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Compulsivity in mouse strains homologous with chromosomes 7p and 15q linked to obsessive-compulsive disorder.

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RESEARCH ARTICLE
Neuropsychiatric Genetics
Compulsivity in Mouse Strains Homologous
With Chromosomes 7p and 15q Linked to
Obsessive-Compulsive Disorder
Martien J.H. Kas,1* Cigdem Gelegen,1,2 Filip van Nieuwerburgh,3 Herman G.M. Westenberg,4
Dieter Deforce,3 and Damiaan Denys5
1
Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht,
The Netherlands
2
Department of Medicine, University College London, London, United Kingdom
3
Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium
Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, The Netherlands
4
5
Department of Psychiatry, Academic Medical Center (AMC), University of Amsterdam, and the Institute for Neuroscience,
an institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands
Received 30 October 2008; Accepted 5 May 2009
Obsessive-compulsive disorder (OCD) is a severe anxiety disorder characterized by obsessions and compulsions. The core
symptom of OCD is compulsivity, the inability to stop thinking
or acting when you want to, despite being aware of the uselessness
of the content or the adverse consequences. To initiate a systematic search for genetic mechanisms underlying the pathophysiology of compulsivity, a panel of chromosome substitution (CS)
strains, derived from mice that suppress (C57BL/6J strain) or
maintain (A/J strain) high levels of repetitive wheel running
during 2 hr of daily limited food access, was screened for this
compulsive behavior. Following the genetic screen, we found
linkage between compulsive wheel running and mouse chromosomes 2, 6, and 7 that show overlap with recently identified human
linkage regions for OCD on chromosomes 7p and 15q. In the
overlapping (human/mouse) genomic region, the CRH receptor 2
(CRHR2) gene was tested in a human case–control study. An
initial exploration in OCD cases versus controls failed to detect an
association between four-candidate CRH2R SNP’s within this
homologous linkage region and OCD. Genetic fine mapping of
compulsivity in mice provides new opportunities to reveal mechanisms underlying this significant psychiatric trait.
2009 Wiley-Liss, Inc.
Key words: psychiatry; animal model; endophenotype; genetics; behavior
INTRODUCTION
Obsessive-compulsive disorder (OCD) is a severe anxiety disorder
characterized by obsessions (intrusive, unwanted thoughts) and
compulsions (ritualized behaviors intended to overcome the anxiety resulting from the obsessions). The core symptom of OCD is
compulsivity, the feeling of loss of voluntary control, the inability to
stop acting when you want to, despite being aware of the uselessness
2009 Wiley-Liss, Inc.
How to Cite this Article:
Kas MJH, Gelegen C, van Nieuwerburgh F,
Westenberg HGM, Deforce D, Denys D. 2010.
Compulsivity in Mouse Strains Homologous
With Chromosomes 7p and 15q Linked to
Obsessive-Compulsive Disorder.
Am J Med Genet Part B 153B:252–259.
of the content, or the adverse consequences in order to relieve
anxiety or stress [Denys, 2006]. Compulsivity is epitomized by
OCD, but is also present in substance-related disorders, eating
disorders, and impulse-control disorders [Holden, 2001].
Though the neurobiological basis of OCD still is unclear, family
and twin studies suggest that genetic factors are important in the
manifestation of OCD [Hanna et al., 2002; Shugart et al., 2006;
Samuels et al., 2007]. Familial studies of OCD indicate that the risk
to first-degree relatives is 3–12 times greater than the general
population, and twin studies reveal that concordance for OCD is
greater among pairs of monozygotic (80–87%) than dizygotic
Grant sponsor: The Netherlands Organization for Scientific Research
(NWO); Grant number: 91786327; Grant sponsor: ZonMW VIDI;
Grant number 91786327.
The authors declare that they have no competing financial interests.
*Correspondence to:
Dr. Martien J.H. Kas, Rudolf Magnus Institute of Neuroscience,
Universiteitsweg 100, 3584CG Utrecht, The Netherlands.
E-mail: m.j.h.kas@umcutrecht.nl
Published online 9 June 2009 in Wiley InterScience
(www.interscience.wiley.com)
DOI 10.1002/ajmg.b.30994
252
KAS ET AL.
