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Preliminary evidence for an association between a dopamine D3 receptor gene variant and obsessive-compulsive personality disorder in patients with major depression.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 141B:409 –413 (2006)
Preliminary Evidence for an Association Between a
Dopamine D3 Receptor Gene Variant and
Obsessive-Compulsive Personality Disorder in
Patients With Major Depression
Katrina J. Light,1* Peter R. Joyce,1 Suzanne E. Luty,1 Roger T. Mulder,1 Christropher M.A. Frampton,1
Laura R.M. Joyce,1 Allison L. Miller,2 and Martin A. Kennedy2
1
Department of Psychological Medicine, Christchurch School of Medicine & Health Sciences, Christchurch, New Zealand
Department of Pathology, Christchurch School of Medicine & Health Sciences, Christchurch, New Zealand
2
We have previously reported that the Ser9Gly
dopamine D3 receptor (DRD3) polymorphism was
associated with increased rates of obsessivecompulsive personality disorder (OCPD) symptomology. We tested the replicability of this association within a further two independent groups of
individuals with a history of depression, from a
clinical sample (n ¼ 149) and a family study
(n ¼ 213). The data from the replication samples
and the original sample, within which the association was found, were compiled within a metaanalysis. Although the independent samples
did not replicate the original finding, the metaanalysis elucidated significant evidence supporting the association. An individual with Gly/Gly
genotype is 2.4 (P ¼ 0.017) times more likely to
be diagnosed with OCPD. Male gender was
also found to be a significant predictor of OCPD
diagnosis (OR ¼ 2.82, P ¼ 0.001). An exploration of
an association of DRD3 with Axis I anxiety
disorder diagnoses and Temperament and Character Inventory (TCI) traits, in particular persistence, revealed no support for an association. We
conclude that DRD3 may contribute to the development of OCPD.
ß 2006 Wiley-Liss, Inc.
KEY WORDS:
dopamine D3 receptor gene;
obsessive-compulsive personality
disorder
Please cite this article as follows: Light KJ, Joyce PR,
Luty SE, Mulder RT, Frampton CMA, Joyce LRM, Miller
AL, Kennedy MA. 2006. Preliminary Evidence for an
Association Between a Dopamine D3 Receptor Gene
Variant and Obsessive-Compulsive Personality Disorder in Patients With Major Depression. Am J Med Genet
Part B 141B:409–413.
INTRODUCTION
As a constituent of the dopaminergic system, the dopamine
D3 receptor (DRD3) has been recognized as a candidate locus
for voluntary behavior for sometime, however, as yet no
consistent association has emerged. One of the more common
DRD3 polymorphisms involves a residue change from serine to
glycine at position 9 of the N-terminal extracellular domain of
the receptor [Lannfelt et al., 1992]. The polymorphism can be
identified by the resultant creation of a BalI restriction enzyme
site and alteration of a MscI recognition site [Lannfelt et al.,
1992; Wong et al., 2000].
Knockout mice, in accordance with dopaminergic agonists
and antagonists that have a preferred affinity for the D3
receptor, support the notion that the DRD3 gene is involved in
the control of locomotor activity [Daly and Waddington, 1993;
Waters et al., 1994; Svensson et al., 1994a,b; Accili et al., 1996].
Similarly, downregulation of D3 receptor expression via the
administration of an antisense oligodeoxynucleotide results
in increased locomotor activity within rats [Menalled et al.,
1999].
Czermak et al. [2004] identified a significant negative
correlation between the expression of DRD3 (in peripheral
blood lymphocytes) and the personality trait of persistence.
The trait ‘persistence’ (using Cloninger’s Temperament and
Character Inventory (TCI)) is weakly correlated with obsessive-compulsive personality disorder (OCPD) symptoms, as
measured by the Structured Clinical Interview for DSM-III-R
Axis II Personality Disorders (SCID-II) [Mulder and Joyce,
1997].
