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Association study of a functional promoter polymorphism in the XBP1 gene and schizophrenia.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 141B:71 –75 (2006)
Association Study of a Functional Promoter Polymorphism
in the XBP1 Gene and Schizophrenia
Erik G. Jönsson,1* Sven Cichon,2,3 Johannes Schumacher,2 Rami Abou Jamra,2 Thomas G. Schulze,4
Monica Deschner,4 Kaj Forslund,1 Håkan Hall,1 Peter Propping,2 Piotr M. Czerski,5
Monica Dmitrak-Weglarz,5 Pawel Kapelski,5 Martin Driessen,6 Wolfgang Maier,7
Joanna Hauser,5 Marcella Rietschel,4 and Markus M. Nöthen2,3
1
Department of Clinical Neuroscience, Psychiatry Section, R5:00, Karolinska Institutet, Stockholm, Sweden
Institute of Human Genetics, University of Bonn, Bonn, Germany
3
Life & Brain Center, University of Bonn, Bonn, Germany
4
Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany
5
Department of Adult Psychiatry, Poznan University of Medical Sciences, Poznan, Poland
6
Department of Psychiatry, Gilead Hospital, v. Bodelschwingsche Anstalten Bethel, Bielefeld, Germany
7
Department of Psychiatry, University of Bonn, Bonn, Germany
2
A functional promoter polymorphism (116C/G)
of the X-box binding protein 1 gene (XBP1) gene
was reported to be associated with schizophrenia
in Asian subjects. In a replication attempt,
three European case-control samples comprising
2,182 German, Polish, and Swedish subjects, were
genotyped for the XBP1 116C/G polymorphism.
Allele and genotype frequencies were compared
between schizophrenic patients and control subjects. There were no significant case-control
differences in any of the three samples, although
in a meta-analysis with previous results comprising 3,612 subjects there was a borderline association between the 116G-containing genotypes
and schizophrenia. We conclude that the functional XBP1 gene polymorphism is not of major
importance to schizophrenia in the European
populations investigated. It cannot be excluded,
however, that the XBP1 polymorphism is involved
in schizophrenia in other populations or adds
minor susceptibility to the disorder.
ß 2005 Wiley-Liss, Inc.
KEY WORDS:
X-box binding protein 1 gene
(XBP1); case-control association
study; bipolar disorder; metaanalysis
INTRODUCTION
Family, twin, and adoption studies suggest that genetic
factors play a role in the etiology of schizophrenia [McGuffin
Grant sponsor: Fund for Scientific Research Flanders; Grant
sponsor: National Genomic Network of the German Ministry of
Education and Research; Grant sponsor: Deutsche Forschungsgemeinschaft; Grant sponsor: Polish State Committee for Scientific Research; Grant sponsor: Swedish Research Council; Grant
number: 5454þK2004-21X-15078-01A; Grant sponsor: Söderström–Königska Foundation; Grant sponsor: Wallenberg Foundation; Grant sponsor: HUBIN Project.
*Correspondence to: Erik G. Jönsson, Department of Clinical
Neuroscience, Psychiatry Section, R5:00, Karolinska Institutet,
SE-171 76 Stockholm, Sweden. E-mail: erik.jonsson@cns.ki.se
Received 15 June 2005; Accepted 21 October 2005
DOI 10.1002/ajmg.b.30262
ß 2005 Wiley-Liss, Inc.
et al., 2002]. Recently, several suggestive and promising
associations between different gene variants and the disorder
have been reported, although evidence for functionally
relevant susceptibility variants is still lacking [Craddock
et al., 2005; Harrison and Weinberger, 2005]. The X-box
binding protein 1 gene (XBP1) is a pivotal gene involved in a
complex cascade of events in the stress response of the
endoplasmatic reticulum. Recently, a C to G substitution at
position 116 in the XBP1 gene was shown to lead to a loss of
the binding motif of the gene, which subsequently impaired the
XBP1 loop in the endoplasmatic reticulum’s stress response
[Kakiuchi et al., 2003]. The XBP1 116C/G polymorphism was
also associated with bipolar disorder [Kakiuchi et al., 2003],
although recently the genetic evidence has been challenged
[Cichon et al., 2004; Hou et al., 2004]. Bipolar disorder and
schizophrenia are usually treated as separate disorders.