(47–50%) twins [Pauls, 2008]. No genetic factors have yet been
identified as a cause, however, recently, a genome-wide linkage scan
for OCD found evidence for susceptibility loci on chromosomes 3q,
7p, 1q, 15q, and 6q in OCD [Shugart et al., 2006]. These regions still
contain several hundred genes from which some might be potentially relevant for the development of OCD. Animal models may
help to unravel genetic mechanisms related to these genomic
regions; however, it is highly unlikely that they will recapitulate
the entire OCD spectrum. They are inappropriate for investigations
into uniquely human aspects of OCD (e.g., obsessions), but seem
more than adequate for studying different forms of compulsivity.
Some genetic mouse models provide face validity for compulsive
behavior and may have some further translation value. For example,
5-HT2C receptor knockout (KO) mice display compulsive-like
behavior such as compulsive chewing of non-nutritive clay and
plastic-mesh screens [Chou-Green et al., 2003]. Furthermore, a
genetic deletion of the SAPAP3 gene resulted in excessive grooming
behavior in mice, a feature that mimics quite closely the human
characteristics of compulsivity [Welch et al., 2007].
To initiate a systematic search for genetic mechanisms underlying the pathophysiology of compulsivity, the current study examined a panel of chromosome substitution (CS) strains derived from
C57BL/6J (host) and A/J (donor) strains. A previous study has
shown that these mice either suppress (C57BL/6J strain) or maintain (A/J strain) high levels of repetitive wheel running during 2 hr
of daily limited food access [Gelegen et al., 2008]. Mouse models are
widely used to dissect the genetic basis for biological traits and to
characterize their functional consequences, not only because of
their genetic and physiological similarity to humans, but also
because an extraordinary variety of genetic resources enable rigorous functional studies. CS strains are a powerful complement for
studying multigenic traits. By partitioning the genome into a panel
of new inbred strains with single CSs, (one strain for each
chromosome), unique experimental designs and considerable statistical power are possible to accelerate the detection of quantitative
trait loci (QTLs) with small effect sizes [Singer et al., 2004]. Several
published studies demonstrate the considerable utility of these
strains and new applications for CS strains continue to be discovered [Singer et al., 2004; Hill et al., 2006; Kas et al., 2008].
Compulsivity was assumed to be mimicked by continuous and
repetitive wheel running during the 2 hr of food availability as it
expresses the inability to stop wheel running despite the more
appealing food availability. In addition to its face validity, it has
been shown that fluoxetine suppresses compulsive wheel running
activity in rodents during a daily scheduled feeding paradigm
[Altemus et al., 1992].
The behavioral screen of the CS strains revealed that three
individual substitution strains carrying A/J chromosomes 2, 6,
and 7, have significantly higher levels of wheel running during
2 hr of food access when compared to the C57BL/6J control
strain. Interestingly, two of the aforementioned human chromosome regions harboring the OCD susceptibility loci, namely 7p
and 15q, are homologous with regions of mouse chromosomes
that we identified in the present study. In the overlapping
(human/mouse) genomic region, several potential candidate
genes are located of which one was tested, the corticotrophinreleasing hormone receptor 2 (CRHR2) gene. Corticotrophin-
253
releasing hormone (CRH) is a neuropeptide known to be a
regulator of the hypothalamus–pituitary–adrenal (HPA) axis.
Currently there are two known classes of CRH receptors, termed
type 1 and type 2, that have been cloned from a number of
vertebrate species and are encoded by separate genes. In the brain
the highest densities are in the parvoventricular nucleus of the
hypothalamus, the amygdala, and the lateral septum [Lovenberg
et al., 1995]. The CRH2R gene has previously been associated
with anxiety-related behavior [Bale and Vale, 2003; Henry et al.,
2006] and, interestingly, the mouse CRH2R gene contains a nonsynonymous coding single nucleotide polymorphism (SNP) in
exon 2 (rs30120293) that is polymorphic between A/J and
C57BL/6J mice. In an initial case–control study four non-synonymous SNPs in the coding region of the CRHR2 gene were
investigated in 156 unrelated patients with OCD.
