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Poster #M129 GENETIC VARIABILITY IN THE FKBP5 AND NTRK2 GENES AND CLINICAL RESPONSE TO CLOZAPINE
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Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
Poster #M127 CHARACTERISTICS OF A CATCHMENT AREA IN THE STATE OF SÃO PAULO, BRAZIL, FOR CONDUCTING AN INCIDENCE STUDY OF SCHIZOPHRENIA AND OTHER PSYCHOTIC DISORDERS
Poster #M128 TESTING ØDEGAARD’S SELECTIVE MIGRATION HYPOTHESIS: A LONGITUDINAL COHORT STUDY OF RISK FACTORS FOR NON-AFFECTIVE PSYCHOTIC DISORDER AMONG PROSPECTIVE EMIGRANTS
Sílvia H. Tenan 1 , Maristela S. Schaufelberger 2,3 , Rosana Shuhama 4,5 , Juliana Souza 4 , Jair Santos 6 , Geraldo Busatto 7 , Craig Morgan 8 , Jim van Os 9 , Cristina Del Ben 4 , Paulo Menezes 10 1 Dept. of Preventive Medicine, Faculty of Medicine, University of São Paulo, Brazil; 2 Dept. of Neuroscience and Behaviour, School of Medicine of Ribeirão Preto, University of Sao Paulo, Brazil; 3 Laboratory of Psychiatric Neuroimaging, Department of Psychiatry, Faculty of Medicine of São Paulo, University of São Paulo, Brazil; 4 Dept. of Neuroscience and Behavior Sciences, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil; 5 Neuroscience and Behavior Science Department, Faculty of Medicine of Ribeirão Preto. University of São Paulo; 6 Dept. of Social Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil; 7 Dept. of Psychiatry, Faculty of Medicine, University of São Paulo, Brazil; 8 IOP; 9 Maastricht University; 10 Dept. of Preventive Medicine, Faculty of Medicine, University of São Paulo
Elsje van der Ven 1,2 , Christina Dalman 3 , Susanne Wicks 3 , Peter Allebeck 4 , Jim van Os 1 , Jean-Paul Selten 5,6 1 Maastricht University; 2 Rivierduinen; 3 Karolinska Institutet; 4 Karolinska Institute; 5 Rivierduinen Institute for Mental Health Care; 6 Rivierduinen Psychiatric Institute
Background: Schizophrenia and other psychotic disorders are highly prevalent conditions associated with significant morbidity and mortality. However, data on the incidence and progression of these disorders across the globe are still scarce, especially in low- and middle-income countries. Urbanicity and migration have been consistently associated with higher incidence of psychotic disorders in European studies, the incidence being twice as high in urban areas than in rural or less urbanized areas, and three times higher among migrants and ethnic minorities, as compared to native Europeans. The present proposal is part of the European Network of National Schizophrenia Networks Studiyng Gene-Environment Interactions (EU-GEI). We aim to describe the region of Ribeirão Preto, in Southeastern Brazil, in terms of its levels of urbanization and migration, where a study of the incidence of schizophrenia and other psychotic disorders is taking place and may contribute to the present knowledge on the aetiology of such disorders. Methods: Characteristics of the region of Ribeirão Preto in terms of population distribution and migration was performed by consulting the database of the Brazilian Institute of Geography and Statistics (IBGE) for the year 2010 (census data). Results: The region of Ribeirão Preto has a land area of 9,300 km2 , comprising 26 municipalities, with a population of 1,300,000 inhabitants. It is a very heterogeneous region with regards to the general characteristics of the 26 municipalities. The average population density of the region is 132 inhabitants/km 2 , ranging from 886 inhabitants/km2 in Ribeirão Preto to 12 inhabitants/km2 in Santa Cruz da Esperança. The rate of urbanization in the region is 97.4%, with the highest percentage of urbanization in the city of Pontal (98.4%) and lowest in the city of Santa Cruz da Esperança (67.7%). The region’s economy is characterized by agribusiness, having as main activity the culture of cane sugar. This productive activity is responsible for an internal seasonal migration process that occurs through the migration of workers from northeastern Brazil and southern Minas Gerais state to work in the fields of cane sugar. A net migration rate for the region of 6.5 migrants per 100,000 inhabitants is estimated. Discussion: It is speculated that the incidence of schizophrenia and other psychotic disorders has increased in low- and middle-income countries due to demographic and economic changes, which have led to increasing urbanization and migration from rural areas to large urban centers. The region of Ribeirão Preto has demographic characteristics, such as a wide variation in population density between its component municipalities, which allow to test some hypotheses identified in European studies regarding environmental risk factors for the development of schizophrenia and other psychotic disorders. The inclusion of Brazil as part of the EU-GEI European consortium may be very timely and should in the near future bring relevant contribution to the limited evidence produced so far in lowand middle-income countries.
