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Association analysis of ANK3 gene variants in nordic bipolar disorder and schizophrenia caseЦcontrol samples.

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RESEARCH ARTICLE
Neuropsychiatric Genetics
Association Analysis of ANK3 Gene Variants in
Nordic Bipolar Disorder and Schizophrenia
Case–Control Samples
Martin Tesli,1,2* Pernille Koefoed,3,4 Lavinia Athanasiu,1,2,5 Morten Mattingsdal,5 Omar Gustafsson,2,6
Ingrid Agartz,1,7,8 Lars M. Rimol,8 Andrew Brown,1,9,10 Katrine V. Wirgenes,1,2 Lisa-Lena Smorr,1,2
Anna K. K€ahler,2,11,12 Thomas Werge,13 Ole Mors,14 Erling Mellerup,3,4 Erik G. J€onsson,7 Ingrid Melle,1,2
Gunnar Morken,15,16 Srdjan Djurovic,1,2,5 and Ole A. Andreassen1,2
1
Institute of Clinical Medicine, University of Oslo, Oslo, Norway
Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
2
3
Department of Neuroscience and Pharmacology, Laboratory of Neuropsychiatry, University of Copenhagen, Copenhagen, Denmark
4
Psychiatric Centre Copenhagen, Department O, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
5
6
deCODE Genetics, Reykjavik, Iceland
7
Department of Clinical Neuroscience, HUBIN Project, Psychiatry Section, Karolinska Institutet and Hospital, Stockholm, Sweden
Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway
8
9
Department of Biostatistics, University of Oslo, Oslo, Norway
10
Department of Mathematics, University of Oslo, Oslo, Norway
Department of Genetics, University of North Carolina at Chapel Hill, North Carolina 27599
11
12
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
13
Research Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark
Center for Psychiatric Research, Aarhus University Hospital, Aarhus, Denmark
14
15
Østmarka Psychiatric Department, St. Olavs Hospital, Trondheim, Norway
16
Institute of Neuroscience, Norwegian University of Technology and Science, Trondheim, Norway
Received 29 October 2010; Accepted 16 September 2011
Genetic variants in ankyrin 3 (ANK3) have recently been shown
to be associated with bipolar disorder (BD). We genotyped three
ANK3 SNPs previously found to be associated with BD
(rs10994336, rs1938526, and rs9804190) in a Scandinavian BD
case–control sample (N ¼ 854/2,614). Due to evidence of genetic
overlap between BD and schizophrenia (SZ), we also genotyped
these three SNPs in a Scandinavian SZ case–control sample
(N ¼ 1,073/2,919). Combining our Scandinavian samples with
an Icelandic sample (N ¼ 435 BD cases, 651 SZ cases, and 11,491
healthy controls), we found rs10994336 and rs9804190 to be
nominally significantly associated with BD in this combined
Nordic BD sample (N ¼ 1,289/14,105). Nominal P was 0.015/
0.018 (fixed/random effect) for rs10994336 (Bonferroni corrected P ¼ 0.044/0.053) and 0.023 for rs9804190 (Bonferroni
corrected P ¼ 0.069). None of the SNPs were significantly associated with SZ in the combined Nordic SZ case–control sample
(N ¼ 1,724/14,410). These results further support that ANK3 is a
Ó 2011 Wiley Periodicals, Inc.
Additional Supporting Information may be found in the online version of
this article.
Grant sponsor: University of Oslo; Grant sponsor: Research Council of
Norway; Grant numbers: 167153/V50, 163070/V50; Grant sponsor:
SouthEast Norway Health Authority; Grant number: 2004123; Grant
sponsor: Danish National Psychiatric Research Foundation; Grant
sponsor: Lundbeck Foundation; Grant sponsor: Ivan Nielsen
Foundation; Grant sponsor: Stanley Medical Research Institute; Grant
sponsor: Wallenberg Foundation; Grant sponsor: HUBIN Project; Grant
sponsor: Swedish Medical Research Council; Grant numbers: 2006-2992,
2006-986, 2008-2167.