Joyce et al. [2003] recently reported a novel association of
DRD3 with OCPD, which has yet to be replicated. The primary
purpose of this study is to attempt to replicate the finding using
two independent samples of depressed individuals. To identify
a consistent trend in association across the three samples, a
meta-analysis, with the benefit of its increased power, was
undertaken. OCPD is regarded as an ‘anxious’ personality
disorder [Samuels et al., 2000], consistent with increased
comorbidity of anxiety disorders, such as phobia and obsessivecompulsive disorder [Nestadt et al., 1991]. The secondary aims
of this study were to explore the possibility of an association
of DRD3 with Axis I anxiety diagnoses (including obsessivecompulsive disorder, panic disorder, simple and social
phobia) and also Cloninger’s temperament traits, in particular,
persistence.
METHODS
Grant sponsor: Health Research Council of New Zealand.
*Correspondence to: Katrina J. Light, Department of Psychological Medicine, Christchurch School of Medicine & Health
Sciences, PO Box 4345, Christchurch, New Zealand.
E-mail: katrina.light@chmeds.ac.nz
Received 27 September 2005; Accepted 5 January 2006
DOI 10.1002/ajmg.b.30308
ß 2006 Wiley-Liss, Inc.
Patient selection, assessment, and demographic information
for the original sample are reported by Joyce et al. [2003]. The
sample of 157 individuals included 151 New Zealand (NZ)
Europeans, 3 Maoris, 2 Asians, and 1 who identified as ‘other.’
This sample was recruited as part of a Christchurch Outcome
of Depression study examining predictors of outcome in
patients randomized to treatment with either fluoxetine or
nortriptyline [Joyce et al., 2002].
410
Light et al.
Replication Sample 1 (Clinical Sample)
Patients. The depressed patients within this clinical
sample were recruited for a study examining predictors of
response to interpersonal psychotherapy (IPT) and cognitivebehavioral therapy (CBT). This study was approved by the
Canterbury (New Zealand) Ethics Committee. Individuals
were 18 years or older, with a principal current diagnosis of
major depression. Patients were excluded if they had a history
of mania (i.e., bipolar I disorder) or schizophrenia, or a severe
current alcohol or drug dependence as their principal diagnosis. Patients were required to be physically healthy and to be
free of psychotropic drugs for a minimum of 2 weeks or five drug
half lives.
Assessment. After giving informed consent, the patients
attended a detailed clinical and neurobiological assessment,
which included giving a blood sample for DNA extraction. The
clinical assessment was conducted by a psychiatrist or clinical
psychologist using the Structured Clinical Interview for DSMIV (SCID) [Spitzer et al., 1992]. Ratings on the Hamilton and
Montgomery–Asberg [Montgomery and Asberg, 1979] depression rating scales were also made. Patients completed a series
of self-report questionnaires, including the SCID Personality
Questionnaire (SCID-PQ) and the TCI [Cloninger et al., 1993].
After these baseline assessments, patients were randomized to
treatment with either IPT or CBT. After commencing treatment, a trained psychiatrist or clinical psychologist completed
the SCID-II for DSM-IV [Spitzer et al., 1987] to assess the
presence of Axis II personality disorders.
The mean age of the sample was 34.8 years (SD, 10.3 years)
and 72.5% were female. Eighty-nine percent of the sample
were NZ Europeans, 5% were Asian, 5% were Maori, 2%
identified as ‘other,’ and one individual was a Pacific Islander.
The mean Montgomery–Asberg depression score was 23.8
(6.4), 72% had recurrent depression and 38% met DSM-IV
criteria for melancholia. Of the 177 depressed patients, DRD3
genotyping data and OCPD data were available for 152
individuals. This included three individuals who were part of
the sample in the original study, so their data were excluded,
yielding a final sample of 149 individuals.
Replication Sample 2 (Depressed
Individuals From a Family Study)
Patients. Subjects were recruited for a family study
examining the molecular genetics of mood disorders and
personality. Recruitment was via an advertisement for
subjects who had received treatment for a major depressive
episode (regardless of a history of mania or hypomania), and
had two parents and/or siblings who were willing to be involved
in the study. The full sample consisted of 127 probands, 98
mothers, 56 fathers, 67 sisters, and 30 brothers. To ensure
consistency with the other two samples, which were composed
solely of depressed individuals, only individuals in this study
who had received a principal affective diagnosis of major
depressive disorder, bipolar II or bipolar not otherwise
specified, were included as depressed individuals. This was to
have diagnostic consistency with the original and first
replication studies (which excluded bipolar I disorder). Of the
total 378 individuals, 237 had a history of non-bipolar I major
depression—this included 110 probands, 56 mothers, 16
fathers, 39 sisters, and 16 brothers. Only these 237 depressed
individuals were included in the analyses. This study was
approved by the Canterbury Ethics Committee, Christchurch,
New Zealand.
