- Email: [email protected]
IDENTIFICATION OF YWHAE, A GENE ENCODING 14-3-3EPSILON, AS A NOVEL SUSCEPTIBILITY GENE FOR SCHIZOPHRENIA
186
Abstracts / Schizophrenia Research 102/1–3, Supplement 2 (2008) 1–279
References [1] Fiore R, Schratt G. MicroRNAs in synapse development: tiny molecules to remember. Expert Opin Biol Ther. 2007 Dec;7(12):1823-31. [2] Chang TC, Mendell JT. microRNAs in vertebrate physiology and human disease. Annu Rev Genomics Hum Genet. 2007;8:215-39.
390 – TOWARDS A VALID CLASSIFICATION OF ENDOGENOUS PSYCHOSIS:TIME TO PAY ATTENTION TO THE WERNICKE-KLEIST-LEONHARD SCHOOL Jack Foucher 1 , Valerie Benouna-Greene 2 , Gerald Stoeber 3 Strasbourg, France; 2 HUS/ULP, Strasbourg; 3 Würtzburg University, Würtzburg, Germany [email protected]
1 HUS/ULP/INSERM,
Introduction: International psychiatric classifications are today at a major turning point: once turned towards reliability alone, they are now addressing validity. In the "medical paradigm" this means defining “diseases” based on their etiology or physiopathology.The WernickeKleist-Leonhard school has long been working on this project. Methods: We review the German, English and Spanish literature to describe the reliability and validity of the WKL classification. Results: Reliability: inter-rater reproducibility and time reproducibility at 30 years follow-up are high (kappa > 0.8). Construct validity is ascertained by the building principles of the classification. A hundred of clinical pictures were merged according to 2 principles: i) the longitudinal one, ie when different clinical pictures are expressed by the same patients they are the manifestations of the same disorder, ii) the intra-familial aggregation principle, ie when different clinical pictures are expressed by members of the same family they are likely the manifestations of the same genetic liability. This classification results in 35 major "disorders", grouped into 5 families on the basis of the evolution and the homomorphic/polymorphic character of their clinical pictures (schizophrenia corresponds to 20 different disorders). The classification’s face validity has been addressed by showing that different disorders come up with highly significant differences in genetic load and neuro-develop mental history. Two studies replicated a linkage for periodic catatonia with 15q15. Moreover the classification advances high predictive validity in prognosis and treatment response. Conclusions: The WKL school offers the most validated classification system according to current epistemological criteria. References [1] Stober, G., Seelow, D., Ruschendorf, F., Ekici, A., Beckmann, H. & Reis, A. (2002b). Periodic catatonia: confirmation of linkage to chromosome 15 and further evidence for genetic heterogeneity. Hum Genet, 111, pp. 323-330. [2] Franzek, E. & Beckmann, H. (199 8). Different genetic background of schizophrenia spectrum psychoses: a twin study. Am J Psychiatry, 155, pp. 76-83.
391 – A REANALYSIS OF 409 EUROPEAN-ANCESTRY AND AFRICAN AMERICAN SCHIZOPHRENIA PEDIGREES REVEALS SIGNIFICANT LINKAGE TO 8p23.3 WITH EVIDENCE OF LOCUS HETEROGENEITY Elizabeth Holliday 1 , Bryan Mowry 2 , Dale Nyholt 3 1 Queensland Centre for Mental Health Research, QLD; 2 1. Queensland Centre for Mental Health Research. 2. University of Queensland, QLD; 3 Queensland Institute for Medical Research, QLD, Australia [email protected] Introduction: The detection and replication of schizophrenia risk loci via linkage analysis can require substantial sample sizes. This has prompted various collaborative efforts for combining multiple, independent samples.However, pooled samples may comprise sub -samples with substantial population genetic differences, including allele frequency differences.
