- Email: [email protected]
Poster #101 COMT VAL158MET GENOTYPE AND SCHIZOTYPY DIMENSIONS
Abstracts of the 3rd Biennial Schizophrenia International Research Conference / Schizophrenia Research 136, Supplement 1 (2012) S1–S375
October 2010. The majority of controls (1700) were derived from a crosssectional survey of randomly selected households within the South East London catchment area. A further 400 controls were recruited using local newspaper adverts and leaflets. Social risk factors: Key markers of social risk were identifiable from the initial social dataset after the implementation of data reduction methods. These were used to derive a personalised account of social risk exposure for each subject. These social risk “scores” summed up the tendency of the individual to have experienced adverse social exposures during their lifetime. SNP selection: SNP selection involved an interrogation of both pre-existing and emerging large-scale biological datasets and bioinformatics resources. 52 common SNPs coinciding with various genomic, proteomic and epigenetic functional landmarks were prioritised for further study. These SNPs were appraised systematically, using a Bayesian framework to compare individual performance, in a GxE model that used neuroimaging and neurocognition as the primary indicators of outcome. Neuroimaging: A region-of-interest approach was adopted to explore brain activation in relation to working memory (Dorso-lateral Pre-Frontal Cortex) and attentional processing tasks (Cingulate Cortex). Task performance and activation state were the two outcomes used for Bayesian-driven nomination of SNPs for initial, and then final GxE models. Results: The approach succeeded in narrowing down the range of functional loci within the AKT1 signalling network that could plausibly explain the differential genetic sensitivity to the generalised measure of environmental risk exposure derived in our sample. The result enabled explicit hypothesis-tests to be conducted on an independent cohort. We report the outcome of these analyses. Discussion: Our alternative approach to the discovery of novel GxE interactions relies on “homing-in” on only those genetic candidates with the strongest interaction potential. The novel method used is statistically efficient as it reduces the statistical costs traditionally associated with a heavy multiple testing burden. References: [1] Blasi G, Napolitano F, et al. DRD2/AKT1 interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia. Proc Natl Acad Sci U S A 108(3): 1158-63 (2010). [2] Nicodemus KK, Law AJ, et al. Biological validation of increased schizophrenia risk with NRG1, ERBB4, and AKT1 epistasis via functional neuroimaging in healthy controls. Arch Gen Psychiatry 67(10): 991-1001 (2010).
Poster #101 COMT VAL158MET GENOTYPE AND SCHIZOTYPY DIMENSIONS Araceli Rosa 1,2 , Artal Moreno 1 , Agnès Ros-Morente 3 , Thomas R. Kwapil 4 , Neus Barrantes-Vidal 2,3,5 1 Unitat d’Antropologia, Departament Biologia Animal. Universitat de Barcelona (UB), Barcelona, Spain; 2 CIBERSAM, Spanish Ministry of Health, Instituto Carlos III, Madrid, Spain; 3 Departament de Psicologia Clínica i de la Salut Facultat de Psicologia. Universitat Autònoma de Barcelona (UAB), Barcelona, Spain; 4 Department of Psychology. University of North Carolina at Greensboro, Greensboro, United States; 5 Sant Pere Claver - Fundació Sanitària, Barcelona, Spain Background: The neurodevelopmental vulnerability for schizophrenia is expressed across a dynamic continuum referred to as schizotypy that ranges from mild impairment to psychosis. The catechol-O-Methyltransferase (COMT) Val158Met polymorphism is a candidate susceptibility gene for schizophrenia because its involvement regulating dopamine in the prefrontal cortex. Diminished prefrontal dopamine availability is linked to negative symptom schizotypy and schizophrenia. The aim of the present study was to examine the association of COMT Val158Met (rs4680) and psychometrically assessed positive and negative schiztypy in a sample young healthy undergraduates. Methods: The sample consisted of 548 undergraduates enrolled in psychology courses at the UAB. The mean age was 20.6 years (SD=4.1). The sample was 17% male and 83% female. All participant were genotyped for COMT Val158Met polymorphism (rs4680) using Taqman 5’exonuclease assay. The distribution of all genotypes was in Hardy-Weinberg equilibrium All the individuals completed self-report questionnaires assessing schizotypy. These questionnaires included the Magical ideation (Eckblad & Chapman, 1983), Perceptual aberration (Chapman et al, 1978), Physical Anhedonia (Chapman et al., 1976) and Revised Social Anhedonia (Eckblad et al. 1982). Exploratory and confirmatory factor analyses of the four scales reliably produced two
S317
factors, positive and negative schizotypy, that account for 80% of the variance. Results: ANOVAs revealed a significant association of COMT Val158Met genotype with negative schizotypy (F(2,481)=4.34, p>0.05, but not positive schizotypy scores F(2,481)=1.96, ns. Our results indicated that the Val/Val group significantly exceeded the Val/Met and Met/Met groups on negative schizotypy scores. Discussion: These findings support the idea that a biological differentiation underlies positive and negative schizotypy, consistent with the multidimensional model of schizotypy. The results from the present study are consistent with recent work providing a connection for negative schizotypy and COMT (Kaczorowski et al. 2011).