Assessment. Subjects gave written informed consent for
the study and were then interviewed by a trained research
interviewer. For Axis I diagnoses the major interview schedule
was the Mini-International Neuropsychiatric Interview
(MINI) [Sheehan et al., 1998], although the alcohol and drug
section of the MINI was replaced by the comparable modules of
the Structured Clinical Interview for DSM-III-R (SCID)
[Spitzer et al., 1992]. For selected Axis II personality disorders,
the interviewer asked structured questions about personality
traits and associated impairment, followed by the SCID-II
interview for DSM-IV [Spitzer et al., 1987] for all disorders
except paranoid and narcissistic personality disorders. After
each interview, a psychiatrist (PRJ) reviewed the interview
plus any other relevant diagnostic information (i.e., medical
records), from which DSM-IV diagnoses were assigned.
Further to this, individuals completed the TCI [Cloninger
et al., 1993]. Each individual provided a blood sample, from
which genomic DNA was extracted by the method of Ciulla
et al. [1988].
The mean age of the sample was 44.3 years (SD, 15.02).
Seventy-seven percent of the sample were females. Ninty-four
percent of the sample were NZ European, 4% were non-NZ
European, and 2% identified as being of ‘other’ ethnicity.
Within this sample, 42% had recurrent depression and 54%
met DSM-IV criteria for melancholia. Of the 237 depressed
individuals, DNA was available for 228. Fifteen of these 228
individuals had already been included within the original
study or replication sample 1. As such, replication sample 2
included 213 depressed individuals for whom complete genetic
and personality data were available.
Laboratory Methodology
As described in Joyce et al. [2003], the DRD3 Ser9Gly
polymorphism was assayed by a polymerase chain reaction
followed by digestion with MscI. This identified three genotypes (Ser/Ser, Ser/Gly, and Gly/Gly). Based on the original
findings, the following analyses characterized individuals by
the presence or absence of the Gly/Gly genotype.
Statistical Methods
Preliminary univariate analyses to identify differences in
age, gender, genotype, and OCPD diagnosis across the three
studies, were conducted. A one-way analysis of variance
(ANOVA) was used to evaluate age, while w2-tests were used
for the other three analyses. An association of age with rate of
OCPD diagnosis was examined using a one-way ANOVA.
Similarly, gender and rate of OCPD diagnosis were evaluated
using a chi-squared or Fisher’s exact test as appropriate, in
each of the three samples.
An association of the Gly/Gly genotype with OCPD was
examined using a Fisher’s exact test, within both replication
samples. A meta-analysis across the three samples was
conducted using Breslow-Day and Tarone’s homogeneity w2tests, Cochran’s and Mantel–Haenszel conditional independence w2-tests, and Mantel–Haenszel common odds ratio
estimate. Logistic regression was undertaken using the
presence or absence of OCPD as the dependent variable, and
age, gender, and presence or absence of the Gly/Gly genotype as
potential predictors. To identify the effect of more substantial
changes in age (i.e., per decade), the logistic regression
calculations utilized the following age groupings: 18–29 years,
30–39 years, 40–49 years, and 50þ years. A meta-analysis of
the logistic regression results used a combined dataset
(incorporating the three samples) and included the above
predictors, along with gender sample and genotype samsample. On the basis that these interactions were not
significant, just sample, age, gender, and genotype were
entered into the regression model.
An ANOVA was utilized to examine associations of the
dimensional measures of OCPD symptoms and TCI temperament traits with the Gly/Gly genotype in the individual
replication samples. The presence or absence of APA-defined
Axis I anxiety disorder diagnoses were each evaluated with
Dopamine D3 Receptor and Obsessive-Compulsive Personality Disorder
respect to the genetic polymorphism using a chi-squared or
Fisher’s exact test, in each replication sample.