Methods: We investigated the impact of population differences by reanalysing Molecular Genetics of Schizophrenia 1 (MGS1) affected sibling-pair data,comprising two samples of distinct ancestral origin: European- (EA: 263 pedigrees) and African-American (AA: 146 pedigrees). To exploit the information contained within these distinct continental samples, we performed separate analyses of the EA and AA samples, allowing for within-sample locus heterogeneity, and the pooled sample, allowing for both within-sample and between-sample heterogeneity. Significance levels, corrected for the multiple tests, were determined empirically. Results: For all suggestive peaks, stronger linkage evidence was obtained in either the EA or AA sample than the combined sample, regardless of how heterogeneity was modeled for the latter. Notably, we detected genomewide significant linkage to 8p23.3 and evidence for a second, independent susceptibility locus, reaching suggestive linkage, 29 cM away on 8p21.3. We also detected suggestive linkage on chromosomes 5p13.3 and 7q36.2 and provide evidence for the presence of multiple, small-effect susceptibility loci. Many regions showed pronounced differences in linkage evidence between the EA and AA samples. Conclusions: This analysis highlights the potential impact of population differences upon linkage evidence in pooled data and demonstrates a useful approach for the analysis of samples drawn from distinct continental populations. References [1] Suarez BK, Duan J, Sanders AR, Hinrichs AL, Jin CH, Hou C, Buccola NG, Hale N, Weilbaecher AN, Nertney DA and others. 2006. Genomewide Linkage Scan of 409 European-Ancestry and African American Families with Schizophrenia: Suggestive Evidence of Linkage a t 8p23.3-p21.2 and 11p13.1-q14.1 in the Combined Sample. Am J Hum Genet 78(2):315-33. [2] Vieland VJ, Wang K, Huang J. 2001. Power to detect linkage based on multiple sets of data in the presence of locus heterogeneity: comparative evaluation of model-base d linkage methods for affected sib pair data. Hum Hered 51(4):199-208.
392 – IDENTIFICATION OF YWHAE, A GENE ENCODING 14-3-3EPSILON, AS A NOVEL SUSCEPTIBILITY GENE FOR SCHIZOPHRENIA Iwata Nakao 1 , Shinichiro Taya 2 , Takao Hikita 2 , Junko Uraguchi-Asaki 2 , Kazuto Toyo-oka 3 , Anthony Wynshaw-Boris 3 , Keizo Takao 4 , Tsuyoshi Miyakawa 4 , Norio Ozaki 2 , Kozo Kaibuchi 2 , Masashi Ikeda 1 1 Fujita Health University School of Medicine, Toyoake, Aichi; 2 Nagoya University, Nagoya; 3 UCSD School of Medicine, La Jolla; 4 Kyoto University Graduate School of Medicine, Kyoto, Japan [email protected] Introduction: Although the causes of schizophrenia remain essentially unknown, it has been widely accepted that this psychiatric illness with high heritability is a neurodevelopmental and neurodegenerative disorder with a disconnectivity and disorder of the synapse. DisruptedIn-Schizophrenia 1 (DISC1) is a promising candidate susceptibility gene for schizophrenia and has been implicated in neurodevelopment, including maturation of the cerebral cortex. Methods: To identify other novel susceptibility gene for schizophrenia, we investigated the genetic association between DISC1-interacting molecules and schizophrenia in a Japanese population, and identified a promoter SNP for 14-3-3e gene (YWHAE). The promoter SNP, which minor allele frequencies were higher in controls than those of schizophrenia, enhanced transcription of the luciferase gene in reporter gene assay. Both mRNA transcription and protein expression of 14-3-3e were increased in the lymphocytes of healthy control subjects harboring heterozygous and homozygous minor allele compared to homozygous major allele subjects. In support of a role for YWHAE in schizophrenia, we studied Ywhae+/- mice, in which the level of 14-3-3e protein is reduced to half level compared with their wild-type littermates. Results: These mice displayed defects in working memory and en-
Abstracts / Schizophrenia Research 102/1–3, Supplement 2 (2008) 1–279 hancement of anxiety-like behavior. These results strongly suggest that the YWHAE is a novel susceptibility gene for schizophrenia. Conclusions: A novel DISC1 binding protein, 14-3-3epsilon, is possibly a new candidate gene for susceptibility of schizophrenia. The promoter variant affects the expression level of mRNA and protein in peripheral blood. 14-3-3epsilon +/- mice could be useful to explore for psychosis-related behavior. References [1] Toyo-oka, K. et al. 14-3-3epsilon is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller-Dieker syndrome. Nat Genet 34, 274-85 (2003). [2] Taya, S. et al. DISC1 regulates the transport of the NUDEL/LIS1/ 14-3-3 complex through Kinesin-1. J Neurosci 27, 15-26 (2007). [3] Shinoda, T. et al. DISC1 regulates neurotrophin-induced axon elongation via interaction with Grb2. J Neurosci 27, 4-14 (2007).