Background: The selection hypothesis posits that the increased rate of psychotic disorder among migrants is due to selective migration of predisposed people. To test this hypothesis, we examined whether risk factors for psychosis are more prevalent among future emigrants. Methods: A cohort of 50 087 Swedish military conscripts was assessed at age 18 on cannabis use, IQ, psychiatric diagnosis, social adjustment, history of trauma and urbanicity of place of upbringing. Through data linkage we examined whether these exposures predicted emigration out of Sweden. We also calculated the emigrants’ hypothetical risk for developing a non-affective psychotic disorder. Results: Low IQ (odds ratio (OR) 0.5, 95% confidence interval (95% CI) 0.30.9) and “poor social adjustment” (OR 0.4, 95% CI 0.2-0.8) were significantly less prevalent among prospective emigrants, whereas a history of urban upbringing (OR 2.3; 95% CI 1.4-3.7) was significantly more common. Apart from a non-significant increase in cannabis use among emigrants (OR 1.6, 95% CI 0.8-3.1), there were no major group differences in any other risk factor. The hypothetical risks for developing non-affective psychotic disorder were 1.3% (95% CI 1.1-1.7) and 1.0% (95% CI 0.7-1.3) for non-emigrants and emigrants, respectively. Discussion: This study adds to an increasing body of evidence that does not support the selection hypothesis.
Poster #M129 GENETIC VARIABILITY IN THE FKBP5 AND NTRK2 GENES AND CLINICAL RESPONSE TO CLOZAPINE Rosa Catalan Campos 1,2 , Marina Mitjans 3 , Bárbara Arias 4 , Mireia Vázquez 5 , Alexandre González 5 , Rafael Penadés 6,7 , Alexandre Pons 5 , Guillem Masana 5 , Janet Munro 8 , Mª Jesús Arranz 9 1 Hospital Clínic of Barcelona; 2 Departament of Psychiatry and Psychobiolog, University of Barcelona; 3 Unitat d’Antropologia, Departament de Biologia Animal, Facultat de Biologia, Universitat de Barcelona; 4 Universitat de Barcelona. CIBERSAM; 5 Programa Esquizofrenia Clínic PEC, Institut Clínic de Neurocienciès, Hospital Clínic. Barcelona; 6 Clinical Institute of Neurosciences, Hospital Clínic Barcelona, University of Barcelona, Barcelona, Spain; 7 Departament of Psychiatry and Psychobiology, University of Barcelona; 8 Institute of Psychiatry - KCL; 9 Fundació Docència i Recerca Mútua Terrassa Hospital Universitari Mútua Terrassa Background: Clozapine is an atypical antipsychotic highly effective on patients with poor response or resistance to treatment (Lieberman et al., 1994; Kane 1992). Approximately 50% of patients who do not respond to typical antipsychotics benefit from clozapine (Reynolds GP, 2012). However, the mechanism of action of clozapine and the reasons for its success are still unclear. Numerous studies have demonstrated that atypical antypsychotics may suppress hypothalamic-pituitary-adrenal (HPA) activity which may contribute to their therapeutic action (Walker et al., 2008). The aim of this study was to investigate the influence of genetic variants in the HPA axis (FKBP5 ad NR3C1 genes) and in neurotrophic factors (BDNF and NTRK2 genes) on clinical response to clozapine treatment. Methods: The sample consisted of 590 unrelated patients (32.2% females) with a DSMIII-R diagnosis of schizophrenia. All patients were British Caucasians recruited in hospitals in London, Cambridge and Burnley (UK). Clinical response was retrospectively assessed based on medical notes using the GAS scales (Endicott et al., 1976). A 20-point improvement in GAS scores after a minimum of 3 months treatment was considered as cut-off for response. According to these criteria, the sample was divided into 436 responders (Rp) and 154 non-responders (n-Rp). Ethical approval was obtained for these studies. Genomic DNA was extracted from blood samples from each participant, according to standard protocols. A total of 16 polymor-
Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