RESULTS
Sample Characteristics
Within the original sample, the mean age was 32.4 years
(SD, 11.5 years), 43% were male and 96% were Caucasian. The
Ser9 and Gly9 allele frequencies were 66% and 34%, respectively. 8.3% (n ¼ 13) had been diagnosed with OCPD, of whom
the mean age was 32.5 years (SD, 14.9 years) and 76.9% were
male. The first replication sample had a mean age of 35.3 years
(SD, 10.3 years), 26% were males and 88% were Caucasian.
Within this sample, the Ser9 allele occurred in 69% and the
Gly9 allele 31%. 12.1% (n ¼ 18) of this sample had OCPD,
the mean age was 39.0 years (SD, 10.7 years) and 38.9% were
male. Within the second replication sample, the mean age was
44.8 years (SD, 15.0 years), 21.1% were male and 93% were
Caucasian. The allele frequencies of the Ser9 and Gly9 alleles
were 69% and 31%, respectively. 10.3% (n ¼ 22) had received
the diagnosis of OCPD, the mean age was 44.2 years (SD, 13.2
years) and 40.9% were male.
The three samples significantly differed in age (F ¼ 48.16,
df ¼ 2,516, P < 0.001) and gender distribution (w2 ¼ 22.5, df ¼ 2,
P < 0.001). Conversely, rate of OCPD diagnosis and presence of
Gly/Gly genotype was not significantly different across the
three samples. The allele frequencies of the three samples were
each in Hardy–Weinberg equilibrium and are comparable
with other studies [Lannfelt et al., 1992; Henderson et al.,
2000; Jonsson et al., 2003]. Age was not significantly associated
with rate of OCPD diagnosis across the three studies, while
gender was associated (OR ¼ 2.9, 95% CI ¼ 1.6–5.4, P < 0.001).
There was a significantly greater propensity for males to have
been diagnosed with OCPD in the original (OR ¼ 4.9, 95%
CI ¼ 1.3–18.7, P ¼ 0.011) and second replication samples
(OR ¼ 2.9, 95% CI ¼ 1.2–7.5, P ¼ 0.025). This trend was also
present within the first replication sample, but was not
significant (OR ¼ 2.0, 95% CI ¼ 0.7–5.5, P ¼ 0.251).
DRD3 Polymorphism and
Obsessive-Compulsive Personality Disorder
No support for an association of OCPD diagnosis with the
presence of the Gly/Gly genotype was found in either of the
replication samples (Table I). However, tests for homogeneity
of the odds ratios illustrated that the three samples did not
significantly differ with respect to the association of an OCPD
diagnosis with the presence of a Gly/Gly genotype (w2 ¼ 3.12,
df ¼ 2, P ¼ 0.210). Further to this, Cochran’s and Mantel–
Haenszel tests of conditional independence indicated an
411
overall significant association across the studies (Cochran’s:
w2 ¼ 6.13, df ¼ 1, P ¼ 0.013; Mantel–Haenszel: w2 ¼ 4.99, df ¼ 1,
P ¼ 0.025). Therefore, although the two replication samples did
not individually contribute support, a meta-analysis of these
samples as well as the original sample identified a consistent
association of the Gly/Gly genotype with the presence of an
OCPD.
Multivariate logistic regression analyses were applied to
each of the three samples, incorporating age, gender, and Gly/
Gly genotype as potential predictors of OCPD diagnosis
(Table II). The original sample identified the presence of
homozygous glycine alleles and male gender as being significant predictors (OR ¼ 7.30, 95% CI ¼ 1.9–28.2, P ¼ 0.004
and OR ¼ 5.37, 95% CI ¼ 1.3–21.7, P ¼ 0.018, respectively).
Similarly, the second replication sample identified the
male gender as a significant predictor of OCPD diagnosis
(OR ¼ 3.0, 95% CI ¼ 1.2–7.7, P ¼ 0.020). The proposed multivariate model showed no significant effects within the first
replication sample. A meta-analysis of the three studies
elucidated the Gly/Gly genotype (OR ¼ 2.53, 95% CI ¼ 1.2–
5.4, P ¼ 0.016) and male gender (OR ¼ 2.82, 95% CI ¼ 1.5–5.1,
P ¼ 0.001) as significant predictors, independent of study, for
occurrence of OCPD. Exclusion of non-Caucasian individuals
did not alter the results for either the individual studies or the
meta-analysis.