393 – GENE-WIDE REPLICATION STUDY OF BRAINDERIVED NEUROTROPHIC FACTOR (BDNF) WITH SCHIZOPHRENIA: POPULATION BASED ASSOCIATION ANALYSIS AND META-ANALYSIS Kunihiro Kawashima 1 , Masashi Ikeda 1 , Taro Kishi 1 , Tsuyoshi Kitajima 1 , Yoshio Yamanouchi 1 , Yoko Kinoshita 1 , Tomo Okochi 1 , Makoto Tomita 2 , Toshiya Inada 3 , Norio Ozaki 4 , Nakao Iwata 1 1 Fujita Health University School of Medicine, Toyoake; 2 Nanzan University, Seto; 3 Teikyo University School of Medicine, Ichihara; 4 Nagoya University Graduate School of Medicine, Nagoya, Japan [email protected] Introduction: Brain-derived neurotrophic factor (BDNF) plays an important role as a mediator for neuronal survival and plasticity of dopaminergic, cholinergic, and serotonergic neurons in the central nerve system, therefore BDNF is considered as an attractive can didate gene for schizophrenia. Several genetic studies reported the significant association between BDNF gene and schizophrenia, yet no conclusive results have been established. Methods: In this study we examined gene-based association study between tagging SNPs in BDNF and schizophrenia in the large Japanese samples (1117 cases and 1102 controls). Eight SNPs were genotyped; seven tagging SNPs (rs1491851, rs11030121, rs7934165, rs12291063, rs11030101, rs1519480, rs6265 [also called Val66Met polymorphism or G196A]) and a C270T polymorphism. Results: No association was obtained in each SNP. In addition, we performed an updated meta-analysis between two common SNPs (rs6265 and C270T polymorphism) and schizophrenia, again, this did not provide evidence for association of these two SNPs. Conclusions: Our data suggests that BDNF gene does not play an important role in schizophrenia through gene-based and meta-analytic approaches. Our results indicate that BDNF gene do not play a major role in the patients with schizophrenia in the Japanese population.In additon, we performed an updated meta-analysis between two common SNPs (rs6265 and C270T polymorphism) and schizophrenia, again,t his did not provide evidence for association of these two SNPs. Acknowledgements: We thank Ms S Nakaguchi and Ms M Miyata for their technical support. This work was supported in part by research grants from the Ministry of Education, Culture, Sports, Science and Technology, the Ministry of Health, Labor and Welfare, and the Japan Health Sciences Foundation (Research on Health Sciences Focusing on Drug Innovation). References [1] Angelucci, F., S. Brene, and A.A. Mathe, BDNF in schizophrenia, depression and corresponding animal models. Mol Psychiatry, 2005. 10(4): p. 345-52. [2] Iritani, S., et al., Immunohistochemical study of brain-derived neurotrophic factor and its receptor, TrkB, in the hippocampal formation of schizophrenic brains. Prog Neuropsychopharmacol Biol Psychiatry, 2003. 27(5): p. 801-74 [3] Durany, N., et al., Brain-derived neurotrophic factor and neu-
187
rotrophin 3 in schizophrenic psychoses. Schizophr Res, 2001. 52(1-2): p. 79-86. [4] Zintzaras, E., Brain-derived neurotrophic factor gene polymorphisms and schizophrenia: a meta-analysis. Psychiatr Genet, 2007. 17(2): p. 69-754
394 – INFLUENCE OF NRG1 ON NEURONAL CORRELATES OF WORKING MEMORY Axel Krug 1 , Valentin Markov 1 , Tony Stöcker 2 , N. Jon Shah 2 , Karl Zilles 2 , Markus H Skowronek 3 , Thomas Eggermann 1 , Klaus Zerres 1 , Sören Krach 1 , Frank Schneider 1 , Marcella Rietschel 3 , Tilo Kircher 1 1 RWTH Aachen University, Aachen; 2 Institute of Neurosciences and Biophysics (INB), Research Centre Jülich, Jülich; 3 Central Institute of Mental Health, Mannheim, Germany [email protected] Introduction: Neuregulin1 is a well replicated susceptibility gene for schizophrenia. The pathophysiological mechanisms of this gene are not yet fully understood. Correlations of susceptibility genes have been found in isolated endophenotypic markers. The aim of the present study was to test the influence of NRG1 on neural correlates of working memory, an endophenotypic marker for schizophrenia Methods: fMRI data on 85 healthy individuals were acquired using a 3T system while a 2-back version of the CPT (working memory task) was performed. NRG1 (SNP8NRG221532) status of each individual was determined (34 T/T, 23 T/C, 28 C/C). The CPT consists of th ree conditions: Fixation of presented letters (baseline), response to a target letter (0-back) or response to any target letter that was identical to the one presented two trials before (2-back). In the fMRI analysis, working memory was modelled as the 2-back condition minus the 0-back condition and compared between the groups. Results: While there were no effects on performance, a linear effect of NRG1 on neuronal activation emerged. Hyperactivation of the superior frontal gyrus (BA 10) was correlated with the number of risk-alleles. Conclusions: The data suggest that performance measures between groups did not differ due to a compensational activation of BA 10 in risk-allele carriers. The results of our study are in line with findings of research groups comparing CPT performance between controls and schizophrenic patients (e.g. Thermenos et al. 2005) and therefore document the particular relevance of research on susceptibility genes. References [1] Thermenos HW, Goldstein JM, Buka SL, Poldrack RA, Koch JK, Tsuang MT, et al. The effect of working memory performance on functional MRI in schizophrenia. Schizophrenia research. 2005;74(2-3):179-94
395 – THE SINGLE NUCLEOTIDE POLYMORPHISM (SNP) rs1018381 IN SCHIZOPHRENIA-RISK-GENE DYSBINDIN 1 MODULATES BRAIN ACTIVATION DURING LANGUAGE PRODUCTION Valentin Markov 1 , Axel Krug 1 , Sören Krach 1 , Tony Stöcker 2 , N. Jon Shah 2 , Markus H. Skowronek 3 , Thomas Eggermann 4 , Klaus Zerres 4 , Frank Schneider 1 , Marcella Rietschel 3 , Tilo Kircher 1 1 Department of Psychiatry and Psychotherapy, RWTH Aachen University, Aachen; 2 Research Centre Jülich, Jülich; 3 Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Heal, Mannheim; 4 Institute of Human Genetics, RWTH Aachen University, Aachen, Germany [email protected] Introduction: Since Straub et al. (2002) implicated an association between genetic variants in dysbindin 1 and schizophrenia numerous studies have reported evidence supporting this association in worldwide populations (Williams et al. 2005). Since speech disorder is a core symptom of schizophrenia, the aim of the present study was to
Abstracts / Schizophrenia Research 102/1–3, Supplement 2 (2008) 1–279
References [1] Fiore R, Schratt G. MicroRNAs in synapse development: tiny molecules to remember. Expert Opin Biol Ther. 2007 Dec;7(12):1823-31. [2] Chang TC, Mendell JT. microRNAs in vertebrate physiology and human disease. Annu Rev Genomics Hum Genet. 2007;8:215-39.
390 – TOWARDS A VALID CLASSIFICATION OF ENDOGENOUS PSYCHOSIS:TIME TO PAY ATTENTION TO THE WERNICKE-KLEIST-LEONHARD SCHOOL Jack Foucher 1 , Valerie Benouna-Greene 2 , Gerald Stoeber 3 Strasbourg, France; 2 HUS/ULP, Strasbourg; 3 Würtzburg University, Würtzburg, Germany [email protected]
1 HUS/ULP/INSERM,
Introduction: International psychiatric classifications are today at a major turning point: once turned towards reliability alone, they are now addressing validity. In the "medical paradigm" this means defining “diseases” based on their etiology or physiopathology.The WernickeKleist-Leonhard school has long been working on this project. Methods: We review the German, English and Spanish literature to describe the reliability and validity of the WKL classification. Results: Reliability: inter-rater reproducibility and time reproducibility at 30 years follow-up are high (kappa > 0.8). Construct validity is ascertained by the building principles of the classification. A hundred of clinical pictures were merged according to 2 principles: i) the longitudinal one, ie when different clinical pictures are expressed by the same patients they are the manifestations of the same disorder, ii) the intra-familial aggregation principle, ie when different clinical pictures are expressed by members of the same family they are likely the manifestations of the same genetic liability. This classification results in 35 major "disorders", grouped into 5 families on the basis of the evolution and the homomorphic/polymorphic character of their clinical pictures (schizophrenia corresponds to 20 different disorders). The classification’s face validity has been addressed by showing that different disorders come up with highly significant differences in genetic load and neuro-develop mental history. Two studies replicated a linkage for periodic catatonia with 15q15. Moreover the classification advances high predictive validity in prognosis and treatment response. Conclusions: The WKL school offers the most validated classification system according to current epistemological criteria. References [1] Stober, G., Seelow, D., Ruschendorf, F., Ekici, A., Beckmann, H. & Reis, A. (2002b). Periodic catatonia: confirmation of linkage to chromosome 15 and further evidence for genetic heterogeneity. Hum Genet, 111, pp. 323-330. [2] Franzek, E. & Beckmann, H. (199 8). Different genetic background of schizophrenia spectrum psychoses: a twin study. Am J Psychiatry, 155, pp. 76-83.