*Correspondence to:
Martin Tesli, MD, Oslo University Hospital HF, Division of Mental Health
and Addiction Psychosis Research Unit/TOP, Kirkeveien 166, N-0407
Oslo, Norway. E-mail: m.s.tesli@medisin.uio.no
Published online 3 October 2011 in Wiley Online Library
(wileyonlinelibrary.com).
DOI 10.1002/ajmg.b.31244
969
970
susceptibility gene specific to BD and that more than one risk
locus is involved. Ó 2011 Wiley Periodicals, Inc.
Key words: bipolar disorder; schizophrenia; ANK3; genetic
association
INTRODUCTION
Bipolar disorder (BD) and schizophrenia (SZ) are common, severe,
and highly heritable psychiatric disorders [Smoller and Finn, 2003;
Sullivan, 2005]. However, few susceptibility genes have been firmly
established for these two disorders and the underlying pathophysiological mechanisms are not well understood [Nothen et al.,
2010]. Findings from epidemiological [Craddock et al., 1995]
and molecular genetic [Owen et al., 2009] studies suggest that
these disorders have a polygenic basis, and that multiple genes, each
with a small effect, interact with each other and with environmental
factors to give rise to BD and SZ. Moreover, results from recent
epidemiological studies [Lichtenstein et al., 2009] and genetic
association studies [Moskvina et al., 2009] indicate a genetic overlap between these two disorders.
Of the most promising recent findings from BD genome-wide
association studies (GWAS) is ANK3. In a collaborative GWAS
comprising 4,387 cases and 6,209 controls, a genome-wide significant association between the two ANK3 SNPs rs10994336
(P ¼ 9.1 109) and rs1938526 (P ¼ 1.3 108) and BD was
found [Ferreira et al., 2008]. The association between
rs10994336 and BD has been replicated in a sample of 1,668 cases
and 1,604 controls (P ¼ 1.7 105) [Schulze et al., 2009] as well as
in a sample of 638 cases and 904 controls (P ¼ 0.042) [Scott et al.,
2009]. Furthermore, the association between rs1938526 and BD
(P ¼ 0.036) (N ¼ 1,001 cases and 1,033 controls) has also been
replicated [Smith et al., 2009]. All the above mentioned studies
consisted of European individuals, but there is also evidence from
other populations that genetic variants in ANK3 are involved in the
etiology of BD. In the first GWAS on bipolar I disorder in the Han
Chinese population (N ¼ 1,000 cases and 1,000 controls) one SNP
nearby the ANK3 SNP rs1938526 was found to be significantly
associated with bipolar I disorder (P ¼ 6.55 105) [Lee et al.,
2010].
ANK3 is expressed in the central and peripheral nervous system,
where its encoded protein Ankyrin G was first discovered in the
axonal initial segments and nodes of Ranvier [Kordeli et al., 1995].
Ankyrin G has been shown to link membrane proteins to the
spectrin–actin cytoskeleton, and to be important for clustering
of ion channels at axon initial segments and for normal action
potential firing [Kordeli et al., 1995; Zhou et al., 1998; Pan et al.,
2006]. These findings have led to the hypothesis that ANK3 is
involved in BD pathophysiology through ion channel dysregulation
[Ferreira et al., 2008].
We investigated the association between the three most significant ANK3 loci from previous BD studies (rs10994336, rs1938526,
and rs9804190) [Ferreira et al., 2008; Schulze et al., 2009] in a
Scandinavian case–control sample independent of the abovementioned samples. Due to the evidence of genetic overlap between
AMERICAN JOURNAL OF MEDICAL GENETICS PART B
How to Cite this Article:
Tesli M, Koefoed P, Athanasiu L, Mattingsdal
M, Gustafsson O, Agartz I, Rimol LM, Brown
A, Wirgenes KV, Smorr L-L, K€ahler AK,
Werge T, Mors O, Mellerup E, J€
onsson EG,
Melle I, Morken G, Djurovic S, Andreassen
OA. 2011. Association Analysis of ANK3 Gene
Variants in Nordic Bipolar Disorder and
Schizophrenia Case–Control Samples.