phisms were genotyped at the FKBP5 (rs1360780, rs3777747, rs17542466, rs2766533), NR3C1 (rs2963156, rs1837262, rs4634384, rs4912910), BDNF (rs11030076, rs11030096, rs6265, rs1552736) and NTRK2 (rs1619120, rs1778929, rs10465180, rs4388524) genes were genotyped using KASPTM (Kompetitive Allele Specific PCR) technology by Design (LGC Genomics). Single marker analyses were performed using the SPSSv18 and EpiInfo statistical packages. Linkage disequilibrium between markers was tested with Haploview v.4.1. Haplotype analyses were conducted using the “R” software (v.2.2.1) from the “haplo.stat” package. Results: Significant differences were observed for genotype (P=0.02) and allele (P=0.03) distributions of the FKBP5 rs1360780 polymorphism between Rp and n-Rp. Individuals who were homozygous for the rs1360780 T allelepresented 2.11 times higher risk of non-response than individuals who were C-carriers [P=0.006; OR= 2.11; 95%CI (1.22-3.64)]. Haplotype analysis showed that the A-T-A-G allele combination (rs1360780-rs3777747rs17542466-rs2766533) was more frequent in Rp (P=0.03). Regarding the NTRK2 gene, significant differences were found for genotype and allele distributions for both rs1778929 (genotype: P=0.03; allele P=0.01) and rs10465180 (genotype: P=0.009; allele: P=0.01) polymorphisms. Individuals with rs1778929 T/T genotypes were 1.7 times more likely to respond poorly to clozapine treatment than than C-carriers [P=0.008; OR=1.7 95%CI (1.132.59)], while rs10465180 CC-homozygous presented 2.15 times higher risk of non-response than T-carriers [P=0.002; OR= 2.15 95%CI (1.3-3.55)]. Haplotype analysis showed that the C-T allele combination (rs1778929rs10465180) was more frequent in Rp (p=0.007) while the T-C allele combination was more frequent in n-Rp (p=0.02). No other significant results were found between any of the other analyzed polymorphisms and clozapine response Discussion: Genetic variability in the FKBP5 and NTRK2 genes may partially explain clinical response to clozapine. However, more studies are needed in order to clarify the involvement of these genes in the clinical response to atypical antipsychotics. The detection of individual genetic differences in the response to clozapine may provide new strategies for the treatment of schizophrenia.
Poster #M130 EFFECTS OF GENETIC VARIATIONS IN NRG1 ON COGNITIVE DOMAINS IN PATIENTS WITH SCHIZOPHRENIA AND HEALTHY SUBJECTS Youngah Cho 1 , Seunghyong Ryu 1 , Iksoo Huh 2 , Eun Young Cho 3 , Hyeji Oh 3 , Yu-Sang Lee 4 , Taesung Park 2 , Kyung Sue Hong 1 1 Department of Psychiatry, Sungkyunkwan University School of Medicine, Samsung Medical Center; 2 Department of Statistics, Seoul National University; 3 Center for Clinical Research, Samsung Biomedical Research Institute; 4 Yong-In Mental Hospital Background: Neuregulin 1 gene (NRG1) has been widely investigated as a candidate susceptibility gene for schizophrenia. A number of association studies have also explored a genetic effect of NRG1 on cognitive deficits related to schizophrenia, and generated inconsistent results. The current study aimed to determine whether genetic variations in NRG1 are associated with cognitive domains in schizophrenia patients and healthy subjects. Methods: One hundred thirty-five patients with schizophrenia and hundred nineteen healthy volunteers were recruited. Comprehensive neuropsychological tests were administered which composed of six cognitive domains of the MATRICS consensus battery. Based on previous reports of positive association, six SNPs (rs35753505, rs62510682, rs6994992, rs3924999, rs2439272, rs10503929) were selected and genotyped. In testing the genotype effect on cognitive domains, we used repeated measure analysis regarding six cognitive domain scores of each individual as values of repeated measurement. Results: Rs6994992 noted significant association with the performance of “verbal learning and memory” domain, “reasoning and problem solving” domain and general cognitive ability in the patients group. Rs2439272 showed significant associations across multiple cognitive domains in both patients and control groups. A significant association of rs3924999 with “reasoning and problem solving”, and rs35753505 with general cognitive ability were observed only in the control group. For rs6994992, rs3924999, and rs2439272, more than one of those SNP-cognitive domain association remained statistically significant even after the Bonferonni correction. Discussion: This study suggests that NRG1 might be involved in the sus-
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ceptibility for developing cognitive deficits in schizophrenia patients. For some cognitive domains, its genetic effect was also significant in generating inter-individual variability within the normal functional range.
