Download A possible association between panic disorder

A possible association between panic disorder
and a polymorphism in the preproghrelin gene
Caroline Hansson, Kristina Annerbrink, Staffan Nilsson, Jessica Bah, Marie Olsson, Christer
Allgulander, Sven Andersch, Ingemar Sjödin, Elias Eriksson and Suzanne L. Dickson
Linköping University Post Print
N.B.: When citing this work, cite the original article.
Original Publication:
Caroline Hansson, Kristina Annerbrink, Staffan Nilsson, Jessica Bah, Marie Olsson, Christer
Allgulander, Sven Andersch, Ingemar Sjödin, Elias Eriksson and Suzanne L. Dickson, A
possible association between panic disorder and a polymorphism in the preproghrelin gene,
2013, Psychiatry Research, (206), 1, 22-25.
http://dx.doi.org/10.1016/j.psychres.2012.09.051
Copyright: Elsevier
http://www.elsevier.com/
Postprint available at: Linköping University Electronic Press
http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-93863
Psychiatry Research 206 (2013) 22–25
Contents lists available at SciVerse ScienceDirect
Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres
A possible association between panic disorder and a polymorphism
in the preproghrelin gene
Caroline Hansson a,n, Kristina Annerbrink b, Staffan Nilsson c, Jessica Bah b, Marie Olsson b,
Christer Allgulander d, Sven Andersch e, Ingemar Sjödin f, Elias Eriksson b, Suzanne L. Dickson a
a
Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
c
Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden
d
Karolinska Institutet, The Department of Clinical Neuroscience, Section of Psychiatry, Stockholm, Sweden
e
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
f
Psychiatry Section, Department of Neuroscience and Locomotion, Linköping University, Linköping, Sweden
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 January 2012
Received in revised form
22 August 2012
Accepted 27 September 2012
The aim of the study was to investigate whether polymorphisms in the preproghrelin gene are
associated with anxiety disorders, such as panic disorder, in humans. Panic disorder is a severe anxiety
disorder, characterized by sudden attacks of intense fear or anxiety in combination with somatic
symptoms. The preproghrelin gene codes for two gut-derived circulating peptides that have been
linked to anxiety-like behaviour in rodents: ghrelin (an orexigenic, pro-obesity hormone) and obestatin.
In the present study, we genotyped three missense mutations in the preproghrelin gene in 215 patients
suffering from panic disorder and in 451 controls. The A allele of the rs4684677 polymorphism was
significantly associated with panic disorder, while there were no significant associations with the two
other polymorphisms studied. We conclude that the rs4684677 (Gln90Leu) polymorphism in the
preproghrelin gene may be associated with increased risk of panic disorder. It will be important to
confirm these findings in additional panic disorder patient groups.
& 2012 Elsevier Ireland Ltd. Open access under CC BY-NC-ND license.
Keywords:
Ghrelin
Obestatin
SNP
Anxiety
rs4684677
Gln90Leu
Panic disorder
1. Introduction
Panic disorder is a severe anxiety disorder, characterized by
sudden attacks of intense fear or anxiety, often in combination
with physical symptoms such as heart palpitations and shortness
of breath (American Psychiatric Association, 2000). Panic disorder
has been shown to be hereditary (Hettema et al., 2001), but the
genes responsible for the disease still remain to be elucidated.
Several genes have been studied in relation to panic disorder.
These include genes involved in serotonergic signalling, such as
the serotonin transporter, several serotonergic receptors and
genes involved in production and degradation of serotonin, but
also other genes, such as brain-derived neurotrophic factor
(BDNF), angiotensin and genes involved in hormonal systems,
such as sex hormones and the hypothalamic-pituitary-adrenal
(HPA) axis. These studies have yielded both positive and negative
results. The most consistent finding is the association
n
Corresponding author. Current address: Department of Molecular and Clinical
Medicine, Institute of Medicine, The Sahlgrenska Academy at the University of
Gothenburg, Box 425, SE-415 30 Gothenburg, Sweden. Tel.: þ46 31 786 6747.
E-mail address: [email protected] (C. Hansson).
0165-1781 & 2012 Elsevier Ireland Ltd. Open access under CC BY-NC-ND license.
http://dx.doi.org/10.1016/j.psychres.2012.09.051
between panic disorder and a polymorphism in the catechol-Omethyltransferase (COMT) gene (Na et al., 2011).
