The third factor accounted for 14.95% of the variance and included
symmetry obsession and ordering compulsion. The fourth factor
accounted for 14.60% of the variance and included aggressive
obsessions and checking compulsion. The combination of these
two categories is commonly supported by evidence from the study
of Mataix-Cols et al. [1999, 2002]. The fifth factor accounted for
9.15% of the variance and included somatic obsession and repeat-
ing compulsion. Mataix-Cols et al. classified obsessions with
hoarding and symmetry and compulsions with hoarding, ordering,
repeating, and counting into a single factor [Pinto et al., 2007].
However, unlike the results of Mataix-Cols et al. [Pinto et al., 2007],
in our study, we classified obsessions with hoarding and symmetry
and compulsions with hoarding, ordering, repeating, and somatic
into three factors, sexual obsession and counting compulsion was
not included in any of the five factors. The slight variations between
LIU ET AL.
399
TABLE VI. Analysis of Variance for the Three COMT 287 Genotype
Factor score
Hoarding
Contamination
Symmetry
Aggressive
Somatic
(115) AA
0.092 0.169
0.012 0.994
0.043 0.953
0.084 0.998
0.025 1.042
(63) AG
0.212 1.754
0.008 0.994
0.199 1.193
0.190 0.987
0.074 0.943
(22) GG
0.129 0.213
0.038 1.090
0.346 0.293
0.104 1.019
0.343 0.900
F
2.106
0.025
2.719
1.677
1.511
P-value
0.124
0.976
0.068
0.190
0.223
DF
2,197
2,197
2,197
2,197
2,197
P < 0.01.
studies on the inclusion of obsessions and compulsions in factors
reflect differences in sample sizes, social and cultural backgrounds,
and research methods.
We estimated the association between obsessive–compulsion
contents and genetic distributions of COMT 287A/G polymorphism. Our findings suggest that there is no association between the
category-based factor of obsession–compulsion and genotypic and
allelic frequencies (data of allele frequency not shown). This might
be the result of phenotypic heterogeneity of some of the categorybased symptom dimensions. A recent study by Pinto et al. [2007]
suggests that aggressive obsessions may be heterogeneous.
In conclusion, we found there were remarkable differences in the
genotypic frequencies of COMT 287A/G between the OCD and
control groups, and in the genotypic frequencies of GG genotype
versus AA and AG genotypes of COMT 287. There was a trend for
an association in the genotypic distributions of COMT 287A/G
polymorphism of males and females between the OCD patients and
the controls. Using principal component analysis, we derived five
factors from 12 main contents of OCD symptoms from the Y-BOCS
checklist and found no association with COMT 287A/G polymorphism. Our study supports the involvement of the COMT
287A/G polymorphism in the genetic susceptibility to OCD in
Chinese Han population. However, further investigations will be
needed to determine the association between COMT polymorphisms and OCD by using a larger sample size, different population,
and other SNPs.
ACKNOWLEDGMENTS
We thank all probands for their participation. This work was
supported by the National Basic Research Program of China
(2007CB511905), the National Infrastructure Program of Chinese
Genetic Resources (2006DKA21300), and the National Natural
Science Foundation of China (30470953).
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