Association analysis of PALB2 and BRCA2 in bipolar disorder and schizophrenia in a scandinavian caseЦcontrol sample.код для вставкиСкачать
RESEARCH ARTICLE Neuropsychiatric Genetics Association Analysis of PALB2 and BRCA2 in Bipolar Disorder and Schizophrenia in a Scandinavian Case–Control Sample Martin Tesli,1,2* Lavinia Athanasiu,1,2,3 Morten Mattingsdal,3 Anna K. K€ahler,1,2,3 Omar Gustafsson,2 Bettina K. Andreassen,4,5 Thomas Werge,6 Thomas Hansen,6 Ole Mors,7 Erling Mellerup,8,9 Pernille Koefoed,8,9 Erik G. J€onsson,12 Ingrid Agartz,1,12,13 Ingrid Melle,1,2 Gunnar Morken,10,11 Srdjan Djurovic,1,2,3 and Ole A. Andreassen1,2 1 Institute of Psychiatry, University of Oslo, Oslo, Norway Department of Psychiatry, Oslo University Hospital, Ulleval, Oslo, Norway 2 3 Department of Medical Genetics, Oslo University Hospital, Ulleval, Oslo, Norway 4 Department of Biostatistics, University of Oslo, Oslo, Norway Department of Mathematics, University of Oslo, Oslo, Norway 5 6 Research Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark 7 Center for Psychiatric Research, Aarhus University Hospital, Aarhus, Denmark Department of Neuroscience and Pharmacology, Laboratory of Neuropsychiatry, University of Copenhagen, Copenhagen, Denmark 8 9 Department of Neuroscience and Pharmacology, Center of Psychiatry, Copenhagen, Denmark 10 Østmarka Psychiatric Department, St. Olavs Hospital, Trondheim, Norway Institute of Neuroscience, Norwegian University of Technology and Science, Trondheim, Norway 11 12 Department of Clinical Neuroscience, HUBIN Project, Psychiatry Section, Karolinska Institutet and Hospital, Stockholm, Sweden 13 Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway Received 19 January 2010; Accepted 9 April 2010 A recent genome-wide association study (GWAS) found significant association between the PALB2 SNP rs420259 and bipolar disorder (BD). The intracellular functions of the expressed proteins from the breast cancer risk genes PALB2 and BRCA2 are closely related. Therefore, we investigated the relation between genetic variants in PALB2 and BRCA2 and BD. Due to increasing evidence of genetic overlap between BD and schizophrenia (SCZ), we also investigated association with SCZ. In a Scandinavian case–control sample (n ¼ 686/2,538) we found the BRCA2 SNP rs9567552 to be significantly associated with BD (Nominal P ¼ 0.00043). Additionally, we replicated the association between PALB2 SNP rs420259 and BD (Nominal P ¼ 0.025). We then combined our sample with another Nordic case–control How to Cite this Article: Tesli M, Athanasiu L, Mattingsdal M, K€ahler AK, Gustafsson O, Andreassen BK, Werge T, Hansen T, Mors O, Mellerup E, Koefoed P, J€ onsson EG, Agartz I, Melle I, Morken G, Djurovic S, Andreassen OA. 2010. Association Analysis of PALB2 and BRCA2 in Bipolar Disorder and Schizophrenia in a Scandinavian Case–Control Sample. Am J Med Genet Part B 153B:1276–1282. 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: 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, M.D., Section for Psychosis Research, Division of Psychiatry, Department for Research and Development, Oslo University Hospital, Building 49, Ulleval, Kirkeveien 166, N-0407 Oslo, Norway. E-mail: firstname.lastname@example.org Published online 24 May 2010 in Wiley Online Library (wileyonlinelibrary.com) DOI 10.1002/ajmg.b.31098 Ó 2010 Wiley-Liss, Inc. 1276 TESLI ET AL. sample (n ¼ 435/11,491) from Iceland, and added results from the Wellcome Trust Case Control Consortium (WTCCC) (n ¼ 1,868/2,938) and the STEP-UCL/ED-DUB-STEP2 study (n ¼ 2,558/3,274) in a meta-analysis which revealed a P-value of 1.2 105 for association between PALB2 SNP rs420259 and BD (n ¼ 5,547/20,241). Neither the PALB2 SNP rs420259 nor the BRCA2 SNP rs9567552 were nominally significantly associated with the SCZ phenotype in our Scandinavian sample (n ¼ 781/ 2,839). Our findings support PALB2 and BRCA2 as risk genes specifically for BD, and suggest that altered DNA repair related to neurogenesis may be involved in BD pathophysiology. 1277 Ó 2009 Wiley-Liss, Inc. [WTCCC, 2007], was associated with BD in a Scandinavian sample of 686 BD cases and 2,538 controls, from now on called ‘‘Total SCOPE BD sample.’’ We also genotyped 10 BRCA2 tagSNPs selected by using the HapMap in a smaller but overlapping BD sample comprising 554 cases and 1,419 controls, from now on called ‘‘SCOPE BD Subsample.’’ The most significant BRCA2 SNPs from this subsample was genotyped in the remaining subjects of the Total SCOPE BD sample. In the second phase of our study, we investigated if the PALB2 SNP rs420259 and the nominally significant BRCA2 tagSNPs from the SCOPE BD Subsample were associated with SCZ in the SCOPE SCZ sample of 781 cases and 2,839 controls. Key words: bipolar disorder; schizophrenia; PALB2; BRCA2; genetic association Sample Description INTRODUCTION Bipolar disorder (BD) and schizophrenia (SCZ) are severe mental disorders with high heritability, but the underlying molecular genetic mechanisms are still not well understood [Keshavan et al., 2008; Newberg et al., 2008]. Epidemiological as well as molecular genetic studies are consistent with a polygenic model [Craddock et al., 1995; Owen et al., 2009], in which many genetic variants must interact with each other and with environmental factors to give rise to BD and SCZ. Furthermore, results from recent epidemiological and association studies indicate a genetic overlap between these two disorders [Lichtenstein et al., 2009; Moskvina et al., 2009]. A recent genome-wide association study (GWAS) found a significant association between BD and the single nucleotide polymorphism (SNP) rs420259 in PALB2 (partner and localizer of BRCA2) (Genotypic P-value ¼ 6.3 108) [WTCCC, 2007]. PALB2 is located on chromosome 16 and encodes for the protein PALB2, which co-localizes with BRCA2 (breast cancer 2, early onset) in the cell nucleus and promotes its localization and stability in cellular structures like chromatin and nuclear matrix [Xia et al., 2006]. BRCA2 is located on chromosome 13 and encodes for the protein BRCA2, which is involved in DNA repair. A dysfunction in BRCA2 leads to an increased risk of developing certain forms of cancer [Tutt and Ashworth, 2002], and recent evidence suggests that mutations in PALB2 itself also increases the risk for breast cancer [Rahman et al., 2007]. Interestingly, a recent study showed that BRCA2 is required for normal neurogenesis in mice [Frappart et al., 2007]. Thus, it is possible that alterations in these two functionally related genes may lead to abnormal neurogenesis in humans, which in turn might give rise to severe psychiatric disorders. In this study we investigated the association between PALB2 and BRCA2 and severe psychiatric disorders, as well as the potential genetic overlap between BD and SCZ. For that purpose we genotyped PALB2 and BRCA2 SNPs in Scandinavian BD and SCZ case–control samples. MATERIALS AND METHODS In the first phase of our study, we investigated if the PALB2 SNP rs420259 which was highly associated with BD in the WTCCC study The bipolar disorder case–control sample. The BD sample is based on two independent case–control samples from Norway and Denmark, all included in the Scandinavian Collaboration of Psychiatric Etiology (SCOPE) study. The total number of subjects was 686 BD cases and 2,538 controls. The Norwegian patients (n ¼ 246) had been diagnosed with Bipolar I disorder (n ¼ 155), Bipolar II disorder (n ¼ 81) or Bipolar disorder NOS (n ¼ 10), according to DSM-IV using Structural Clinical Interview for DSM-IV (SCID) [Spitzer et al., 1992]. The Danish sample (n ¼ 440) consisted of patients with Bipolar affective disorder F31 (n ¼ 354) and Manic episode F30 (n ¼ 2) according to ICD-10, Bipolar I disorder according to DSM-IV (n ¼ 1), and Bipolar disorder (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 BD, SCZ, and control samples are further described in Table I. The schizophrenia case–control sample. The SCZ association study was based on three independent case–control samples from Norway, Sweden, and Denmark, included in the SCOPE. The Norwegian patients (n ¼ 166) had been diagnosed with Schizophrenia (n ¼ 133), Schizoaffective disorder (n ¼ 26) and Schizophreniform disorder (n ¼ 7) according to DSM-IV using Structural Clinical Interview for DSM-IV (SCID) [Spitzer et al., 1992]. The Danish sample (n ¼ 363) consisted of patients with Schizophrenia (n ¼ 333), Persistent delusional disorder (n ¼ 2) and Schizoaffective disorder (n ¼ 28) according to ICD-10 F20, F22, and F25 using clinical interviews. The Swedish patients (n ¼ 252) had been diagnosed with Schizophrenia (n ¼ 220), Schizoaffective disorder (n ¼ 24), or Schizophreniform disorder (n ¼ 8), according to DSM-III-R/DSM-IV criteria using record reviews and clinical interviews. The sample is described in more detail elsewhere [Hansen et al., 2007; Kahler et al., 2008]. A total of 781 SCZ cases and 2,839 controls subjects were successfully 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. 