However, there are difficulties to draw clear borders between
the syndromes. There are several reports of families where
both disorders segregate [St. Clair et al., 1990]. Subjects with
the same genetic makeup have been diagnosed with each of
the two syndromes [McGuffin et al., 1982], and evidence for
both common and shared genetic contributions of the two
disorders have been reported [Cardno et al., 2002]. All this has
challenged the dual Kraepelinian way of looking at bipolar
disorder and schizophrenia and it has been suggested that the
disorders rather constitute different points in a continuum of
psychosis [Crow, 1990]. The XBP1 gene is located on chromosome 22q12 [Liou et al., 1991], one of several areas where claim
for linkage has been reported in both bipolar and schizophrenic
families [Riley and McGuffin, 2000]. As a consequence,
the XBP1 116C/G polymorphism has also been investigated
in schizophrenia and association was reported in two
Asian studies [Chen et al., 2004; Kakiuchi et al., 2004]. In a
replication attempt, we investigated the functional promoter
XBP1 polymorphism for association with schizophrenia in
German, Polish, and Swedish cases and controls.
MATERIALS AND METHODS
Subjects
The study was performed in accordance with the Code of
Ethics of the World Medical Association (Declaration
of Helsinki) and approved by the ethical committees in each
of the participating centers (Bonn, Mannheim, Poznan, and
Stockholm). All subjects participated after giving informed
consent. Subjects have been previously described [Van
Den Bogaert et al., 2003]. They consisted of patients fulfilling
252
403
115
126
64
60
106
191
178
144
258
349
131
117
43
55
111
195
148
173
G/G G/C
45
64
27
39
15
19
17
65
48
54
C/C
Genotype (counts)
OR, odds ratio; CI, confidence interval.
a 2
w ¼ 5.20, degree of freedom (df) ¼ 1, P < 0.05. Heterogeneity w2 ¼ 1.18, df ¼ 1, not significant (NS).
b 2
w ¼ 4.64, df ¼ 1, P < 0.05. Heterogeneity w2 ¼ 3.02, df ¼ 1, NS.
c 2
w ¼ 7.97, df ¼ 1, P < 0.01. Heterogeneity w2 ¼ 0.00, df ¼ 1, NS.
d 2
w ¼ 1.05, df ¼ 1, NS. Heterogeneity w2 ¼ 2.92, df ¼ 2, NS.
e 2
w ¼ 0.71, df ¼ 1, NS. Heterogeneity w2 ¼ 1.56, df ¼ 2, NS.
f 2
w ¼ 0.16, df ¼ 1, NS. Heterogeneity w2 ¼ 2.65, df ¼ 2, NS.
g 2
w ¼ 0.38, df ¼ 1, NS. Heterogeneity w2 ¼ 9.97, df ¼ 4, P < 0.05.
h 2
w ¼ 4.18, df ¼ 1, P < 0.05. Heterogeneity w2 ¼ 5.74, df ¼ 4, NS.
i 2
w ¼ 2.16, df ¼ 1, NS. Heterogeneity w2 ¼ 8.61, df ¼ 4, NS.
Total
Total European
Present study
Present study
Present study
Total Asian
Chen et al. [2004]
N
Patients 234
Controls 451
Shanghai, China;
Patients 374
Han Chinese
Controls 371
Patients 608
Controls 822
Bonn, Mannheim,
Patients 555
Germany; Caucasian
Controls 816
Poznan, Poland; Caucasian
Patients 273
Controls 282
Stockholm, Sweden; Caucasian Patients 122
Controls 134
Patients 950
Controls 1,232
Patients 1,558
Controls 2,054
Subjects’ residence; ethnicity
Kakiuchi et al. [2004] Tokyo, Japan; Japanese
References
Subject
category
0.83–2.23
0.77–1.08
0.91–1.19
0.91d
1.04g
0.64–1.26
1.36
0.90
0.69–1.06
1.04–1.59
1.28a
0.85
1.07–1.92
0.82–1.55
95% CI
1.43
1.13
OR
G/G versus (G/CþC/C)
1.26h
1.13e
1.18
1.46
0.96
1.44b
1.16
2.15
OR
1.01–1.57
0.85–1.51
0.57–2.44
0.87–2.46
0.65–1.44
1.03–2.02
0.76–1.76
1.23–3.76
95% CI
(G/GþG/C) versus C/C
TABLE I. XBP1 116C/G Polymorphism and Schizophrenia: Meta-Analysis of Association Studies
69
71
66
65
70
65
69
64
67
62
G allele
frequency (%)
95% CI
1.08i 0.98–1.19
0.97f 0.86–1.11
1.24 0.86–4.81
1.03 0.80–1.32
0.90 0.77–1.07
1.26c 1.07–1.47
1.26 1.02–1.56
1.25 0.99–1.59
OR
G versus C allele
Patients
Control
Patients
Controls
Patients
Controls
Patients
Controls
Patients
Controls
Patients
Controls
Subject category
Patients
Controls
Patients
Controls
Patients
Controls
Patients
Controls
Patients
Controls
Patients
Controls
Subject category
307
411
160
109
75
73
542
593
224
197
766
790
N
w ¼ 0.98, df ¼ 1, NS. Heterogeneity w2 ¼ 8.06, df ¼ 2, P < 0.02.