Although the number of OCPD symptoms was significantly
associated with presence of the Gly/Gly genotype (F
(1,155) ¼ 4.85, P ¼ 0.029) within the original sample, no
support for such an association was found in either of the
replication samples.
DRD3 Polymorphism and Axis I Anxiety Disorder
Diagnoses and TCI Temperament Traits
Within the original sample, DRD3 genotype was significantly associated with obsessive-compulsive disorder (OCD)
diagnosis (w2 ¼ 6.21, df ¼ 2, P ¼ 0.045), yet the presence of a
Gly/Gly genotype did not appear to be associated. Similarly,
Gly/Gly genotype was not significantly associated with OCD
diagnosis in either of the replication samples. None of the
phobic disorders or panic disorder were found to be associated
with Gly/Gly genotype. Furthermore, both replication samples
failed to find support for a significant association of Gly/Gly
genotype with any of Cloninger’s temperament measures,
including persistence.
DISCUSSION
In this study we set out to replicate an association of the
DRD3 Gly/Gly genotype with OCPD. Two independent
TABLE I. DRD3 Ser9Gly Genotype Frequency Among Individuals With and Without Obsessive-Compulsive Personality Disorder
(OCPD) Diagnosis, in Three Independent Samples
Genotype
Previous study
Without OCPD (n ¼ 144)
With OCPD (n ¼ 13)
Replication sample 1
Without OCPD (n ¼ 131)
With OCPD (n ¼ 18)
Replication sample 2
Without OCPD (n ¼ 191)
With OCPD (n ¼ 22)
Meta-analysis
Without OCPD (n ¼ 466)
With OCPD (n ¼ 53)
Ser/Ser
Ser/Gly
Gly/Gly
Presence of Gly/Gly
genotype OR (95% CI)
P-value
46% (66)
15% (2)
45% (65)
46% (6)
9% (13)
38% (5)
6.30 (1.8–22.08)
0.008
50% (66)
44% (8)
39% (51)
39% (7)
11% (14)
17% (3)
1.67 (0.43–6.5)
0.435
48% (91)
50% (11)
43% (82)
36% (8)
9% (18)
14% (3)
1.52 (0.41–5.63)
0.462
48% (223)
40% (21)
42% (198)
40% (21)
10% (45)
21% (11)
2.44 (1.18–5.05)
0.017
412
Light et al.
TABLE II. Multivariate Logistic Regression Predicting Obsessive-Compulsive PD Diagnosis in
Three Samples Adjusting for Age and Gender and a Meta-Analysis
Previous study
Predictor
Gly/Gly genotype
Age (per decade)
Male
Sample 1
Sample 2
Meta-analysis
OR
P-value
OR
P-value
OR
P-value
OR
P-value
7.298
1.071
5.374
0.004
0.819
0.018
2.010
1.470
2.224
0.329
0.148
0.137
1.340
0.965
3.023
0.671
0.871
0.020
2.527
1.113
2.821
0.016
0.462
0.001
samples of depressed individuals failed to individually yield
support for a previously identified association; however, a
meta-analysis of the three samples elucidated an overall
significant association, whereby an individual with Gly/Gly
genotype is 2.4 times more likely to be diagnosed with OCPD.
As with all single-gene association studies, our findings need to
be interpreted tentatively within the broader context of OCPD
etiology. The DRD3 provides just one explanation for OCPD
behavior and hypothesizing how it does so is complicated by the
paucity of research relating to this personality disorder.
The DRD3 Ser9Gly mutation does not affect the insertion of
the receptor into the membrane [Lundstrom and Turpin,
1996]. Instead the mutation, although it occurs within the
extracellular N-terminus and hence is unlikely to affect
agonist or antagonist binding, has demonstrated significantly
higher affinity for dopamine [Lundstrom and Turpin, 1996].