1278 AMERICAN JOURNAL OF MEDICAL GENETICS PART B TABLE I. Sample Characterization BD Sample Women Denmark N Mean age (SD)a Norway N Mean age (SD)a Sweden N Mean age (SD)a SCZ Controls Men Women Men Women Men Sum 255 53.1 (14.0) 185 49.4 (14.1) 153 48.7 (13.0) 210 46.1 (11.8) 1,040 46.1 (12.8) 1,167 44.8 (11.6) 3,010 135 42.7 (13.2) 111 42.4 (13.0) 76 40.9 (11.5) 90 38.0 (9.7) 172 39.2 (10.4) 158 39.7 (10.4) 742 96 60.3 (16.9) 156 55.3 (14.0) 114 54.0 (10.5) 187 53.0 (10.3) 553 4,305 BD, bipolar disorder; SCZ, schizophrenia; SD, standard deviation.aMean age in 2009. Replication Samples Icelandic bipolar disorder case–control sample. The Icelandic BD sample consisted of 435 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 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]. The 11,491 controls were recruited as a part of various genetic programs at deCODE genetics and were not screened for psychiatric disorders. WTCCC bipolar disorder case–control sample. The WTCCC BD sample consisted of 1,868 cases and 2,938 controls, all from a British population [WTCCC, 2007]. STEP-UCL/ED-DUB-STEP2 bipolar disorder case–control sample. The STEP-UCL/ED-DUB-STEP2 BD sample (n ¼ 2,558/3,274) consisted of the STEP-UCL BD sample (n ¼ 1,460/ 2,007) and the ED-DUB-STEP2 BD sample (n ¼ 1,098/1,267), and is better described elsewhere [Ferreira et al., 2008; Sklar et al., 2008]. SNP Selection and Genotyping To cover most of the common variants in BRCA2 in the SCOPE BD Subsample with tagSNPs, we used a structured gene-wide approach, based on the HapMap CEU population. TagSNP selection was performed at the HapMap website using pair-wise tagging, with r2 0.8 [de Bakker et al., 2005] (www.hapmap.org; HapMap Data Rel 22/phaseII Apr07) and minor allele frequency (MAF) 0.05. The actual tagging efficiency of successfully genotyped tagSNPs was calculated at the Tagger website (www.broad. mit.edu/mpg/tagger/server.html). Genomic DNA was extracted from whole blood. Ten BRCA2 tagSNPs were genotyped in the SCOPE BD Subsample using the GoldenGate 1536plex assay (Illumina, Inc., San Diego, CA) on Illumina BeadStation 500GX at the SNP Technology Platform, Uppsala University, Sweden (www.genotyping.se), accredited by the Swedish accreditation agency SWEDAC, and approved according to a quality system based on the international SS-EN ISO/IEC 17025 standard. For the rest of the genotyping in this study we used the TaqMan SNP Genotyping Assay (Applied Biosystems, Foster City, CA), predesigned assays, according to 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. In each experiment, a minimum of four ‘‘no template Controls’’ (NTC) were also used. None of these NTCs showed any signal in the experiments performed. 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 1.04; http://pngu.mgh.harvard.edu/purcell/plink/) [Purcell et al., 2007]. SNPs with P < 0.01 in controls were considered in Hardy– Weinberg disequilibrium (HWD) and excluded. Single SNP association tests were performed in PLINK, with the function ‘‘model,’’ investigating best-fitting model and inheritance pattern. Correction was done for multiple testing with Bonferroni correction for all SNPs tested in each gene. Although a recent report found no population stratification between our three Scandinavian SCZ subsamples [Kahler et al., 2008], potential differences in allele frequencies between the cases and controls were investigated with the Cochran–Mantel–Haenzsel (CMH) test, using the population as stratification factor. The heterogeneity of the population-based odds ratios (ORs) of the different populations was evaluated with the Breslow–Day test. Pairwise SNP SNP interaction analysis was performed for the PALB2 SNP rs420259 and the most significant BRCA2 tagSNPs. All these tests were undertaken