w ¼ 0.39, df ¼ 1, NS. Heterogeneity w2 ¼ 0.35, df ¼ 2, NS.
c 2
w ¼ 0.21, df ¼ 1, NS. Heterogeneity w2 ¼ 4.46, df ¼ 2, NS.
d 2
w ¼ 0.16, df ¼ 1, NS. Heterogeneity w2 ¼ 14.61, df ¼ 3, P < 0.01.
e 2
w ¼ 0.67, df ¼ 1, NS. Heterogeneity w2 ¼ 0.35, df ¼ 3, NS.
f 2
w ¼ 0.48, df ¼ 1, NS. Heterogeneity w2 ¼ 8.31, df ¼ 3, P < 0.05
b 2
a 2
Total
Chen et al. [2004]
Present study, total
Present study, Sweden
Present study, Poland
Present study, Germany
References
248
405
113
173
47
61
408
639
150
174
558
813
N
69
71
122
203
47
73
20
31
G/G
63
79
108
176
57
77
21
20
G/C
18
24
18
26
9
23
6
10
C/C
1.00
1.24
d
0.81–1.25
0.80–1.92
0.73–1.20
0.94
0.33–1.54
a
0.60–1.58
0.70–1.32
95% CI
0.72
0.98
0.96
OR
G/G versus (G/CþC/C)
1.17
e
1.17
1.17
b
1.34
1.77
0.88
OR
0.81–1.70
0.61–2.26
0.75–1.84
0.45–3.99
0.79–3.98
0.47–1.63
95% CI
(G/GþG/C) versus C/C
109
73
130
200
68
53
44
29
G/G
85
94
150
173
74
40
40
35
G/C
30
30
27
38
18
16
9
9
C/C
Genotype (counts)
1.04
d
1.61
0.89
a
2.15
0.78
0.77
OR
0.85–1.28
1.09–2.38
0.70–1.12
1.12–4.15
0.48–1.27
0.48–1.27
95% CI
1.14
e
1.16
1.13
b
1.03
1.36
1.06
OR
0.83–1.56
0.67–2.01
0.77–1.66
0.38–2.76
0.66–2.80
0.63–1.77
95% CI
G/G versus (G/CþC/C) (G/GþG/C) versus C/C
67
60
67
70
66
67
74
64
G allele
frequency (%)
67
64
71
72
67
65
65
67
G allele
frequency (%)
TABLE III. XBP1116C/G Polymorphism and Schizophrenia in Men: Meta-Analysis of Association Studies
w ¼ 0.26, df ¼ 1, NS. Heterogeneity w2 ¼ 0.53, df ¼ 2, NS.
w ¼ 0.47, df ¼ 1, NS. Heterogeneity w2 ¼ 1.89, df ¼ 2, NS.
c 2
w ¼ 0.01, df ¼ 1, NS. Heterogeneity w2 ¼ 0.58, df ¼ 2, NS.
d 2
w ¼ 0.00, df ¼ 1, NS. Heterogeneity w2 ¼ 1.67, df ¼ 3, NS.
e 2
w ¼ 0.70, df ¼ 1, NS. Heterogeneity w2 ¼ 1.89, df ¼ 3, NS.
f 2
w ¼ 0.17, df ¼ 1, NS. Heterogeneity w2 ¼ 1.28, df ¼ 3, NS.
b 2
a 2
Total
Chen et al. [2004]
Present study, total
Present study, Sweden
Present study, Poland
Present study, Germany
References
Genotype (counts)
TABLE II. XBP1 116C/G Polymorphism and Schizophrenia in Women: Meta-Analysis of Association Studies
0.88–1.22
0.84–1.61
0.82–1.20
0.51–1.59
0.78–1.58
0.75–1.23
95% CI
f
1.05
1.34
0.96
c
1.56
0.94
0.87
OR
0.91–1.23
1.01–1.78
0.80–1.15
0.96–2.57
0.65–1.36
0.70–1.09
95% CI
G versus C allele
1.03
f
1.17
0.99
c
0.90
1.11
0.96
OR
G versus C allele
74
Jönsson et al.
DSM-IV or DSM-III-R criteria for schizophrenia, schizoaffective disorder, or schizophreniform disorder, and control
subjects from Germany (555 cases, 45% women; 816 controls,
50% women), Poland (273 cases, 41% women; 282 controls, 61%
women), and Sweden (122 cases, 39% women; 134 controls,
46% women), respectively.
