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Keywords:

  • bipolar disorder;
  • schizophrenia;
  • ANK3;
  • genetic association

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

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 = 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 = 1,073/2,919). Combining our Scandinavian samples with an Icelandic sample (N = 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 = 1,289/14,105). Nominal P was 0.015/0.018 (fixed/random effect) for rs10994336 (Bonferroni corrected P = 0.044/0.053) and 0.023 for rs9804190 (Bonferroni corrected P = 0.069). None of the SNPs were significantly associated with SZ in the combined Nordic SZ case–control sample (N = 1,724/14,410). These results further support that ANK3 is a susceptibility gene specific to BD and that more than one risk locus is involved. © 2011 Wiley Periodicals, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

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 = 9.1 × 10−9) and rs1938526 (P = 1.3 × 10−8) 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 = 1.7 × 10−5) [Schulze et al., 2009] as well as in a sample of 638 cases and 904 controls (P = 0.042) [Scott et al., 2009]. Furthermore, the association between rs1938526 and BD (P = 0.036) (N = 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 = 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 = 6.55 × 10−5) [Lee et al., 2011].

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 above-mentioned samples. Due to the evidence of genetic overlap between 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

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

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 = 345) had been diagnosed with bipolar I disorder (N = 230), bipolar II disorder (N = 96), or BD not otherwise specified (N = 19), according to DSM-IV using the Structural Clinical Interview for DSM-IV (SCID) [Spitzer et al., 1992]. The Danish sample (N = 509) consisted of patients with bipolar affective disorder F31 (N = 423) and manic episode F30 (N = 3) according to ICD-10 (http://www.who.int/classifications/icd/en), bipolar I disorder according to DSM-IV (N = 1), and BD (N = 15), mania with psychosis (N = 1), and bipolar with psychosis (N = 66) according to the OPCRIT classification system. [McGuffin et al., 1991].

The SCOPE BD, SZ, and control samples are further described in Table I.

Table I. Characteristics for the SCOPE BD and SZ Case–Control Samples
SampleBDSZCTRSum
  • SCOPE, Scandinavian Collaboration on Psychiatric Etiology; BD, bipolar disorder; SZ, schizophrenia; CTR, controls; SD, standard deviation.

  • a

    Mean age in 2010.

Denmark
 N (females, %)509 (0.58)467 (0.41)2182 (0.46)3,158
 Mean age (SD)a53.1 (15.0)47.8 (12.3)46.0 (11.8) 
Norway
 N (females, %)345 (0.58)349 (0.44)432 (0.50)1,126
 Mean age (SD)a41.2 (13.1)37.2 (10.7)39.2 (10.4) 
Sweden
 N (females, %) 257 (0.38)305 (0.38)562
 Mean age (SD)a 58.1 (15.2)54.3 (10.4) 
Sum8541,0732,9194,846
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 = 349) had been diagnosed with SZ (N = 272), schizoaffective disorder (N = 59), schizophreniform disorder (N = 15), and persistent delusional disorder (N = 3) according to DSM-IV using the Structural Clinical Interview for DSM-IV (SCID) [Spitzer et al., 1992]. The Danish sample (N = 467) consisted of patients with SZ (N = 422), schizotypal personality disorder (N = 4), persistent delusional disorder (N = 2), and schizoaffective disorder (N = 39) according to ICD-10 F20, F21, F22, and F25 using clinical interviews. The Swedish patients (N = 257) had been diagnosed with SZ (N = 224), schizoaffective disorder (N = 25), or schizophreniform disorder (N = 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 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 sample (N = 1,289/14,105) and SZ case–control sample (N = 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

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

No SNPs had genotype distributions in Hardy–Weinberg disequilibrium in controls (P < 0.05).

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 = 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).

Table II. Association Analyses of ANK3 SNPs in Nordic Bipolar Disorder and Schizophrenia Case–Control Samples
Sample SNPSCOPEIcelandicCombined Nordic
Total number cases/controlsMinor/major alleleMAFCMH P (Bonferroni corrected)OR (95%CI)Total number cases/controlsMinor/major alleleMAF affectedMAF unaffectedAllelic P (Bonferroni corrected)OR (95%CI)Total number cases/controlsMinor/major alleleP F/R (Bonferroni corrected)OR F/RQI
  1. 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).

BD sample
 rs10994336839/2,596T/C0.0680.30 (0.90)1.13 (0.90–1.41)421/11,429T/C0.0710.0500.012 (0.036)1.45 (1.09–1.90)1,260/14,025T/C0.015/0.018 (0.044/0.053)1.25/1.240.355.05
 rs1938526806/2,542G/A0.0720.75 (1)1.04 (0.83–1.30)433/11,473G/A0.0700.0580.32 (0.96)1.23 (0.93–1.61)1,226/14,012G/A0.24/0.24 (0.71/0.71)1.11/1.110.600
 rs9804190749/2,354T/C0.210.18 (0.54)0.90 (0.78–1.05)434/11,489T/C0.190.220.050 (0.15)0.84 (0.70–0.99)1,183/13,843T/C0.023/0.023 (0.069/0.069)0.88/0.880.680
SZ sample
 rs109943361,054/2,895T/C0.0680.64 (1)1.05 (0.86–1.29)629/11,429T/C0.0550.0500.56 (1)1.08 (0.83–1.39)1,683/14,324T/C0.46/0.46 (1/1)1.06/1.060.940
 rs19385261,069/2,847G/A0.0730.95 (1)0.99 (0.81–1.22)651/11,473G/A0.0600.0580.32 (0.96)1.03 (0.81–1.31)1,720/14,320G/A0.91/0.91 (1/1)1.01/1.010.740
 rs98041901,022/2,634T/C0.210.88 (1)0.99 (0.87–1.13)651/11,489T/C0.230.220.50 (1)1.05 (0.92–1.20)1,673/14,123T/C0.70/0.78 (1/1)1.02/1.020.2134.5

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.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

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., 2011] combining and comparing results from the aforementioned GWAS on BD (N = 4,387 BD cases and 6,209 controls) [Ferreira et al., 2008] with a GWAS on Major Depressive Disorder (MDD) (N = 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 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 = 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.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

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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  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. Acknowledgements
  8. REFERENCES
  9. Supporting Information

Additional Supporting Information may be found in the online version of this article.

FilenameFormatSizeDescription
ajmg_31244_sm_SupplTab1.doc115KSupplementary Table I
ajmg_31244_sm_SupplTab2.doc30KSupplementary Table II

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