in PLINK. Meta-analysis. Association tests between BD and the PALB2 SNP rs420259 in the SCOPE/Icelandic/WTCCC BD sample (n ¼ 2,989/16,967) were performed in PLINK. To evaluate and correct for population stratification, the CMH and the TESLI ET AL. The main findings of the present study were a replication of the association between the PALB2 SNP rs420259 and BD from the 0.50 0.23 1.04 (0.91–1.20) 1.05 (0.91–1.20) 0.54 0.52 0.26 0.23 0.26 0.23 G/A T/G 765/2,591 762/2,685 0.61 0.51 0.88 0.82 0.84 (0.72–0.98) 1.32 (1.13–1.54) 0.025 0.00043 (0.0043) 0.26 0.23 0.22 0.27 G/A T/G 0.83 0.19 Breslow–Day test P OR (95% CI) CMH test P (Bonferroni corrected) 618/2,305 554/2,388 CI, confidence interval; CMH, Cochran–Mantel–Haenszel; OR, odds ratio. DISCUSSION SNP (gene) Total BD sample rs420259 (PALB2) rs9567552 (BRCA2) Total SCZ sample rs420259 (PALB2) rs9567552 (BRCA2) All P-values presented here are based on the CMH test. More detailed results are presented in Tables II and III and Table I in Supplementary Material. SCOPE bipolar disorder case–control sample. As seen in Table II, P-value for association between PALB2 SNP rs420259 and BD was 0.025. OR for the minor allele G was 0.84, A was risk allele. Two of 10 BRCA2 tagSNPs showed nominal significant association with BD in the SCOPE BD Subsample (P ¼ 0.00037 for rs9567552 and P ¼ 0.027 for rs2320236), but only rs9567552 survived Bonferroni correction (P ¼ 0.0037) (Table I Supplementary material). rs9567552 attained a P-value of 0.00043 in the Total SCOPE BD sample (P ¼ 0.0043 after Bonferroni correction) (Table II). OR for minor allele T was 1.32, G was major allele. There was no indication of interaction effect between PALB2 SNP rs420259 and BRCA2 SNP rs9567552 in the Total SCOPE BD sample (P > 0.05). SCOPE schizophrenia case–control sample. None of the two SNPs were associated with SCZ in our sample (P > 0.05) (Table II). Meta-analysis. As seen in Table III, P-value for association between PALB2 SNP rs420259 and BD in the combined sample was 1.2 105, and A was risk allele in all subsamples. A population stratification between the SCOPE BD sample, the Icelandic BD sample and the WTCCC BD sample was seen as indicated by the differences in allele frequencies, but there was no indication of OR heterogeneity, as the Breslow–Day test P-value was non-significant (P ¼ 0.97). Control frequency Single SNP Association Data Case frequency No SNPs had genotype distributions in HWD in controls (P < 0.01). The results are shown in Tables II and III and Table I in Supplementary Material. HWE controls Hardy–Weinberg Equilibrium Minor allele/ major allele SNP conversion rate for BRCA2 in the SCOPE BD Subsample was 92.6%, reproducibility was 99.996% (there were 5 duplicate errors in 124,684 duplicate genotype calls); and the average sample call rate per SNP assay was 96.9%. Our BRCA2 tagSNPs in the SCOPE BD Subsample covered 56% of the common variants with r2 0.8 and 95% with r2 0.5. Total number cases/control RESULTS Genotyping and tagSNP Coverage TABLE II. Nominally Significant PALB2 and BRCA2 SNPs in Single Marker Analyses of Scandinavian Bipolar Disorder (BD) and Schizophrenia (SCZ) Case–Control Samples Breslow–Day tests, also implemented in PLINK, were undertaken. For the combined BD sample (n ¼ 5,547/20,241) consisting of the SCOPE/Icelandic/WTCCC BD sample and the STEP-UCL/EDDUB-STEP2 BD sample, we performed Fisher’s combined probability test to assess the P-value for association between BD and the PALB2 SNP rs420259. 1279 CI, confidence interval; CMH, Cochran–Mantel–Haenszel; OR, odds ratio.aP-value from Fisher’s combined probability test. 0.97 Total number Minor allele/ HWE Case Control cases/controls major allele controls frequency frequency P OR (95% CI) P OR (95% CI) SCOPE BD sample 618/2,305 G/A 0.83 0.22 0.26 0.025 0.84 (0.72–0.98) Icelandic BD sample 435/11,491 G/A 0.53 0.19 0.22 0.13 0.88 (0.74–1.04) WTCCC BD sample 1,868/2,938 G/A 0.016 0.25 0.28 0.00022 0.84 (0.76–0.92) SCOPE/Icelandic/WTCCC BD sample 2,921/16,735 G/A 0.026 0.23 0.23 5.5 106 0.85 (0.79–0.91) STEP-UCL/ED-DUB-STEP2 BD sample 2,558/3,274 G/A 0.16 0.94 a 1.2 105a Combined BD sample 5,479/20,008 G/A CMH test Allele test TABLE III. Meta-Analysis of PALB2 SNP rs420259 and Bipolar Disorder (BD) P 0.88 