Molecular Genetics
Venous blood was drawn from all participants. After DNA
isolation, the XBP1 116C/G variant was genotyped as
described by Kakiuchi et al. [2004]. Genotyping was performed
using the MassARRAY system (Sequenom Inc., San Diego, CA)
on a modified Bruker Biflex MALDI-TOF mass spectrometer
(Sequenom) according to Ding and Cantor [2003] with minor
modifications. The resulting mass spectra were analyzed
automatically for peak identification using the SpectroTYPER
RT 3.1.4.0 software (Sequenom). For quality reasons, two
independent persons controlled 10% of the spectra. Individual
genotypes were called without the knowledge of phenotypic
status. Detailed information of PCR-amplification and genotyping procedure can be obtained by request.
Statistics
The allele and genotype frequencies among cases and
controls were compared using Pearson’s contingency and
2 2 w2-test. Odds ratios (OR), confidence intervals (CI),
pooling of data, and testing of heterogeneity between effect
sizes were calculated according to Woolf [1955] as previously
described [Emery, 1986; Kahn and Sempos, 1989; Jönsson
et al., 2004].
RESULTS
Genotype distribution in the three different samples is given
in Table I. There were no significant deviations from Hardy–
Weinberg equilibrium in either patients or controls in any of
the samples (data not shown). Neither were there any
significant allele (P ¼ 0.23, P ¼ 0.81, and P ¼ 0.25 in the
German, Polish, and Swedish sample, respectively), or genotype (P ¼ 0.34, P ¼ 0.19, and P ¼ 0.47, in the German, Polish,
and Swedish sample, respectively) differences between cases
and controls in either of the samples. Furthermore, there were
no significant differences when subjects were analyzed
separately according to gender with one exception, that is, in
the Swedish sample, schizophrenic men displayed higher G/G
frequencies than control men (59% vs. 40%; w2 ¼ 6.02, degree of
freedom ¼ 2, P < 0.05). When the three samples were analyzed
together, there were no significant association between the G
allele, G/G genotype, or C/C genotype, and schizophrenia in the
total sample (Table I) or among women (Table II) or men
(Table III). When the present samples were analyzed together
with previous reported results, there was a significant
association between the G-containing genotypes and schizophrenia in the analysis including both genders (Table I). When
the original Japanese report was excluded in this metaanalysis, there was no longer evidence for association
(w2 ¼ 1.17, odds ratio 1.14, 95% confidence interval 0.90–
1.45). In the remaining meta-analyses no significant differences were detected (Tables I–III).
Kakiuchi et al., 2004]. When the data were analyzed, divided
with regard to gender, we were not able to detect any
significant case-control differences in the total European
sample, although in the relatively small Swedish sample there
was a higher frequency of the G/G genotype among schizophrenic than control men. When we analyzed all the five
different samples comprising 3,612 subjects, there were no
significant allele or G/G genotype differences (Table I). However, in the comparison between the GG/GC and CC genotypes
there was a borderline association with the G-containing
genotypes without evidence for heterogeneity (Table I). This
association relied however, to a great extent on the first
published study [Kakiuchi et al., 2004], and the meta-analysis
was no longer significant when this study was excluded.
Although our data do not provide convincing evidence for an
association, it cannot be excluded that the XBP1 116C/G
variant may confer a small risk to schizophrenia similar to that
reported for a functional dopamine D2 receptor variant [Glatt
et al., 2003; Jönsson et al., 2003]. It is noteworthy that we
observe different odds ratios among Asian and European
subjects, which may support an effect in Asian but not
Caucasian subjects. A possibly different effect of 116C/G
polymorphism in these two populations, however, would be
difficult to explain against the notion by Kakiuchi et al. [2003]
that this polymorphism is, in itself, a functionally relevant
susceptibility variant. To further clarify this topic, additional
studies in the Asian and other populations, as well as future
meta-analyses are warranted.
In conclusion, no firm significant associations were found
between the XBP1 116C/G variant and schizophrenia in the
present European samples. However, a preliminary metaanalysis of 3,612 subjects suggested an association between the
XBP1 functional promoter variant and schizophrenia, and
underline the need for further investigations.
ACKNOWLEDGMENTS
TGS was supported through a Young Investigator Award
from the National Alliance for Research on Schizophrenia and
Depression (NARSAD). PMC was supported by an Annual
Stipend for Young Scientists from the Foundation for Polish
Science. We thank Alexandra Tylec, Kjerstin Lind, and
Elisabeth Hollsten for technical assistance.
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