The preproghrelin gene codes for two circulating peptides,
ghrelin (Kojima et al., 1999) and obestatin (Zhang et al., 2005),
that are produced predominantly by the stomach. Ghrelin is
perhaps best known for its orexigenic (Wren et al., 2000) and
adipogenic effects (Tschop et al., 2000). Interestingly, ghrelin has
been shown to affect anxiety-like behaviour in rodents, although
both anxiogenic (Asakawa et al., 2001; Carlini et al., 2002, 2004;
Hansson et al., 2011; Kanehisa et al., 2006) and anxiolytic (Lutter
et al., 2008) effects of ghrelin have been reported. Recently, we
performed the first long-term study showing that chronic central
infusion of ghrelin to rats increases anxiety-like behaviour
(Hansson et al., 2011). We have also shown that gastrectomy,
which substantially reduces circulating ghrelin levels, decreases
anxiety- and depression-like behaviour in rats (Salome et al.,
2011). Obestatin has also been implicated in anxiety-related
behaviour but, in contrast to ghrelin, it decreases anxiety-like
behaviour in rats (Carlini et al., 2007). Central infusion of antisense against GPR39 (previously thought to be a receptor for
obestatin) to rats has also been shown to influence anxiety-like
behaviour (Ishitobi et al., 2012). Inspired by the hypothesis
C. Hansson et al. / Psychiatry Research 206 (2013) 22–25
23
emerging from these animal studies, that peptides derived from
the preproghrelin gene may have a role in anxiety behaviour, we
have begun to explore the clinical relevance of these findings.
Here we sought to determine whether there is an association
between panic disorder and polymorphisms in the preproghrelin
gene in a Swedish population.
Hardy–Weinberg equilibrium was checked in the control sample using Haploview. Association between polymorphisms and panic disorder was analysed with
logistic regression using the count of the rare allele as numeric predictor. p-Values
were corrected for multiple testing using permutation tests due to the linkage
disequilibrium between the single nucleotide polymorphisms (SNPs).
2. Materials and methods
3. Results
2.1. Experimental design
The genotype frequencies in the control sample were in
Hardy–Weinberg equilibrium. Clinical data are summarized in
Table 1. About 83% of the patients with panic disorder had
agoraphobia as a second diagnosis (Table 1). The minor allele
frequencies of the three SNPs rs4684677, rs34911341 and
rs696217 were, respectively, 0.105, 0.012 and 0.105 in cases
and 0.068, 0.004 and 0.099 in controls. The A allele of the
rs4684677 polymorphism was significantly associated with panic
disorder (odds ratio ¼1.57, p¼0.025). No significant associations
were found for either of the other two SNPs tested (rs34911341
and rs696217; Table 2).
The preproghrelin gene contains three known exonic polymorphisms, all of
which are missense mutations. These are rs4684677, situated in exon 4, implying
the amino acid exchange Gln90Leu; rs34911341, located in exon 3, implying the
amino acid exchange Arg51Gln; and rs696217, also located in exon 3, and
implying the amino acid exchange Leu72Met.
2.2. Subjects
The panic disorder group consisted of 215 patients (63 men and 152 women),
meeting the DSM-IV criteria for panic disorder. Their mean age was 43 years
(range 15–77 years). All of the patients had panic disorder as the main diagnosis
and 83% also suffered from agoraphobia. Patients were screened with diagnostic
interview schedules to exclude those with concurrent major depression, psychoses or substance use disorders. The controls were originally collected for a
study of obesity, anthropometrics, and cardiovascular risk factors comprising 199
men born in 1944 (51 years old at the time of the assessment) and 252 women
born in 1956 (40 years old at the time of the assessment) and living in
Gothenburg, Sweden, who were drafted from a larger cohort recruited from the
general population as previously described (Rosmond and Bjorntorp, 1998;
Rosmond et al., 1998). Both patients and controls were Caucasians. These cohorts
of patients and controls have been studied previously (Annerbrink et al., 2010; Ho
et al., 2004; Olsson et al., 2004). The study was approved by the Research Ethics
Committee at the University of Gothenburg. All participants provided written
informed consent.
2.4. Statistical analysis
4. Discussion
The present study supports an association between panic
disorder and variations in the preproghrelin gene. We found that
the A allele of the rs4684677 T4A polymorphism in the preproghrelin gene is significantly associated with increased risk of
panic disorder (OR ¼1.57). This polymorphism is a missense
mutation located in exon 4 and is responsible for an amino acid
exchange from Leu to Gln.
The SNP rs4684677 is situated in the part of the preproghrelin
gene that codes for obestatin. It is possible therefore that the
2.3. Genotyping
Venous blood was collected from each subject, and genomic DNA was isolated
using the QIAamp DNA blood Mini Kit (Qiagen, Chatsworth, CA, USA). Initially, the
polymorphisms were assessed for 175 patients and all controls using sequenom.
For the polymorphism rs4684677, the remaining 40 panic disorder patients, as
well as samples for which the sequenom analysis failed, were analysed using
pyrosequencing. For the polymorphisms rs34911341 and rs696217, these samples
were analysed using TaqMan SNP genotyping assays.