MATERIALS AND METHODS
The Chromosome Substitution Strain Panel in Mice
A CS strains panel (C57BL/6J-Chr 1A/NaJ to C57BL/6J-Chr 19A/
NaJ, C57BL/6J-Chr XA/NaJ; referred to as CS strains; except for CS
strains 13, 16, and Y, due to low availability) [Singer et al., 2004] and
their parental strains, C57BL/6J (host strain) and A/J (donor
strain), were studied in this experiment. Original CS-strain, C57BL/
6J and A/J breeding pairs were obtained from the Jackson Laboratory (Bar Harbor, ME) and used in our internal breeding program.
In total, 321 mice were generated and all tested in the 11 days lasting
behavioral paradigm (described below). This concerned female
mice of the C57BL/6J strain (n ¼ 53), A/J strain (n ¼ 24), and of the
18 tested CS strains (n ¼ 244; on average, 13–14 mice per CSstrain). Four weeks after birth, mice were weaned and socially
housed (2–4 same sex littermates per cage) with ad libitum access to
food and water. The animals were maintained in a 12-hr light/12-hr
dark cycle (light intensity of 60 lx; lights off at 13.00 hr). Room
temperature was 21.0 1.0 C. At the age of 3–4 months mice were
tested in the scheduled feeding paradigm. All experimental procedures were approved by the ethical committee for animal experimentation of the Utrecht University, The Netherlands.
The Scheduled Feeding Paradigm in Mice
The scheduled feeding paradigm is similar to that used in previous
studies [Gelegen et al., 2007]. Briefly, to adapt the animals to
running wheel cages, all mice were individually housed in cages
with running wheels for 1 week before the start of the experiment.
The running wheel activity was registered by a small magnet and a
counter that was activated by the magnet when it passed the counter
during a revolution of the running wheel. The first week of
adaptation to the wheel running cages is termed ‘‘baseline
conditions.’’ Under baseline conditions, mice had unrestricted
access to food, water, and the running wheel. Body weight and
food intake were measured daily just before the beginning of the
dark phase. Individual wheel running revolutions were continuously registered using Cage Registration Software (Department of
Biomedical Engineering, UMC Utrecht, The Netherlands). Following the first week of baseline, mice were placed on a restricted
feeding schedule for 4 consecutive days (2 hr of daily access to food)
254
and this period is defined as ‘‘restriction conditions.’’ During the
restriction period, the food was given during the first 2 hr of the dark
phase (the habitual activity phase of this nocturnal species). Body
weight and food intake were measured before and after food access
and running wheel revolutions were registered continuously.
Statistics of the Mouse Wheel Running
Mouse wheel running revolutions were expressed in the mean standard error of the means for each strain. Differences in wheel
running revolutions during the 2 hr of food availability were
assessed by a repeated measures ANOVA procedure (SPSS, version
12.0.1. for windows Chicago, IL), using a between subject factor
(strain) and within subject factor (days) (a ¼ 0.05). In case of a
significant difference between the strains, a one-way ANOVA was
performed on each day (with a ¼ 0.05) to identify on which days
C57BL/6J mice differ from A/J mice regarding wheel running levels
during the 2 hr of food availability. Differences in food intake
during ad libitum and 2 hr food access conditions in A/J mice were
analyzed using a paired t-test (a ¼ 0.05). For the CS strains to
C57BL/6J comparisons (average wheel running activity during the
2 hr of food access on days 3 and 4), significance levels (a ¼ 0.05)
were corrected using Dunnett’s method to account for the multiple
strain comparison [Belknap, 2003].
The Human OCD Sample
The patient sample consists of 156 unrelated patients with OCD
from consecutive referrals to the Anxiety Research Unit of the
Department of Psychiatry at the University Medical Centre Utrecht,
who gave written informed consent for participation in this study
that had been approved by the University of Utrecht Medical Ethical
Review committee (Utrecht, The Netherlands). All patients were
diagnosed with OCD according to DSM-IV criteria and the MiniInternational Neuropsychiatric Interview (MINI), a clinical and
structured interview, was used to confirm the diagnosis [Sheehan
et al., 1998]. Severity of obsessive-compulsive symptoms was rated
with the Y-BOCS, depression with the Hamilton depression scale
(HAM-D), and anxiety with the Hamilton anxiety scale (HAM-A)
[Hamilton, 1959, 1960; Goodman et al., 1989]. Information
on family history was obtained by direct interviews with the
patients and the presence of vocal and/or motor tics was assessed
during the clinical interview (Table I). The control sample was
composed of 156 ethnically matched and unrelated Caucasian
subjects from the Netherlands, selected among healthy volunteers.