Poster #M131 EPIGENETIC SIGNATURES IN IGF2 AND RELATED GENES AND THEIR LINK TO BIRTH WEIGHT, WORKING MEMORY AND PSYCHOTIC EXPERIENCES: A STUDY BASED ON INFORMATIVE MZ TWINS Aldo Córdova-Palomera 1 , Silvia Alemany 2,3 , José Ignacio Martín-Subero 4 , Mar Fatjó-Vilas 5 , Ximena Goldberg 5 , Igor Nenadic 6 , Lourdes Fañanás 7 1 University of Barcelona; 2 University of Barcelona, Centro de Investigaciones Biomédicas en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III; 3 Centro de Investigaciones Biomédicas en Red de Salud Mental (CIBERSAM); 4 Bellvitge Biomedical Research Institute (IDIBELL) and Institut d’Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona; 5 Universitat de Barcelona. CIBERSAM; 6 Jena University Hospital; 7 Dept. Biologia Animal, Facultat de Biologia, Universitat de Barcelona, IBUB, CIBERSAM Background: Epidemiological evidence demonstrates that neurodevelopmental disruptions caused by obstetric complications play a role in the etiology of schizophrenia and attenuated psychotic experiences in the general population (Kelleher and Cannon, 2011, Matheson et al., 2011). Importantly, it has been noticed that epigenetic processes may mediate associations between environmental insults very early in life and several health alterations across the human lifespan (Burdge and Lillycrop, 2010). In this regard, there is evidence indicating that DNA methylation levels of the insulin-like growth factor 2 (IGF2) and related developmental genes are linked to human prenatal insults (Heijmans et al., 2008, Wehkalampi et al., 2013) and correlate with neuroanatomical features (Pidsley et al., 2010); in addition, this gene has also been related to neurodevelopmentallyinfluenced cognitive and psychopathological traits (Chen et al., 2011, Mikaelsson et al., 2013). Methods: Peripheral blood DNA methylation levels were examined in 34 healthy adult monozygotic (MZ) twins (17 pairs, from the UB-Twin Registry), at IGF2 and in three genes codifying for allied mRNA binding proteins (IGF2-binding proteins 1-3, IGF2BP1-3). Data was extracted from the Illumina Infinium HumanMethylation450 (450K) BeadChip, which includes methylation levels at 248 CpG sites across the four genes of interest. Associations were tested between methylation and: i) birth weight (BW), ii) adult working memory (WM) performance and iii) subclinical psychotic experiences (PEs). Using MZ twins allowed the study of methylation changes and their putative phenotypic correlates controlling for confounding factors common to both twins (i.e. genes and shared environment). Multivariate linear regression models were applied to test for associations between methylation levels and the phenotypes of interest. Results: A link was detected between DNA methylation levels at a region in IGF2BP1 and both BW (p = 0.033) and adult WM performance (p = 0.009), but not PEs. The BW-IGF2BP1 methylation association seemed due to non-shared environmental factors influencing BW, whereas the relationship between WM and IGF2BP1 DNA methylation levels seemed mediated by both genes and environment. Discussion: Considering previous reports indicative of an association between some intrauterine events and DNA methylation marks in adulthood (Reynolds et al., 2013), one could speculate that methylation of IGF2-related genes may serve as a proxy for some traits of interest in neurodevelopmental psychiatric conditions. As long as this study is exploratory, results should be interpreted with caution. Replication of the findings is needed in larger and independent samples. Supported by EUTwinsS MRTN-CT-2006-035987, SAF2008-05674-C03, 2009SGR827 and CONACyT (Mexico). References: [1] [2] [3] [4] [5] [6] [7] [8] [9]
Burdge, G.C. & Lillycrop, K.A. (2010). Annu Rev Nutr 30, 315–39. Chen, D.Y., et al. (2011). Nature 469, 491–7. Heijmans, B. T., et al. (2008). Proc Natl Acad Sci U S A 105, 17046–9. Kelleher, I. & Cannon, M. (2011). Psychol Med 41, 1–6. Matheson, S. L., et al. (2011). Schizophr Res 133, 133–42. Mikaelsson, M. A., et al. (2013). Nat Commun 4, 2311. Pidsley, R., et al. (2010). Mol Psychiatry 15, 880–1. Reynolds, R. M., et al. (2013). Clin Endocrinol (Oxf) 78, 814–22. Wehkalampi, K., et al. (2013). PLoS One 8, e67379.
Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
Poster #M127 CHARACTERISTICS OF A CATCHMENT AREA IN THE STATE OF SÃO PAULO, BRAZIL, FOR CONDUCTING AN INCIDENCE STUDY OF SCHIZOPHRENIA AND OTHER PSYCHOTIC DISORDERS
Poster #M128 TESTING ØDEGAARD’S SELECTIVE MIGRATION HYPOTHESIS: A LONGITUDINAL COHORT STUDY OF RISK FACTORS FOR NON-AFFECTIVE PSYCHOTIC DISORDER AMONG PROSPECTIVE EMIGRANTS
Sílvia H. Tenan 1 , Maristela S. Schaufelberger 2,3 , Rosana Shuhama 4,5 , Juliana Souza 4 , Jair Santos 6 , Geraldo Busatto 7 , Craig Morgan 8 , Jim van Os 9 , Cristina Del Ben 4 , Paulo Menezes 10 1 Dept. of Preventive Medicine, Faculty of Medicine, University of São Paulo, Brazil; 2 Dept. of Neuroscience and Behaviour, School of Medicine of Ribeirão Preto, University of Sao Paulo, Brazil; 3 Laboratory of Psychiatric Neuroimaging, Department of Psychiatry, Faculty of Medicine of São Paulo, University of São Paulo, Brazil; 4 Dept. of Neuroscience and Behavior Sciences, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil; 5 Neuroscience and Behavior Science Department, Faculty of Medicine of Ribeirão Preto. University of São Paulo; 6 Dept. of Social Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil; 7 Dept. of Psychiatry, Faculty of Medicine, University of São Paulo, Brazil; 8 IOP; 9 Maastricht University; 10 Dept. of Preventive Medicine, Faculty of Medicine, University of São Paulo
Elsje van der Ven 1,2 , Christina Dalman 3 , Susanne Wicks 3 , Peter Allebeck 4 , Jim van Os 1 , Jean-Paul Selten 5,6 1 Maastricht University; 2 Rivierduinen; 3 Karolinska Institutet; 4 Karolinska Institute; 5 Rivierduinen Institute for Mental Health Care; 6 Rivierduinen Psychiatric Institute
Background: Schizophrenia and other psychotic disorders are highly prevalent conditions associated with significant morbidity and mortality. However, data on the incidence and progression of these disorders across the globe are still scarce, especially in low- and middle-income countries. Urbanicity and migration have been consistently associated with higher incidence of psychotic disorders in European studies, the incidence being twice as high in urban areas than in rural or less urbanized areas, and three times higher among migrants and ethnic minorities, as compared to native Europeans. The present proposal is part of the European Network of National Schizophrenia Networks Studiyng Gene-Environment Interactions (EU-GEI). We aim to describe the region of Ribeirão Preto, in Southeastern Brazil, in terms of its levels of urbanization and migration, where a study of the incidence of schizophrenia and other psychotic disorders is taking place and may contribute to the present knowledge on the aetiology of such disorders. Methods: Characteristics of the region of Ribeirão Preto in terms of population distribution and migration was performed by consulting the database of the Brazilian Institute of Geography and Statistics (IBGE) for the year 2010 (census data). Results: The region of Ribeirão Preto has a land area of 9,300 km2 , comprising 26 municipalities, with a population of 1,300,000 inhabitants. It is a very heterogeneous region with regards to the general characteristics of the 26 municipalities. The average population density of the region is 132 inhabitants/km 2 , ranging from 886 inhabitants/km2 in Ribeirão Preto to 12 inhabitants/km2 in Santa Cruz da Esperança. The rate of urbanization in the region is 97.4%, with the highest percentage of urbanization in the city of Pontal (98.4%) and lowest in the city of Santa Cruz da Esperança (67.7%). The region’s economy is characterized by agribusiness, having as main activity the culture of cane sugar. This productive activity is responsible for an internal seasonal migration process that occurs through the migration of workers from northeastern Brazil and southern Minas Gerais state to work in the fields of cane sugar. A net migration rate for the region of 6.5 migrants per 100,000 inhabitants is estimated. Discussion: It is speculated that the incidence of schizophrenia and other psychotic disorders has increased in low- and middle-income countries due to demographic and economic changes, which have led to increasing urbanization and migration from rural areas to large urban centers. The region of Ribeirão Preto has demographic characteristics, such as a wide variation in population density between its component municipalities, which allow to test some hypotheses identified in European studies regarding environmental risk factors for the development of schizophrenia and other psychotic disorders. The inclusion of Brazil as part of the EU-GEI European consortium may be very timely and should in the near future bring relevant contribution to the limited evidence produced so far in lowand middle-income countries.