391 – A REANALYSIS OF 409 EUROPEAN-ANCESTRY AND AFRICAN AMERICAN SCHIZOPHRENIA PEDIGREES REVEALS SIGNIFICANT LINKAGE TO 8p23.3 WITH EVIDENCE OF LOCUS HETEROGENEITY Elizabeth Holliday 1 , Bryan Mowry 2 , Dale Nyholt 3 1 Queensland Centre for Mental Health Research, QLD; 2 1. Queensland Centre for Mental Health Research. 2. University of Queensland, QLD; 3 Queensland Institute for Medical Research, QLD, Australia [email protected] Introduction: The detection and replication of schizophrenia risk loci via linkage analysis can require substantial sample sizes. This has prompted various collaborative efforts for combining multiple, independent samples.However, pooled samples may comprise sub -samples with substantial population genetic differences, including allele frequency differences.
Methods: We investigated the impact of population differences by reanalysing Molecular Genetics of Schizophrenia 1 (MGS1) affected sibling-pair data,comprising two samples of distinct ancestral origin: European- (EA: 263 pedigrees) and African-American (AA: 146 pedigrees). To exploit the information contained within these distinct continental samples, we performed separate analyses of the EA and AA samples, allowing for within-sample locus heterogeneity, and the pooled sample, allowing for both within-sample and between-sample heterogeneity. Significance levels, corrected for the multiple tests, were determined empirically. Results: For all suggestive peaks, stronger linkage evidence was obtained in either the EA or AA sample than the combined sample, regardless of how heterogeneity was modeled for the latter. Notably, we detected genomewide significant linkage to 8p23.3 and evidence for a second, independent susceptibility locus, reaching suggestive linkage, 29 cM away on 8p21.3. We also detected suggestive linkage on chromosomes 5p13.3 and 7q36.2 and provide evidence for the presence of multiple, small-effect susceptibility loci. Many regions showed pronounced differences in linkage evidence between the EA and AA samples. Conclusions: This analysis highlights the potential impact of population differences upon linkage evidence in pooled data and demonstrates a useful approach for the analysis of samples drawn from distinct continental populations. References [1] Suarez BK, Duan J, Sanders AR, Hinrichs AL, Jin CH, Hou C, Buccola NG, Hale N, Weilbaecher AN, Nertney DA and others. 2006. Genomewide Linkage Scan of 409 European-Ancestry and African American Families with Schizophrenia: Suggestive Evidence of Linkage a t 8p23.3-p21.2 and 11p13.1-q14.1 in the Combined Sample. Am J Hum Genet 78(2):315-33. [2] Vieland VJ, Wang K, Huang J. 2001. Power to detect linkage based on multiple sets of data in the presence of locus heterogeneity: comparative evaluation of model-base d linkage methods for affected sib pair data. Hum Hered 51(4):199-208.