Am J Med Genet Part B 156:969–974.
BD and SZ [Lichtenstein et al., 2009; Moskvina et al., 2009], we also
tested for association between these three ANK3 SNPs and SZ.
MATERIALS AND METHODS
Sample Description
The SCOPE bipolar disorder case–control sample. The SCOPE
BD sample is based on two independent case–control samples from
Norway and Denmark, all included in the Scandinavian Collaboration on Psychiatric Etiology (SCOPE) study. The total number of
subjects was 854 BD cases and 2,614 controls. The Norwegian
patients (N ¼ 345) had been diagnosed with bipolar I disorder
(N ¼ 230), bipolar II disorder (N ¼ 96), or BD not otherwise
specified (N ¼ 19), according to DSM-IV using the Structural
Clinical Interview for DSM-IV (SCID) [Spitzer et al., 1992]. The
Danish sample (N ¼ 509) consisted of patients with bipolar affective disorder F31 (N ¼ 423) and manic episode F30 (N ¼ 3) according to ICD-10 (http://www.who.int/classifications/icd/en), bipolar
I disorder according to DSM-IV (N ¼ 1), and BD (N ¼ 15), mania
with psychosis (N ¼ 1), and bipolar with psychosis (N ¼ 66)
according to the OPCRIT classification system. [McGuffin et al.,
1991].
The SCOPE BD, SZ, and control samples are further described in
Table I.
The SCOPE schizophrenia case–control sample. The SZ association study was based on three independent case–control samples
from Norway, Sweden and Denmark, included in the SCOPE. The
Norwegian patients (N ¼ 349) had been diagnosed with SZ
(N ¼ 272), schizoaffective disorder (N ¼ 59), schizophreniform
disorder (N ¼ 15), and persistent delusional disorder (N ¼ 3)
according to DSM-IV using the Structural Clinical Interview for
DSM-IV (SCID) [Spitzer et al., 1992]. The Danish sample
(N ¼ 467) consisted of patients with SZ (N ¼ 422), schizotypal
personality disorder (N ¼ 4), persistent delusional disorder
(N ¼ 2), and schizoaffective disorder (N ¼ 39) according to
ICD-10 F20, F21, F22, and F25 using clinical interviews. The
Swedish patients (N ¼ 257) had been diagnosed with SZ
(N ¼ 224), schizoaffective disorder (N ¼ 25), or schizophreniform
disorder (N ¼ 8), according to DSM-III-R/DSM-IV criteria using
medical record reviews and clinical interviews. A total of 1,073 SZ
cases and 2,919 control subjects were genotyped in this study.
The Norwegian Scientific-Ethical Committees, the Norwegian
Data Protection Agency, the Danish Scientific Committees, the
TESLI ET AL.
971
TABLE I. Characteristics for the SCOPE BD and SZ Case–Control Samples
Sample
Denmark
N (females, %)
Mean age (SD)a
Norway
N (females, %)
Mean age (SD)a
Sweden
N (females, %)
Mean age (SD)a
Sum
BD
SZ
CTR
Sum
509 (0.58)
53.1 (15.0)
467 (0.41)
47.8 (12.3)
2182 (0.46)
46.0 (11.8)
3,158
345 (0.58)
41.2 (13.1)
349 (0.44)
37.2 (10.7)
432 (0.50)
39.2 (10.4)
1,126
305 (0.38)
54.3 (10.4)
2,919
562
854
257 (0.38)
58.1 (15.2)
1,073
4,846
SCOPE, Scandinavian Collaboration on Psychiatric Etiology; BD, bipolar disorder; SZ, schizophrenia; CTR, controls; SD, standard deviation.
a
Mean age in 2010.
Danish Data Protection Agency, the Ethical Committee of the
Karolinska Hospital, the Stockholm Regional Ethical Committee,
and the Swedish Data Inspection Board approved the study. All
subjects have given written informed consent prior to inclusion into
the project.