The specific influence of this polymorphism on an animal
behavior has yet to be modeled. However, functional analyses
using knockout mice, DRD3 agonists and antagonists suggest
that this receptor is involved in locomotor inhibition [Daly and
Waddington, 1993; Waters et al., 1994; Svensson et al.,
1994a,b; Accili et al., 1996]. This is corroborated by the finding
of functional D3 receptors specifically throughout the ‘‘motor’’
circuit [Larson and Ariano, 1995].
Clarification is required regarding the etiology of obsessivecompulsive behavior. For example, based on our findings
implicating DRD3 as a risk factor for OCPD, it could be
suggested that such behavior arises from impairment in one’s
motor control, utilization of sensory information, and/or
reward system. Firstly, evidence for impaired motor control,
as a result of DRD3, has been presented above. Consistent with
this, Villemarette-Pittman et al. [2004], based on findings of cooccurrence of OCPD with impulsive aggression, proposed that
OCPD may be a compensatory mechanism for some individuals
that have innate behavioral disinhibition. Secondly, DRD3
mRNA has been identified within the sensory relay nuclei,
suggesting a possible role in modality-specific sensory processing [Sokoloff et al., 1990; Suzuki et al., 1998]. Sachdev and
Malhi [2005], in their proposal of obsessive-compulsive
disorder (OCD) as a disorder of decision-making, suggested
that sensory-perceptual evidence is ineffective within individuals with OCD. While there is only partial phenotypic overlap
between OCD and OCPD, it is possible that OCPD individuals
may have impaired sensory information processing. Thirdly,
mice mutant for the D3 receptor, as well as DRD3 agonists and
antagonists, have suggested an inhibitory influence of the
receptor on reward mechanisms [Caine and Koob, 1993; KlingPetersen et al., 1995; Xu et al., 1997]. Individuals with OCPD
are characterized by unrelenting perfectionism, which is
evident in their excessive devotedness to work and selfcriticalness [Villemarette-Pittman et al., 2004].
In addition to our finding of an association of DRD3 with
OCPD, we also found gender to be a significant predictor of
OCPD within the original and second replication sample, and a
trend towards an effect was present within the first replication
sample. In the meta-analysis, male gender increased risk of
OCPD 2.8 times. The finding of an increased prevalence in
males is concordant with the findings of an epidemiological
survey conducted in Baltimore, MD [Nestadt et al., 1991].
Within this community-based survey, there were five times
more males than females who had received the DSM-III
diagnosis of compulsive personality disorder.
A strength of this study is its incorporation of a metaanalysis. The probabilistic, rather than deterministic, nature
of genetic effects within psychiatric disorders brings about
small, inconsistent effect sizes when undertaking association
studies. This study presents findings from two previously
unpublished, independent samples and utilizes a metaanalysis to elucidate a consistent trend. One limitation of the
study may be the inclusion of just three samples, all of which
originated from the same outpatient clinical unit. However, the
samples were ascertained for different purposes and all clinical
data were collected using a validated structured clinical
interview. A second limitation of this study is that, although
subjects were asked to respond in accordance with how they
usually are, it is not possible for us to identify the existence of
these traits independent of clinical depression. This association of DRD3 with OCPD needs to be replicated among
individuals who have never been diagnosed with depression.
Finally, this study is limited by the relatively small number of
individuals within each of the samples that had been diagnosed
with OCPD.
This article presents data supporting an association of DRD3
with OCPD, which although not significant in two of the three
samples, is consistent overall. Although OCPD is a relatively
narrowly defined diagnosis, it still encompasses an admixture
of symptom criteria. Specifically how the DRD3 is a risk factor
for some or all of these behaviors, remains to be understood.
Analyses directly examining the biological basis of OCPD have
generally been non-existent, possibly due to the difficulty of
representing OCPD behaviors within an animal model.
Instead, inferences have been made based on the proposed
obsessive-compulsive spectrum, yet, to date, the dopamine
system has not primarily been implicated [Villemarette-Pittman et al., 2004].
ACKNOWLEDGMENTS
We thank Elisabeth Wells for her statistical assistance. For
both clinical samples, we thank Robyn Abbott, Isobel Stevens,
and Andrea Bartram. For the family study, we thank Andrea
Bartram, Sarah Rowe, and other interviewers.
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major, patients, obsessive, dopamine, disorder, personality, preliminary, associations, evidence, variant, genes, receptov, depression, compulsive
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