2.3.1. Sequenom analysis
Genotyping was performed at Sequenom Inc. in Hamburg, Germany, using the
Sequenom iPLEXs Gold assay and MassARRAYs MALDI-TOF mass spectrometry
platform in accordance with the manufacturer’s instructions (Sequenom Inc., San
Diego, CA). Primers for polymerase chain reaction (PCR) amplification and sequencing
were designed using the Sequenom MassARRAYs System Designer software.
2.3.2. Pyrosequencing
The following primers were used for pyrosequencing (Ahmadian et al., 2006)
(PSQ96 System; Biotage, Uppsala, Sweden) analysis of the rs4684677 polymorphism: forward: 50 -CATGTGGGGCTGCAAGGA-30 , reverse: 50 -TCCCTGCCCTGCCTCCTA30 , and sequence: 50 -GCTGTGCTGCTGGTA-30 . The DNA was amplified using
HotstarTaq Master mix kit (Qiagen), each reaction containing one unit HotStarTaq
DNA polymerase, 1.5 mM magnesium chloride, 200 mM of each dNTP, 50 ng
genomic DNA and 0.15 mM of each primer, in a total volume of 20 ml. The PCR
comprised an initial denaturing step at 95 1C for 15 min, 45 cycles of 95 1C for 15 s,
58 1C for 15 s, and 72 1C for 15 s, followed by a final extension at 72 1C for 7 min.
Twenty microlitres of the PCR product was used for the pyrosequencing. Fifteen
picomoles of the sequencing primers was used to detect the polymorphism.
2.3.3. TaqMan SNP genotyping
The SNPs rs34911341 and rs696217 were analysed using Applied Biosystems
pre-made reagents (C__25607739_20 and C___3151003_20, respectively, Applied
Biosystems Inc., Foster City, CA, USA). The assays were performed under recommended conditions on an Applied Biosystems Prisma 7900 HT real-time PCR
instrument, using standard reagents from Applied Biosystems.
Table 1
Clinical data.
Number of cases
Age (S.D.)
Agoraphobia
Panic disorder
Male subsample
Female subsample
215
63
152
43.4 (12.4)
43.9 (11.4)
43.2 (13.0)
179
47
132
Controls
Male subsample
Female subsample
451
199
252
44.9 (5.5)
51
40
n.a.
n.a.
n.a.
Number of cases: number of subjects in each group, age (S.D.): mean age of each
group (standard deviation is given in parentheses), agoraphobia: number of subjects
suffering from agoraphobia as the second diagnosis. Numbers are given for cases and
controls, and are also further divided into male and female subgroups.
Table 2
Association between panic disorder and SNPs in the preproghrelin gene.
SNP
Genotype
PD
Ctrl
OR
p
pc
MAF
rs4684677
TT
AT
AA
174 (81%)
37 (17%)
4 (2%)
393 (87%)
55 (12%)
3 (1%)
1.57
0.025
0.05
0.068
rs34911341
CC
CT
TT
210 (98%)
5 (2%)
0 (0%)
447 (99%)
4 (1%)
0 (0%)
2.66
0.148
0.38
0.004
rs696217
GG
GT
TT
170 (79%)
45 (21%)
0 (0%)
367 (81%)
79 (18%)
5 (1%)
1.07
0.731
0.98
0.099
PD: panic disorder (n¼215), Ctrl: controls (n¼ 451), OR: odds ratio per minor
allele, p: p-value using logistic regression, pc: p-value corrected for multiple
inference by permutation, MAF: minor allele frequency in controls.
24
C. Hansson et al. / Psychiatry Research 206 (2013) 22–25
association between this SNP and panic disorder is due to variations
in the obestatin peptide. Although ghrelin and obestatin are derived
from the same gene, they seem to have opposing effects in some
important aspects. While ghrelin is orexigenic (Wren et al., 2000),
obestatin decreases food intake (Zhang et al., 2005). Moreover, while
most studies indicate that ghrelin is anxiogenic (Asakawa et al., 2001;
Carlini et al., 2002, 2004; Hansson et al., 2011), obestatin has been
shown to decrease anxiety-like behaviour in rats (Carlini et al., 2007).
The polymorphism rs4684677 has previously been studied in
relation to alcohol dependence (Landgren et al., 2010), hypertension and atherosclerosis (Berthold et al., 2010), body composition
and serum lipids (Martin et al., 2008), adult stature (Gueorguiev
et al., 2007), metabolic syndrome (Steinle et al., 2005), and eating
disorders (Kindler et al., 2011), but none of these studies showed
any significant associations between this polymorphism and the
trait studied. The results regarding obesity and this polymorphism
are inconclusive. One study found no association between
rs4684677 and obesity (Larsen et al., 2005), while this SNP was
associated with obesity in two other studies (Gueorguiev et al.,
2009; Hinney et al., 2002). Recently, this SNP was studied in relation
to panic disorder and major depression in a Japanese cohort, but no
significant association was found (Ishii et al., 2009), possibly due to
the small number of subjects (138 patients diagnosed with panic
disorder and 242 controls). In contrast to our finding, in the Japanese
cohort there was a tendency towards fewer mutant alleles in the
patients suffering from panic disorder compared to the controls.