Icelandic bipolar disorder and schizophrenia case–control
samples. The Icelandic BD and SZ samples consisted of 435
BD cases, 651 SZ cases, and 11,491 controls. Patients and controls
were recruited from all over Iceland. For 316 of the BD patients,
diagnoses were assigned according to Research Diagnostic Criteria
(RDC) [Spitzer et al., 1978] through the use of the Schedule for
Affective Disorders and Schizophrenia Lifetime Version (SADS-L)
[Spitzer, 1977]. The remaining BD patients were recruited through
a genetic study of anxiety and depression [Thorgeirsson et al., 2003]
and had been characterized using the Composite International
Diagnostic Interview (CIDI) [Peters and Andrews 1995; Wittchen
et al., 1996]. For the Icelandic SZ patients, diagnoses were assigned
according to RDC [Spitzer et al., 1978] through the use of the
SADS-L [Spitzer, 1977. The 11,491 controls were recruited as a part
of various genetic programs at deCODE genetics and were not
screened for psychiatric disorders.
Genotyping
Genomic DNA was extracted from whole blood. ANK3 SNPs
rs10994336, rs1938526, and rs9804190 were genotyped in the
SCOPE BD and SZ case–control samples with predesigned
TaqMan SNP Genotyping Assays (Applied Biosystems, Foster
City, CA), according to the manufacturer’s instructions. Allelic
discrimination of samples was done using an ABI PRISM 7900HT
Sequence Detection System (Applied Biosystems) in combination
with the SDS 3.2 software. For a subset of the Norwegian
sample, genotype data were based on imputation of a Norwegian
GWAS data set comprising patients with BD and SZ, as well
as healthy controls [Athanasiu et al., 2010; Djurovic et al.,
2010].
Statistical Analysis
SCOPE bipolar disorder and schizophrenia case–control
samples. All SNPs were tested for deviation from Hardy–Weinberg
equilibrium (HWE) in the controls using PLINK (version 1.07;
http://pngu.mgh.harvard.edu/purcell/plink/) [Purcell et al., 2007].
Single SNP association tests were performed in PLINK with the
allelic test for each subsample and the Cochran–Mantel–Haenszel
(CMH) test for the SCOPE BD and SZ samples, using case–control
sample origin as the stratification factor. The heterogeneity of
the sample specific odds ratios (ORs) was evaluated with the
Breslow–Day test.
Icelandic bipolar disorder and schizophrenia case–control
samples. Single SNP allele tests were performed to investigate
for association between the three ANK3 SNPs and BD and SZ in the
Icelandic samples. Additionally, genomic control adjustments were
undertaken for all SNPs.
Combined Nordic bipolar disorder and schizophrenia case–control
samples. Association tests for ANK3 SNPs rs10994336,
rs1938526, and rs9804190 in the combined Nordic BD case–control
control sample (N ¼ 1,289/14,105) and SZ case–control sample
(N ¼ 1,724/14,410) were performed with the meta-analysis function in PLINK.
Power estimates. Statistical power was estimated with the Genetic
Power Calculator (http://pngu.mgh.harvard.edu/purcell/gpc/),
assuming a disease prevalence of 0.01 for BD, an additive allelic
model, a 10:1 control to case ratio and a type I error rate of 0.05. We
used high risk allele frequencies from the HapMap (http://hapmap.
ncbi.nlm.nih.gov/) and ORs from previous studies [Ferreira et al.,
2008; Schulze et al., 2009]. The results from these analyses are
presented in Supplementary material Table II.
RESULTS
No SNPs had genotype distributions in Hardy–Weinberg disequilibrium in controls (P < 0.05).
1,022/2,634
SCOPE, Scandinavian Collaboration on Psychiatric Etiology; BD, bipolar disorder; SZ, schizophrenia; OR, odds ratio; MAF, minor allele frequency; CMH, Cochrane–Mantel–Haenszel test; F/R, fixed/random effect; Q, P-value for Cochrane’s Q statistic;
I, I2 heterogeneity index (0–100).