Background: The selection hypothesis posits that the increased rate of psychotic disorder among migrants is due to selective migration of predisposed people. To test this hypothesis, we examined whether risk factors for psychosis are more prevalent among future emigrants. Methods: A cohort of 50 087 Swedish military conscripts was assessed at age 18 on cannabis use, IQ, psychiatric diagnosis, social adjustment, history of trauma and urbanicity of place of upbringing. Through data linkage we examined whether these exposures predicted emigration out of Sweden. We also calculated the emigrants’ hypothetical risk for developing a non-affective psychotic disorder. Results: Low IQ (odds ratio (OR) 0.5, 95% confidence interval (95% CI) 0.30.9) and “poor social adjustment” (OR 0.4, 95% CI 0.2-0.8) were significantly less prevalent among prospective emigrants, whereas a history of urban upbringing (OR 2.3; 95% CI 1.4-3.7) was significantly more common. Apart from a non-significant increase in cannabis use among emigrants (OR 1.6, 95% CI 0.8-3.1), there were no major group differences in any other risk factor. The hypothetical risks for developing non-affective psychotic disorder were 1.3% (95% CI 1.1-1.7) and 1.0% (95% CI 0.7-1.3) for non-emigrants and emigrants, respectively. Discussion: This study adds to an increasing body of evidence that does not support the selection hypothesis.
Poster #M129 GENETIC VARIABILITY IN THE FKBP5 AND NTRK2 GENES AND CLINICAL RESPONSE TO CLOZAPINE Rosa Catalan Campos 1,2 , Marina Mitjans 3 , Bárbara Arias 4 , Mireia Vázquez 5 , Alexandre González 5 , Rafael Penadés 6,7 , Alexandre Pons 5 , Guillem Masana 5 , Janet Munro 8 , Mª Jesús Arranz 9 1 Hospital Clínic of Barcelona; 2 Departament of Psychiatry and Psychobiolog, University of Barcelona; 3 Unitat d’Antropologia, Departament de Biologia Animal, Facultat de Biologia, Universitat de Barcelona; 4 Universitat de Barcelona. CIBERSAM; 5 Programa Esquizofrenia Clínic PEC, Institut Clínic de Neurocienciès, Hospital Clínic. Barcelona; 6 Clinical Institute of Neurosciences, Hospital Clínic Barcelona, University of Barcelona, Barcelona, Spain; 7 Departament of Psychiatry and Psychobiology, University of Barcelona; 8 Institute of Psychiatry - KCL; 9 Fundació Docència i Recerca Mútua Terrassa Hospital Universitari Mútua Terrassa Background: Clozapine is an atypical antipsychotic highly effective on patients with poor response or resistance to treatment (Lieberman et al., 1994; Kane 1992). Approximately 50% of patients who do not respond to typical antipsychotics benefit from clozapine (Reynolds GP, 2012). However, the mechanism of action of clozapine and the reasons for its success are still unclear. Numerous studies have demonstrated that atypical antypsychotics may suppress hypothalamic-pituitary-adrenal (HPA) activity which may contribute to their therapeutic action (Walker et al., 2008). The aim of this study was to investigate the influence of genetic variants in the HPA axis (FKBP5 ad NR3C1 genes) and in neurotrophic factors (BDNF and NTRK2 genes) on clinical response to clozapine treatment. Methods: The sample consisted of 590 unrelated patients (32.2% females) with a DSMIII-R diagnosis of schizophrenia. All patients were British Caucasians recruited in hospitals in London, Cambridge and Burnley (UK). Clinical response was retrospectively assessed based on medical notes using the GAS scales (Endicott et al., 1976). A 20-point improvement in GAS scores after a minimum of 3 months treatment was considered as cut-off for response. According to these criteria, the sample was divided into 436 responders (Rp) and 154 non-responders (n-Rp). Ethical approval was obtained for these studies. Genomic DNA was extracted from blood samples from each participant, according to standard protocols. A total of 16 polymor-
Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