Genetic differences between Caucasian and Asian subjects may
contribute to the discrepant observations and have been reported
previously in a study showing an association between panic disorder
and a SNP in the COMT gene (Annerbrink et al., 2010). The
functional significance of the rs4684677 polymorphism has not
been studied.
The rare polymorphism rs34911341 C4T implies the amino
acid exchange Arg51Gln. Carriers of the Arg51Gln genotype have
significantly lower plasma ghrelin concentrations than Arg51Arg
carriers, even when adjusted for fat mass (Ukkola et al., 2002).
While this SNP did not show any statistically significant association with panic disorder (p ¼0.148), the odds ratio was still 2.66
and the lack of statistical significance could be due to the fact that
the power is clearly lower for such rare mutations (MAF¼0.004).
The polymorphism rs696217 G4T, implying the amino acid
exchange Leu72Met, is also associated with altered plasma
ghrelin levels. Carriers of the Met allele (Met72Met and Leu72Met) have higher plasma levels of ghrelin than those with the
Leu72Leu genotype after adjustment for body-mass index (Ando
et al., 2007). Leu72Met (rs696217) has previously been studied in
relation to panic disorder, but no significant association was
found, which is in line with our results. On the other hand, these
authors found a significant association between this polymorphism and major depression (Nakashima et al., 2008). Another study
suggested that this polymorphism is associated with anxiety and
depression in methamphetamine users, while it is not associated
with genetic susceptibility for methamphetamine abuse (Yoon
et al., 2005). Polymorphisms in the preproghrelin gene have also
been suggested to be associated with bulimia nervosa (Ando et al.,
2006) and the drive for thinness and body dissatisfaction (Ando
et al., 2007), supporting a role for alterations in the preproghrelin
gene with psychiatry-related disorders.
Panic disorder, like most psychiatric disorders, is a complex
disorder and polymorphisms in several genes likely contribute to
the disease. The serotonin system is probably the most studied
candidate, partly because selective serotonin reuptake inhibitors
(SSRIs) are first choice treatment for the disease. Accordingly, a
polymorphism in the serotonin transporter gene has been shown
to be associated with panic disorder (Gyawali et al., 2010). Several
serotonergic receptors have also been studied in relation to panic
disorder, including, for example, the serotonin receptor 1A, which
is involved in regulating the release of serotonin (Barnes and
Sharp, 1999) and has also been implicated in anxiety (Akimova
et al., 2009). Several polymorphisms in the serotonin receptor 1A
gene, HTR1A, have been shown to be associated with panic
disorder (Blaya et al., 2010). One of these is the functional
polymorphism -1019C/G, which has previously been shown to
be associated with panic disorder with agoraphobia (Rothe et al.,
2004).
The most consistent finding in panic disorder genetics is the
association between panic disorder and a polymorphism in the COMT
gene (Hamilton et al., 2002), which has been replicated several times
(Annerbrink et al., 2010; Domschke et al., 2004; Rothe et al., 2006).
This polymorphism, Val158Met, strongly influences the enzymatic
activity of COMT (Lachman et al., 1996). An interaction between the
V158G polymorphism in COMT and the -1019C/G polymorphism in
HTR1A has been reported (Freitag et al., 2006) and it would be
interesting to investigate how polymorphisms in these and other
genes would interact with the finding of the present study.
A limitation of the present study is the small number of study
subjects, especially in the panic disorder group. The results of this
study should be interpreted with caution as they need to be
confirmed in other populations. However, the findings of the
present study, taken together with the effects of ghrelin on
anxiety-related behaviour in animal studies, suggest that it would
be of interest to further investigate the hypothesis that ghrelin
could be involved in the pathophysiology of anxiety-related
disorders.
We conclude that panic disorder may be associated with a
polymorphism in the preproghrelin gene.
Acknowledgements
The Swedish Research Council for Medicine (2009-S266), European Commission 7th Framework (FP7-HEALTH-2009-241592)
(EurOCHIP), FP7-KBBE-2009-3-245009 (NeuroFAST) and FP7-KBBE2010-4-266408 (Full4Health), FOU/ALF Göteborg (ALFGBG-138741)
and the Swedish Foundation for Strategic Research to Sahlgrenska
Center for Cardiovascular and Metabolic Research (A305-188).
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