392 – IDENTIFICATION OF YWHAE, A GENE ENCODING 14-3-3EPSILON, AS A NOVEL SUSCEPTIBILITY GENE FOR SCHIZOPHRENIA Iwata Nakao 1 , Shinichiro Taya 2 , Takao Hikita 2 , Junko Uraguchi-Asaki 2 , Kazuto Toyo-oka 3 , Anthony Wynshaw-Boris 3 , Keizo Takao 4 , Tsuyoshi Miyakawa 4 , Norio Ozaki 2 , Kozo Kaibuchi 2 , Masashi Ikeda 1 1 Fujita Health University School of Medicine, Toyoake, Aichi; 2 Nagoya University, Nagoya; 3 UCSD School of Medicine, La Jolla; 4 Kyoto University Graduate School of Medicine, Kyoto, Japan [email protected] Introduction: Although the causes of schizophrenia remain essentially unknown, it has been widely accepted that this psychiatric illness with high heritability is a neurodevelopmental and neurodegenerative disorder with a disconnectivity and disorder of the synapse. DisruptedIn-Schizophrenia 1 (DISC1) is a promising candidate susceptibility gene for schizophrenia and has been implicated in neurodevelopment, including maturation of the cerebral cortex. Methods: To identify other novel susceptibility gene for schizophrenia, we investigated the genetic association between DISC1-interacting molecules and schizophrenia in a Japanese population, and identified a promoter SNP for 14-3-3e gene (YWHAE). The promoter SNP, which minor allele frequencies were higher in controls than those of schizophrenia, enhanced transcription of the luciferase gene in reporter gene assay. Both mRNA transcription and protein expression of 14-3-3e were increased in the lymphocytes of healthy control subjects harboring heterozygous and homozygous minor allele compared to homozygous major allele subjects. In support of a role for YWHAE in schizophrenia, we studied Ywhae+/- mice, in which the level of 14-3-3e protein is reduced to half level compared with their wild-type littermates. Results: These mice displayed defects in working memory and en-
Abstracts / Schizophrenia Research 102/1–3, Supplement 2 (2008) 1–279 hancement of anxiety-like behavior. These results strongly suggest that the YWHAE is a novel susceptibility gene for schizophrenia. Conclusions: A novel DISC1 binding protein, 14-3-3epsilon, is possibly a new candidate gene for susceptibility of schizophrenia. The promoter variant affects the expression level of mRNA and protein in peripheral blood. 14-3-3epsilon +/- mice could be useful to explore for psychosis-related behavior. References [1] Toyo-oka, K. et al. 14-3-3epsilon is important for neuronal migration by binding to NUDEL: a molecular explanation for Miller-Dieker syndrome. Nat Genet 34, 274-85 (2003). [2] Taya, S. et al. DISC1 regulates the transport of the NUDEL/LIS1/ 14-3-3 complex through Kinesin-1. J Neurosci 27, 15-26 (2007). [3] Shinoda, T. et al. DISC1 regulates neurotrophin-induced axon elongation via interaction with Grb2. J Neurosci 27, 4-14 (2007).
393 – GENE-WIDE REPLICATION STUDY OF BRAINDERIVED NEUROTROPHIC FACTOR (BDNF) WITH SCHIZOPHRENIA: POPULATION BASED ASSOCIATION ANALYSIS AND META-ANALYSIS Kunihiro Kawashima 1 , Masashi Ikeda 1 , Taro Kishi 1 , Tsuyoshi Kitajima 1 , Yoshio Yamanouchi 1 , Yoko Kinoshita 1 , Tomo Okochi 1 , Makoto Tomita 2 , Toshiya Inada 3 , Norio Ozaki 4 , Nakao Iwata 1 1 Fujita Health University School of Medicine, Toyoake; 2 Nanzan University, Seto; 3 Teikyo University School of Medicine, Ichihara; 4 Nagoya University Graduate School of Medicine, Nagoya, Japan [email protected] Introduction: Brain-derived neurotrophic factor (BDNF) plays an important role as a mediator for neuronal survival and plasticity of dopaminergic, cholinergic, and serotonergic neurons in the central nerve system, therefore BDNF is considered as an attractive can didate gene for schizophrenia. Several genetic studies reported the significant association between BDNF gene and schizophrenia, yet no conclusive results have been established. Methods: In this study we examined gene-based association study between tagging SNPs in BDNF and schizophrenia in the large Japanese samples (1117 cases and 1102 controls). Eight SNPs were genotyped; seven tagging SNPs (rs1491851, rs11030121, rs7934165, rs12291063, rs11030101, rs1519480, rs6265 [also called Val66Met polymorphism or G196A]) and a C270T polymorphism. Results: No association was obtained in each SNP. In addition, we performed an updated meta-analysis between two common SNPs (rs6265 and C270T polymorphism) and schizophrenia, again, this did not provide evidence for association of these two SNPs. Conclusions: Our data suggests that BDNF gene does not play an important role in schizophrenia through gene-based and meta-analytic approaches. Our results indicate that