phisms were genotyped at the FKBP5 (rs1360780, rs3777747, rs17542466, rs2766533), NR3C1 (rs2963156, rs1837262, rs4634384, rs4912910), BDNF (rs11030076, rs11030096, rs6265, rs1552736) and NTRK2 (rs1619120, rs1778929, rs10465180, rs4388524) genes were genotyped using KASPTM (Kompetitive Allele Specific PCR) technology by Design (LGC Genomics). Single marker analyses were performed using the SPSSv18 and EpiInfo statistical packages. Linkage disequilibrium between markers was tested with Haploview v.4.1. Haplotype analyses were conducted using the “R” software (v.2.2.1) from the “haplo.stat” package. Results: Significant differences were observed for genotype (P=0.02) and allele (P=0.03) distributions of the FKBP5 rs1360780 polymorphism between Rp and n-Rp. Individuals who were homozygous for the rs1360780 T allelepresented 2.11 times higher risk of non-response than individuals who were C-carriers [P=0.006; OR= 2.11; 95%CI (1.22-3.64)]. Haplotype analysis showed that the A-T-A-G allele combination (rs1360780-rs3777747rs17542466-rs2766533) was more frequent in Rp (P=0.03). Regarding the NTRK2 gene, significant differences were found for genotype and allele distributions for both rs1778929 (genotype: P=0.03; allele P=0.01) and rs10465180 (genotype: P=0.009; allele: P=0.01) polymorphisms. Individuals with rs1778929 T/T genotypes were 1.7 times more likely to respond poorly to clozapine treatment than than C-carriers [P=0.008; OR=1.7 95%CI (1.132.59)], while rs10465180 CC-homozygous presented 2.15 times higher risk of non-response than T-carriers [P=0.002; OR= 2.15 95%CI (1.3-3.55)]. Haplotype analysis showed that the C-T allele combination (rs1778929rs10465180) was more frequent in Rp (p=0.007) while the T-C allele combination was more frequent in n-Rp (p=0.02). No other significant results were found between any of the other analyzed polymorphisms and clozapine response Discussion: Genetic variability in the FKBP5 and NTRK2 genes may partially explain clinical response to clozapine. However, more studies are needed in order to clarify the involvement of these genes in the clinical response to atypical antipsychotics. The detection of individual genetic differences in the response to clozapine may provide new strategies for the treatment of schizophrenia.
Poster #M130 EFFECTS OF GENETIC VARIATIONS IN NRG1 ON COGNITIVE DOMAINS IN PATIENTS WITH SCHIZOPHRENIA AND HEALTHY SUBJECTS Youngah Cho 1 , Seunghyong Ryu 1 , Iksoo Huh 2 , Eun Young Cho 3 , Hyeji Oh 3 , Yu-Sang Lee 4 , Taesung Park 2 , Kyung Sue Hong 1 1 Department of Psychiatry, Sungkyunkwan University School of Medicine, Samsung Medical Center; 2 Department of Statistics, Seoul National University; 3 Center for Clinical Research, Samsung Biomedical Research Institute; 4 Yong-In Mental Hospital Background: Neuregulin 1 gene (NRG1) has been widely investigated as a candidate susceptibility gene for schizophrenia. A number of association studies have also explored a genetic effect of NRG1 on cognitive deficits related to schizophrenia, and generated inconsistent results. The current study aimed to determine whether genetic variations in NRG1 are associated with cognitive domains in schizophrenia patients and healthy subjects. Methods: One hundred thirty-five patients with schizophrenia and hundred nineteen healthy volunteers were recruited. Comprehensive neuropsychological tests were administered which composed of six cognitive domains of the MATRICS consensus battery. Based on previous reports of positive association, six SNPs (rs35753505, rs62510682, rs6994992, rs3924999, rs2439272, rs10503929) were selected and genotyped. In testing the genotype effect on cognitive domains, we used repeated measure analysis regarding six cognitive domain scores of each individual as values of repeated measurement. Results: Rs6994992 noted significant association with the performance of “verbal learning and memory” domain, “reasoning and problem solving” domain and general cognitive ability in the patients group. Rs2439272 showed significant associations across multiple cognitive domains in both patients and control groups. A significant association of rs3924999 with “reasoning and problem solving”, and rs35753505 with general cognitive ability were observed only in the control group. For rs6994992, rs3924999, and rs2439272, more than one of those SNP-cognitive domain association remained statistically significant even after the Bonferonni correction. Discussion: This study suggests that NRG1 might be involved in the sus-
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ceptibility for developing cognitive deficits in schizophrenia patients. For some cognitive domains, its genetic effect was also significant in generating inter-individual variability within the normal functional range.