Genotyping of the CRH Receptor 2 (CRHR2)
Gene in a Case–Control Association Study
In an initial case–control study four non-synonymous polymorphisms in the coding region of the CRHR2 gene were investigated.
Blood samples were collected from each subject and frozen at 80 .
DNA was extracted from 10 ml of peripheral blood according to
standard procedures. The samples were genotyped using TaqMan
SNP Genotyping Assays from Applied Biosystems for the NCBI
dbSNP identification numbers rs8192492, rs8192495, rs8192498,
and rs34625936. At this time, these are the only four validated non-
AMERICAN JOURNAL OF MEDICAL GENETICS PART B
TABLE I. Demographic and Clinical Characteristics of the
Patients Sample
Gender (male/female)
Age on admission
Positive family history
Mean age of onset
15 years age of onset
>20 years age of onset
Duration of illness
Symptom dimensions
Contamination fear and washing
Aggressive, sexual, and religious
obsessions
Somatic obsessions and checking
Symmetry and exactness
High-risk assessment and checking
Y-BOCS
HAM-D
HAM-A
Comorbid depressive disorder
Comorbid anxiety disorder
Total sample (n ¼ 156)
56/100
36.6 11.5
43
17.7 8.3
60
45
18.7 11.6
23
14
17
54
47
24.9 5.7
9.5 5.8
1.6 6.7
24
13
synonymous SNPs located in the exons of the CRHR2 gene that are
reported in the NCBI SNP database. The association between the
distribution of the genotypes and allele frequencies with the subjects
and expected frequencies to assess Hardy–Weinberg equilibrium,
were ascertained by cross-tabulation and c2 analysis.
RESULTS
The Scheduled Feeding Paradigm in Mice
During ad libitum food availability, both C57BL/6J and A/J mice
showed marked day–night differences in voluntary wheel running
levels (with high levels during the dark phase, the habitual activity
phase of this nocturnal species). When food was only given during
the first 2 hr of the dark phase, C57BL/6J mice developed high
levels of wheel running in the hours prior to food access. This socalled food anticipatory activity [FAA, Mistlberger, 1994] was not
observed in A/J mice (Fig. 1). Furthermore, as scheduled food
restriction prolonged over days, C57BL/6J mice showed a strong
suppression of wheel running levels during the 2 hr of food
availability (Fig. 2a) (F ¼ 105; P < 0.0001). In contrast, A/J mice
had similar wheel running levels during the 2 hr of food availability
(F ¼ 0.9; P ¼ 0.5), and these wheel running levels were lower
during the initial phase of scheduled feeding (days 1 and 2), but
significantly higher after extended scheduled feeding (on days 3
and 4) when compared to C57BL/6J (day 1: t ¼ 7.2; P < 0.001, day
2: t ¼ 4.2; P < 0.0001, day 3: t ¼ 2.7; P ¼ 0.008, day 4: t ¼ 7.8;
P < 0.001). During the ad libitum period A/J mice ate significantly
more food than during the 2 hr restriction period [4.4 0.1 g (ad
libitum) vs. 1.5 0.1 g (average food intake per day during food
restriction days 1–4) (t ¼ 23.8; P < 0.0001)]. These data indicate
KAS ET AL.