AMERICAN JOURNAL OF MEDICAL GENETICS PART B Breslow– Day test 1280 WTCCC study [WTCCC, 2007], and a strong association between the SNP rs9567552 in the new candidate gene BRCA2 and BD. We did not find significant association between SCZ and these two SNPs, which indicates no genetic overlap between BD and SCZ for these gene variants. The PALB2 SNP rs420259 has been investigated in two previous association studies. The WTCCC study [WTCCC, 2007] found a highly significant association with BD (P ¼ 6.3 108), whereas another large collaborative study also reported a weak but nonsignificant (P ¼ 0.16) tendency to association in the same direction [Ferreira et al., 2008]. Combining our results with these and performing a meta-analysis in a sample of 5,547 BD cases and 20,241 controls, we found rs420259 to be significantly associated with BD (P ¼ 1.2 105). To our knowledge, this is the first hypothesis-driven association study of BRCA2 and BD and SCZ, and the first study of BRCA2 SNP rs9567552 in these two disorders. The aforementioned WTCCC study [WTCCC, 2007] did not find significant association between 22 BRCA2 SNPs and BD (P > 0.05), but this study did not investigate rs9567552. Rs9567552 is, according to www.hapmap.org, in LD with rs1799943 (r2 ¼ 0.96). Neither of these SNPs are described in PubMed as associated with psychiatric disorders or cancer. PALB2 was identified as a BD susceptibility gene in the WTCCC study [WTCCC, 2007], but has been extensively studied as a factor in cancer development. In a Chinese study the PALB2 SNP rs249954 was found to be associated with breast cancer (G/A, A risk allele) [Chen et al., 2008]. This SNP is in linkage disequilibrium (LD) with rs420259 (r2 ¼ 1.0 based on the Chinese HapMap population; r2 ¼ 0.84 in CEU), which was associated with BD in the WTCCC study [WTCCC, 2007] and replicated in the current study. According to www.hapmap.org, the G allele of rs249954 is in LD with A of rs420259. Thus, the risk allele for breast cancer is in LD with the protective allele for BD. This finding may be interpreted in several ways, as we do not know which SNP is causatively associated with these two phenotypes; different SNPs may be involved in different diseases, or the same SNP may have protective effect for one phenotype and increase the risk for developing the other phenotype. There may also be allele heterogeneity at the same locus in different populations, which could imply that the risk allele for BD/ breast cancer in Europeans is the protective allele in the Chinese population and vice versa [Hennah et al., 2008]. The mechanisms by which these two genes may be related to BD are still unclear; but BRCA2 is expressed in the mouse brain, and was shown to be important for normal neurogenesis, particularly in the cerebellum [Frappart et al., 2007]. Cerebellum has been shown to be involved in emotional processing, and cerebellar dysfunction has been observed in BD [Konarski et al., 2005; Bolbecker et al., 2009]. Thus, it is possible that a dysfunction in BRCA2 and PALB2 leads to altered neurogenesis in certain brain regions, which in turn may increase the risk of developing BD. However, this remains speculative. Taken together, the present findings suggest a causal relation between PALB2 and BD and BRCA2 being a new BD candidate gene. However, more studies are needed to investigate the association between these genes and BD and SCZ, as well as potential molecular mechanisms. TESLI ET AL. 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, Bente Bennike, Knut-Erik Gylder, Trude Lien, and Elin Inderhaug for molecular genetic technical assistance, as well as Kristina Larsson, Per Lundmark, Tomas Axelsson, and Ann-Christine Syv€anen at the SNP Technology Platform in Uppsala for performing the genotyping. The SNP Technology Platform is supported by Uppsala University, Uppsala University Hospital and by the Knut and Alice Wallenberg Foundation. 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 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 and Dr. Pamela Sklar from Harvard Medical School, Broad Institute for providing information from replication samples. This study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. 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