0
0.70/0.78 (1/1) 1.02/1.02 0.21 34.5
T/C
1,673/14,123
1.05 (0.92–1.20)
0.50 (1)
0.22
0.23
T/C
651/11,489
0.99 (0.87–1.13)
0.88 (1)
0.21
0
rs9804190
T/C
0.91/0.91 (1/1) 1.01/1.01 0.74
0.46/0.46 (1/1) 1.06/1.06 0.94
T/C
G/A
1,720/14,320
1,683/14,324
1.08 (0.83–1.39)
1.03 (0.81–1.31)
0.32 (0.96)
0.56 (1)
0.050
0.058
0.060
0.055
T/C
G/A
651/11,473
629/11,429
1.05 (0.86–1.29)
0.99 (0.81–1.22)
0.073 0.95 (1)
0.068 0.64 (1)
1,069/2,847
rs1938526
T/C
1,054/2,895
rs10994336
SZ sample
G/A
0
0.88/0.88 0.68
(0.069/0.069)
0.023/0.023
T/C
1,183/13,843
0.84 (0.70–0.99)
0.050 (0.15)
0.22
0.19
T/C
434/11,489
0.18 (0.54) 0.90 (0.78–1.05)
0.21
749/2,354
rs9804190
T/C
1.11/1.11 0.60
(0.71/0.71)
0.24/0.24
G/A
1,226/14,012
1.23 (0.93–1.61)
0.32 (0.96)
0.058
0.070
G/A
433/11,473
1.04 (0.83–1.30)
0.072 0.75 (1)
806/2,542
rs1938526
T/C
839/2,596
rs10994336
G/A
0.050
0.071
T/C
421/11,429
0.068 0.30 (0.90) 1.13 (0.90–1.41)
OR (95%CI)
corrected)
MAF
allele
cases/controls
BD sample
Sample SNP
0
5.05
1.25/1.24 0.35
0.015/0.018
T/C
1,260/14,025
0.012 (0.036) 1.45 (1.09–1.90)
OR (95%CI)
corrected)
affected unaffected
allele
controls
Allelic P
(Bonferroni
MAF
MAF
Minor/major
Total number
cases/
(Bonferroni
CMH P
Minor/
major
Total number
(0.044/0.053)
Q
OR F/R
corrected)
allele
cases/controls
P F/R
(Bonferroni
major
Total number
Minor/
Combined Nordic
Icelandic
The main findings in this study were significant associations
between ANK3 SNPs rs10994336 (Bonferroni corrected) and
rs9804190 (nominally significant) and BD in our combined Nordic
sample. These SNPs have previously been found to be associated
with BD in three studies comprising individuals of European
ancestry [Ferreira et al., 2008; Schulze et al., 2009; Scott et al.,
2009]. We did not find evidence for association between
rs10994336, rs1938526, or rs9804190 and SZ, which indicates
that these three ANK3 SNPs are involved specifically in the pathophysiology of BD, or at least in neurobiological processes more
prevalent in the BD spectrum than in the SZ spectrum in the
proposed continuum of severe psychiatric disorders [Craddock
et al., 2009]. ANK3 being a specific risk gene for BD is further
supported by the findings from a recent meta-analysis [Liu et al.,
2010] combining and comparing results from the aforementioned
GWAS on BD (N ¼ 4,387 BD cases and 6,209 controls) [Ferreira
et al., 2008] with a GWAS on Major Depressive Disorder (MDD)
(N ¼ 1,695 MDD cases and 1761 controls) [Sullivan et al., 2009],
where no evidence for ANK3 involvement in MDD was detected.