FIG. 1. Six days of circadian wheel running patterns of C57BL/6J and
A/J mice during ad libitum and 2-hr scheduled food access. In
contrast to A/J mice (lower panel), C57BL/6J mice (upper panel)
exhibitedhighamplitudewheelrunning levelsduringtheirhabitual
active phase (note the different scales of the y-axis), showed high
levels of wheel running activity in the hours prior to the 2 hr of food
access, and showed a strong suppression of their wheel running
levels during prolonged scheduled feeding [see arrow (upper
panel) and also see Figure 2 (upper panel)]. Black bars below the
x-axis indicate the episodes that food was made available.
that the similar levels of wheel running in A/J mice during the ad
libitum and the food restricted period did not result from equal
levels of food intake during these two conditions (e.g., less motivation to reduce wheel running), and further support the notion
that A/J mice showed compulsive wheel running during daily
scheduled limited food access.
To initiate a search for genetic loci underlying this behavioral
trait, a panel of CS strains derived from the C57BL/6J and A/J
parental strains were tested using the same scheduled feeding
paradigm. This behavioral screen revealed that three strains carrying A/J chromosomes 2, 6, and 7, have significant higher levels of
wheel running during 2 hr of food access when compared to
the C57BL/6J genetic background control strain (Fig. 2b)
(F ¼ 3.0; P < 0.0001, using Dunnett’s method for multiple strain
comparison [Belknap, 2003]).
Homology Between Mouse and Men
Recent human genome-wide linkage studies using OCD patient
populations revealed several susceptibility loci for this disorder
[Hanna et al., 2002; Shugart et al., 2006; Samuels et al., 2007].
255
FIG. 2. During prolonged scheduled food restriction (days 3 and 4),
A/J mice showed significant higher wheel running levels during
the 2 hr that food is available when compared to C57BL/6J mice
(upper panel). Testing a panel of chromosome substitutions
strains derived from these two parental strains revealed that the
individual A/J chromosomes 2, 6, and 7 carry at least one genetic
locus that contributes to this behavioral trait (lower panel).
*Indicates significant differences between the corresponding CS
strains (CSS) and the C57BL/6J genetic background controls
(average wheel running activity during the 2 hr of food access on
days 3 and 4).
Interestingly, two of those human linkage regions (7p and 15q) are
homologous with regions of the mouse chromosomes that we
identified in the present study. The human linkage region for OCD
on 7p [Shugart et al., 2006] is homologous with mouse chromosome 6 (regions 8–13 M bp; 49–57 M bp; 57,700–57,800 K bp).
Furthermore, the human peak marker for the linkage region on
15q [Shugart et al., 2006] is homologous with mouse chromosome
7. In the overlapping (human/mouse) genomic region, several
potential candidate genes are located of which one was tested,
namely the CRH2R gene, in a human case–control study. CRH is a
neuropeptide known to be a regulator of the HPA axis. The CRH2R
gene (on mouse chromosome 6 (55,040,081–55,082,966 bp) and on
human chromosomal region 7p15.1) has previously been associated with anxiety-related behavior [Bale and Vale, 2003; Henry et al.,
2006] and, interestingly, the mouse CRH2R gene contains a non-
256
AMERICAN JOURNAL OF MEDICAL GENETICS PART B
TABLE II. Allele Frequencies and Genotype Distribution of the rs8192492, rs8192495, rs8192498, and rs34625936 Polymorphisms
Allele frequencies
Rs8192492
OCD patients
Controls
Genotypes
n
T
C
TT
T/C
CC
156
156
0.00%
0.00%
100.00%
100.00%
0 (0.00%)
0 (0.00%)
0 (0.00%)
0 (0.00%)
156 (100.00%)
156 (100.00%)
Allele frequencies
Rs8192495
OCD patients
Controls
Genotypes
n
G
A
GG
G/A
AA
156
156
100.00%
100.00%
0.00%
0.00%
156 (100.00%)
156 (100.00%)
0 (0.00%)
0 (0.00%)
0 (0.00%)
0 (0.00%)
Allele frequencies
n
Rs8192498
OCD patients
Controls
156
156
Genotypes
G
A
GG
G/A
AA
98.72%
98.72%
1.28%
1.28%
152 (97.44%)
152 (97.44%)
4 (2.56%)
4 (2.56%)
0 (0.00%)
0 (0.00%)
Allele frequencies
Rs34625936
OCD patients
Controls
Genotypes
n
C
G
CC
C/G
GG
156
156
99.04%
99.36%
0.96%
0.64%
153 (98.08%)
154 (98.72%)
3 (1.92%)
2 (1.28%)
0 (0.00%)
0 (0.00%)
synonymous coding SNP in exon 2 (rs30120293) that is polymorphic between A/J and C57BL/6J mice (the donor and host strains,
respectively, for the CS strains used in this study).