Poster #M131 EPIGENETIC SIGNATURES IN IGF2 AND RELATED GENES AND THEIR LINK TO BIRTH WEIGHT, WORKING MEMORY AND PSYCHOTIC EXPERIENCES: A STUDY BASED ON INFORMATIVE MZ TWINS Aldo Córdova-Palomera 1 , Silvia Alemany 2,3 , José Ignacio Martín-Subero 4 , Mar Fatjó-Vilas 5 , Ximena Goldberg 5 , Igor Nenadic 6 , Lourdes Fañanás 7 1 University of Barcelona; 2 University of Barcelona, Centro de Investigaciones Biomédicas en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III; 3 Centro de Investigaciones Biomédicas en Red de Salud Mental (CIBERSAM); 4 Bellvitge Biomedical Research Institute (IDIBELL) and Institut d’Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona; 5 Universitat de Barcelona. CIBERSAM; 6 Jena University Hospital; 7 Dept. Biologia Animal, Facultat de Biologia, Universitat de Barcelona, IBUB, CIBERSAM Background: Epidemiological evidence demonstrates that neurodevelopmental disruptions caused by obstetric complications play a role in the etiology of schizophrenia and attenuated psychotic experiences in the general population (Kelleher and Cannon, 2011, Matheson et al., 2011). Importantly, it has been noticed that epigenetic processes may mediate associations between environmental insults very early in life and several health alterations across the human lifespan (Burdge and Lillycrop, 2010). In this regard, there is evidence indicating that DNA methylation levels of the insulin-like growth factor 2 (IGF2) and related developmental genes are linked to human prenatal insults (Heijmans et al., 2008, Wehkalampi et al., 2013) and correlate with neuroanatomical features (Pidsley et al., 2010); in addition, this gene has also been related to neurodevelopmentallyinfluenced cognitive and psychopathological traits (Chen et al., 2011, Mikaelsson et al., 2013). Methods: Peripheral blood DNA methylation levels were examined in 34 healthy adult monozygotic (MZ) twins (17 pairs, from the UB-Twin Registry), at IGF2 and in three genes codifying for allied mRNA binding proteins (IGF2-binding proteins 1-3, IGF2BP1-3). Data was extracted from the Illumina Infinium HumanMethylation450 (450K) BeadChip, which includes methylation levels at 248 CpG sites across the four genes of interest. Associations were tested between methylation and: i) birth weight (BW), ii) adult working memory (WM) performance and iii) subclinical psychotic experiences (PEs). Using MZ twins allowed the study of methylation changes and their putative phenotypic correlates controlling for confounding factors common to both twins (i.e. genes and shared environment). Multivariate linear regression models were applied to test for associations between methylation levels and the phenotypes of interest. Results: A link was detected between DNA methylation levels at a region in IGF2BP1 and both BW (p = 0.033) and adult WM performance (p = 0.009), but not PEs. The BW-IGF2BP1 methylation association seemed due to non-shared environmental factors influencing BW, whereas the relationship between WM and IGF2BP1 DNA methylation levels seemed mediated by both genes and environment. Discussion: Considering previous reports indicative of an association between some intrauterine events and DNA methylation marks in adulthood (Reynolds et al., 2013), one could speculate that methylation of IGF2-related genes may serve as a proxy for some traits of interest in neurodevelopmental psychiatric conditions. As long as this study is exploratory, results should be interpreted with caution. Replication of the findings is needed in larger and independent samples. Supported by EUTwinsS MRTN-CT-2006-035987, SAF2008-05674-C03, 2009SGR827 and CONACyT (Mexico). References: [1] [2] [3] [4] [5] [6] [7] [8] [9]
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