There is increasing evidence of interesting molecular and neurobiological mechanisms related to ANK3 in BD. Ion channelopathy
has been proposed as one potential mechanism [Ferreira et al., 2008;
Askland et al., 2009]. This hypothesis is based on the findings from
animal studies showing that a dysfunction in ankyrin G could lead
to abnormal clustering of potassium channels and voltage-gated
sodium channels at axon initial segments and cause abnormal
action potential firing [Zhou et al., 1998; Pan et al., 2006]. Further
support for this hypothesis comes from GWA studies finding
significant association between L-type voltage-gated calcium channel gene (CACNA1C), a gene involved in calcium channel regulation, and BD [Ferreira et al., 2008; Sklar et al., 2008] and from a
recent animal study showing the importance of ankyrin G for
SCOPE
DISCUSSION
TABLE II. Association Analyses of ANK3 SNPs in Nordic Bipolar Disorder and Schizophrenia Case–Control Samples
None of the three SNPs were significantly associated with BD or
SZ in the Scandinavian subsamples, but rs10994336 was nominally
significantly associated with BD in the Icelandic BD sample
(nominal P ¼ 0.012). Rs9804190 attained a nominal P-value of
0.05 for association with BD in the Icelandic sample. When
combining our results from the Scandinavian samples with the
results from the Icelandic samples, we found rs10994336 and
rs9804190 to be nominally significantly associated with BD in
the combined Nordic case–control sample. Nominal P values
were 0.015/0.018 (fixed/random effect) for rs10994336 and 0.023
for rs9804190; the respective P values after Bonferroni correction
were 0.044/0.53 and 0.069. For both these SNPs (rs10994336 and
rs9804190), the risk allele was overrepresented among patients in
the total BD sample, as well as in all of the BD subsamples (Table II
and Supplementary material Table I). None of the SNPs were
significantly associated with SZ in any of the samples (Table II
and Supplementary material Table I).
There was no evidence of heterogeneity for the population-based
ORs amongst the different SCOPE subsamples, as indicated by the
Breslow–Day test (Supplementary material Table I).
More detailed results are presented in Table II and in Supplementary material Table I.
AMERICAN JOURNAL OF MEDICAL GENETICS PART B
I
972
TESLI ET AL.
maintaining appropriate axo-dendritic polarity in vivo [Sobotzik
et al., 2009]. Interestingly, another recent animal study showed that
ANK3 was downregulated in the mouse brain in response to lithium
[McQuillin et al., 2007]. This suggests a potential for drug development based on ANK3 pathophysiology.
However, what effect ANK3 SNPs rs10994336 and rs9804190
might have on the function of the expressed protein ankyrin G is
unknown. According to the Ensembl database (http://www.
ensembl.org/), these two SNPs are located in intronic regions of
ANK3. If rs10994336 and rs9804190 are directly affecting the
ankyrin G protein, gene regulation affecting expression is a tentative
mechanism [Quinn et al., 2010]. It is also possible that these two
SNPs have no functional relevance for BD pathophysiology, and
that their association with BD merely reflects a high linkage
disequilibrium (LD) with the real risk allele.
The two SNPs attaining most significant associations in this
study, rs10994336 and rs9804190, are independent markers in our
SCOPE sample (R2 ¼ 0.00). As hypothesized in a previous study,
this suggests allelic heterogeneity in the involvement of ANK3 in BD
[Schulze et al., 2009].
In conclusion, the present results are in accordance with former
findings, suggesting that ANK3 is a BD susceptibility gene, and that
ion channelopathy may be involved in BD pathophysiology. Future
studies should investigate how ANK3 genetic variants are related to
neurobiological endophenotypes as well as clinical subphenotypes
in bipolar spectrum disorders.
ACKNOWLEDGMENTS
We thank patients and controls for their participation in the study,
and the health professionals who facilitated our work. We also
thank Thomas D. Bjella for assistance with the database, and Bente
Bennike, Knut-Erik Gylder, and Lars Hansson for molecular genetic
technical assistance. The study was supported by grants to the TOP
study group from the University of Oslo, the Research Council of
Norway (#167153/V50, #163070/V50), the SouthEast Norway
Health Authority (#2004123), the Danish National Psychiatric
Research Foundation, the Lundbeck Foundation, the Ivan Nielsen
Foundation, the Stanley Medical Research Institute, the Wallenberg
Foundation, the HUBIN Project, and the Swedish Medical Research
Council (2006-2992, 2006-986, 2008-2167). We would like to
thank Dr. Hreinn Stefansson at deCODE Genetics for providing
information from replication samples.
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