Results of the CRH Receptor 2 (CRHR2) Gene
Association
The genotypic pattern of distribution and the allele frequencies of
the four polymorphisms of the CRHR2 gene and OCD are shown in
Table II. The allele frequencies of the patients group and the control
group are almost identical. The measured allele frequencies are in
accordance with the allele frequencies reported by the HapMap
project and the Applera Genome Resequencing Initiative (AGI).
The HapMap European allele frequencies for rs8192492, rs8192495,
and rs34625936 are 100.0% C-allele, 100.0% G-allele, and 100.0%
C-allele, respectively. The Caucasian AGI allele frequencies for
rs8192498 and rs34625936 are 97% G-allele and 97% C-allele,
respectively.
DISCUSSION
In the present study, we have analyzed compulsive wheel running
behavior in CS strains of mice. This study showed that three A/J
chromosomes (namely chromosomes 2, 6, and 7) contributed to
the significant higher levels of wheel running during 2 hr of food
access when compared to the C57BL/6J genetic background control
strain. Interestingly, the identified mouse chromosomes overlap
with two previously observed human OCD chromosomal regions,
7p and 15q [Shugart et al., 2006]. Several candidate genes are
located in these homologous chromosomal regions of which the
CRH2R gene was tested in a human case–control study. Here, no
association was found between four polymorphisms of the CRHR2
gene and OCD. However, the observed homology at the genome
level between human OCD and compulsive wheel running in mice
provides, in addition to face and predictive validity [Altemus et al.,
1992], a good starting point for further genetic fine mapping of
mouse candidate genes for this neurobehavioral trait. Additional
genetic fine mapping of the mouse chromosomes linked to compulsive wheel running will also further contribute to determine the
level of synteny between the human loci for OCD and the mouse loci
found for compulsive wheel running behavior. The CS strains of
mice have been proven a sensitive detection method for QTL
identification [Singer et al., 2004; Kas et al., 2009a].
In addition to the identification of neurobiological mechanisms
for compulsivity, valid animal models will be required to functionally test potential biological substrates and novel pharmacological
therapies for this neurobehavioral trait that is relevant to a wide
KAS ET AL.
variety of psychiatric disorders. Indeed, several animal models for
compulsivity have been proposed [see Joel, 2006; Korff and Harvey,
2006 for review], and a recent study on the SAPAP3 gene mutation
in mice provided novel insights in the potential mechanisms
underlying excessive grooming behavior [Welch et al., 2007], a
feature reminiscent to compulsive behavior in trichotillomania and
skin picking in humans. While most of these models show face and
(sometimes) predictive validity, construct validity is the most
difficult to provide for animal models of neuropsychiatric disorders, simply because the lack of knowledge about the underlying
etiological mechanisms of these complex disorders. Therefore, the
question remains how these various animal models will translate to
compulsivity observed in a wide variety of psychiatric disorders,
such as in OCD, drug addiction, and eating disorders. Recently, it
was proposed that certain behavioral domains, such as compulsivity, are present across the spectrum of psychiatric disorders [Kas
et al., 2007]. These domains may represent intermediate phenotypes related to a particular disorder that mark the pathway between
the genotype and the endophenotype of interest [Gottesmann and
Gould, 2003]. The observed homologous regions between human
OCD and mouse compulsive running in the present study, therefore, may provide a good starting point to identify genetic factors
for compulsivity and to provide genetic validity [Kas et al., 2009b]
of compulsive wheel running activity in mice for compulsive
behavior in humans.
Though these results indicate that compulsive running may be a
valid animal model for OCD, the face validity of the running wheel
experiment is weakened by the fact that compulsive running/
exercise occurs in association with daily scheduled food restriction.