BDNF gene do not play a major role in the patients with schizophrenia in the Japanese population.In additon, we performed an updated meta-analysis between two common SNPs (rs6265 and C270T polymorphism) and schizophrenia, again,t his did not provide evidence for association of these two SNPs. Acknowledgements: We thank Ms S Nakaguchi and Ms M Miyata for their technical support. This work was supported in part by research grants from the Ministry of Education, Culture, Sports, Science and Technology, the Ministry of Health, Labor and Welfare, and the Japan Health Sciences Foundation (Research on Health Sciences Focusing on Drug Innovation). References [1] Angelucci, F., S. Brene, and A.A. Mathe, BDNF in schizophrenia, depression and corresponding animal models. Mol Psychiatry, 2005. 10(4): p. 345-52. [2] Iritani, S., et al., Immunohistochemical study of brain-derived neurotrophic factor and its receptor, TrkB, in the hippocampal formation of schizophrenic brains. Prog Neuropsychopharmacol Biol Psychiatry, 2003. 27(5): p. 801-74 [3] Durany, N., et al., Brain-derived neurotrophic factor and neu-
187
rotrophin 3 in schizophrenic psychoses. Schizophr Res, 2001. 52(1-2): p. 79-86. [4] Zintzaras, E., Brain-derived neurotrophic factor gene polymorphisms and schizophrenia: a meta-analysis. Psychiatr Genet, 2007. 17(2): p. 69-754
394 – INFLUENCE OF NRG1 ON NEURONAL CORRELATES OF WORKING MEMORY Axel Krug 1 , Valentin Markov 1 , Tony Stöcker 2 , N. Jon Shah 2 , Karl Zilles 2 , Markus H Skowronek 3 , Thomas Eggermann 1 , Klaus Zerres 1 , Sören Krach 1 , Frank Schneider 1 , Marcella Rietschel 3 , Tilo Kircher 1 1 RWTH Aachen University, Aachen; 2 Institute of Neurosciences and Biophysics (INB), Research Centre Jülich, Jülich; 3 Central Institute of Mental Health, Mannheim, Germany [email protected] Introduction: Neuregulin1 is a well replicated susceptibility gene for schizophrenia. The pathophysiological mechanisms of this gene are not yet fully understood. Correlations of susceptibility genes have been found in isolated endophenotypic markers. The aim of the present study was to test the influence of NRG1 on neural correlates of working memory, an endophenotypic marker for schizophrenia Methods: fMRI data on 85 healthy individuals were acquired using a 3T system while a 2-back version of the CPT (working memory task) was performed. NRG1 (SNP8NRG221532) status of each individual was determined (34 T/T, 23 T/C, 28 C/C). The CPT consists of th ree conditions: Fixation of presented letters (baseline), response to a target letter (0-back) or response to any target letter that was identical to the one presented two trials before (2-back). In the fMRI analysis, working memory was modelled as the 2-back condition minus the 0-back condition and compared between the groups. Results: While there were no effects on performance, a linear effect of NRG1 on neuronal activation emerged. Hyperactivation of the superior frontal gyrus (BA 10) was correlated with the number of risk-alleles. Conclusions: The data suggest that performance measures between groups did not differ due to a compensational activation of BA 10 in risk-allele carriers. The results of our study are in line with findings of research groups comparing CPT performance between controls and schizophrenic patients (e.g. Thermenos et al. 2005) and therefore document the particular relevance of research on susceptibility genes. References [1] Thermenos HW, Goldstein JM, Buka SL, Poldrack RA, Koch JK, Tsuang MT, et al. The effect of working memory performance on functional MRI in schizophrenia. Schizophrenia research. 2005;74(2-3):179-94
395 – THE SINGLE NUCLEOTIDE POLYMORPHISM (SNP) rs1018381 IN SCHIZOPHRENIA-RISK-GENE DYSBINDIN 1 MODULATES BRAIN ACTIVATION DURING LANGUAGE PRODUCTION Valentin Markov 1 , Axel Krug 1 , Sören Krach 1 , Tony Stöcker 2 , N. Jon Shah 2 , Markus H. Skowronek 3 , Thomas Eggermann 4 , Klaus Zerres 4 , Frank Schneider 1 , Marcella Rietschel 3 , Tilo Kircher 1 1 Department of Psychiatry and Psychotherapy, RWTH Aachen University, Aachen; 2 Research Centre Jülich, Jülich; 3 Division of Genetic Epidemiology in Psychiatry, Central Institute of Mental Heal, Mannheim; 4 Institute of Human Genetics, RWTH Aachen University, Aachen, Germany [email protected] Introduction: Since Straub et al. (2002) implicated an association between genetic variants in dysbindin 1 and schizophrenia numerous studies have reported evidence supporting this association in worldwide populations (Williams et al. 2005). Since speech disorder is a core symptom of schizophrenia, the aim of the present study was to