Indeed, this paradigm has also been indicated as an animal model
for pathophysiological processes of anorexia nervosa [Kas et al.,
2003; Gelegen et al., 2007]. On the other hand, there is quite some
degree of co-morbidity between OCD and anorexia nervosa, indicating some overlap between these different classified disorders
[Kaye et al., 2004; Swinbourne and Touyz, 2007]. Furthermore,
compulsivity is thought to be driven by stressful events and food
restriction is generally considered as such. It may therefore be
possible that certain mouse strains have, depending on their genetic
background, high levels of compulsivity under various stressful
conditions and that wheel running behavior is one form of compulsive act to deal with these conditions.
CRH is the principal regulator of the HPA axis and an activator of
the sympathoadrenal (SA) and systemic sympathetic (SS) systems.
A number of psychiatric disorders, including major depression and
post-traumatic stress disorder have been associated with dysregulation of the HPA axis [Barden et al., 1995; de Kloet et al., 2008;
Heim et al., 2008]. This study is, to our knowledge, the first report
on CRHR2 gene polymorphisms in OCD. The four non-synonymous SNPs located in the exons of the CRHR2 gene that are
currently reported as validated in the NCBI SNP database, were
analyzed because these four SNPs have the highest chance of giving a
causal association with OCD. Although the CRHR2 gene is a
plausible functional candidate gene influencing the reactivity of
the HPA axis and the development of anxiety disorders, our
findings provide no evidence for an association between the four
investigated polymorphisms of the CRHR2 gene and OCD. Because
not all SNPs in the CRHR2 region were covered in this study, it
257
cannot be concluded that the CRHR2 gene is not involved in the
etiology of OCD. It can only be concluded that the four analyzed
SNPs do not have a major effect on the risk of OCD. Though our
results should be interpreted with caution given the limited sample
sizes, and given the limited number of analyzed SNPs, they are in
accordance with Tharmalingam et al. [2006] who genotyped three
polymorphisms of the CRHR2 gene in 183 patients with DSM-IV
panic disorder and 75 case–controls and failed to find an association with panic disorder. Still, some studies support an association
between CRHR2 genes and anxiety disorders. In animal experiments, CRHR2-deficient mice display stress-sensitive and increased anxiety-like behavior [Bale et al., 2000; Coste et al.,
2000; Kishimoto et al., 2000]. Recently, SNPs in the CRH gene
have been found to be associated with behavioral inhibition, a
childhood risk factor for panic disorder and social phobia [Smoller
et al., 2003, 2005]. These findings suggest that the CRHR2 gene is a
plausible functional candidate gene influencing the reactivity of the
HPA axis and the development of anxiety disorders.
On the other hand, in comparison with findings in depression
patients, relatively little is known of putative CRH system deregulation in OCD and anxiety disorders. Except for Altemus et al. who
reported significantly elevated cerebrospinal fluid (CSF) CRH levels
in patients with OCD compared with controls, the HPA axis has
been studied scarcely in OCD. Initial investigations of CRH deregulation in anxiety disorders have been mostly negative, with
generalized anxiety disorder, panic disorder, and OCD patients
exhibiting no difference from controls [Jolkkonen et al., 1993;
Chappell et al., 1996; Fossey et al., 1996]. These negative findings
are based on using a single lumbar puncture technique for CSF
sampling. This technique is stressful and increases CRH release in all
subjects, which may mask baseline differences in CRH concentrations between anxiety disorder and control populations
[Geracioti et al., 1992, 1997]. Serial CRH sampling techniques, in
which CRH is sampled over longer periods of time, may be a more
sensitive method to detect baseline CRH abnormalities [Risbrough
and Stein, 2006].
Thus, this study showed that mouse chromosomes linked to
compulsive wheel running during scheduled feeding are homologous with human genome linkage regions recently identified for
OCD. These findings provide novel opportunities to obtain genetic
validity for an animal model of human compulsivity and to identify
neurobiological mechanisms underlying this behavioral trait that is
relevant to a wide variety of psychiatric disorders, including OCD,
drug addiction, and eating disorders.
ACKNOWLEDGMENTS
This research was supported by The Netherlands Organization for
Scientific Research (NWO), ZonMW VIDI grant 91786327 to
Dr. M.J. Kas.
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