Poster #102 FAMILY ASSOCIATION STUDY OF CANDIDATE GENES IN SCHIZOPHRENIA Pawel Kapelski, Maria Skibinska, Aleksandra Szczepankiewicz, Monika Dmitrzak-W˛eglarz, Piotr Czerski, Joanna Hauser University of Medical Sciences, Poznan, Poland Background: The aim of the study was to estimate the transmission of candidate genes alleles (according to neurodevelopment and glutamatergic hypothesis of schizophrenia) by parents to their children with schizophrenia. The genes under investigation were the following: Glycogen synthase kinase 3-beta (GSK3B) rs334558, BDNF (Brain-Derived Neurotrophic Factor) - polymorphism rs 6265, rs 988748, rs 2030324, NTRK2 (Neurotrophic Tyrosine Kinase Receptor Type 2) - polymorphism rs1187327, rs993315, rs1187326;Tyrosine protein kinase FYN (rs706895, rs3730353, rs6916861) and GRIN2B (rs1019385, rs890, rs7301328, rs1806201). Methods: There were 154 families in the group under investigation (sick person and his/her both parents). The patients and their parents were examined by two psychiatrists using SCID (Structured Clinical Interview for DSM-IV Axis I Disorders). No mental disturbances were found with all the patients’ parents. All the persons included in the study were of the Polish origin. The statistical analysis of the frequency of tansmission of alleles was carried out by TDT (Transmission Disequilibrium Test) method.To analyse the transmission disequilibrium of alleles Haploview v. 4.2. program was used. Results: Overtransmission of allel T of the rs334558 polymorphism of GSK3B was observed (transmitted:undertransmitted ratio was 83:59). There was significant statistical difference (p=0.044) in transmission of T allel from healthy heterozygous parents to schizophrenic children. In case of polymorphism rs6916861 of gene FYN a trend was observed towards a more frequent transmission of allel G by parents to their children with schizophrenia (p=0,067). Discussion: Our study indicates possible involvement of rs334558 (-50C>T) polymorphism of GSK3B gene and polymorphism rs6916861 of gene FYNin the pathogenesis of schizophrenia.
Poster #103 SEROTONIN TRANSPORTER GENE POLYMORPHISM (5-HTTLPR) AND DEPRESSIVE SYMPTOMS IN SCHIZOPHRENIA Dalibor Karlovic 1 , Ante Silic 1 , Ana Kovak-Mufic 1 , Mario Stefanovic 2 , Jelena Culej 2 , Nada Vrkic 2 1 Department of Psychiatry, University Clinical Center Sestre Milosrdnice, Zagreb, Croatia; 2 Department of Laboratory Medicine, University Clinical Center Sestre Milosrdnice, Zagreb, Croatia Background: A role for the serotonin transporter gene polymorphism in mental illnesses and anxiety/depression traits has been implicated. The contribution of genetic factors in personality traits and the manifestation of specific symptoms in psychiatric illnesses have yet to be elucidated. Depressive symptoms are a significant component in a pattern of schizophrenic symptoms. Methods: This study focused on the relation between 5-HTTLPR polymorphism and clinical presentations of schizophrenia, specifically those related to the depressive symptoms. Using clinical and psychological analyses, we tested the genetic association between the 5-HTTLPR polymorphism (5-HTT gene-linked polymorphic region) and depressive-related symptoms
October 2010. The majority of controls (1700) were derived from a crosssectional survey of randomly selected households within the South East London catchment area. A further 400 controls were recruited using local newspaper adverts and leaflets. Social risk factors: Key markers of social risk were identifiable from the initial social dataset after the implementation of data reduction methods. These were used to derive a personalised account of social risk exposure for each subject. These social risk “scores” summed up the tendency of the individual to have experienced adverse social exposures during their lifetime. SNP selection: SNP selection involved an interrogation of both pre-existing and emerging large-scale biological datasets and bioinformatics resources. 52 common SNPs coinciding with various genomic, proteomic and epigenetic functional landmarks were prioritised for further study. These SNPs were appraised systematically, using a Bayesian framework to compare individual performance, in a GxE model that used neuroimaging and neurocognition as the primary indicators of outcome. Neuroimaging: A region-of-interest approach was adopted to explore brain activation in relation to working memory (Dorso-lateral Pre-Frontal Cortex) and attentional processing tasks (Cingulate Cortex). Task performance and activation state were the two outcomes used for Bayesian-driven nomination of SNPs for initial, and then final GxE models. Results: The approach succeeded in narrowing down the range of functional loci within the AKT1 signalling network that could plausibly explain the differential genetic sensitivity to the generalised measure of environmental risk exposure derived in our sample. The result enabled explicit hypothesis-tests to be conducted on an independent cohort. We report the outcome of these analyses. Discussion: Our alternative approach to the discovery of novel GxE interactions relies on “homing-in” on only those genetic candidates with the strongest interaction potential. The novel method used is statistically efficient as it reduces the statistical costs traditionally associated with a heavy multiple testing burden. References: [1] Blasi G, Napolitano F, et al. DRD2/AKT1 interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia. Proc Natl Acad Sci U S A 108(3): 1158-63 (2010). [2] Nicodemus KK, Law AJ, et al. Biological validation of increased schizophrenia risk with NRG1, ERBB4, and AKT1 epistasis via functional neuroimaging in healthy controls. Arch Gen Psychiatry 67(10): 991-1001 (2010).
Poster #101 COMT VAL158MET GENOTYPE AND SCHIZOTYPY DIMENSIONS Araceli Rosa 1,2 , Artal Moreno 1 , Agnès Ros-Morente 3 , Thomas R. Kwapil 4 , Neus Barrantes-Vidal 2,3,5 1 Unitat d’Antropologia, Departament Biologia Animal. Universitat de Barcelona (UB), Barcelona, Spain; 2 CIBERSAM, Spanish Ministry of Health, Instituto Carlos III, Madrid, Spain; 3 Departament de Psicologia Clínica i de la Salut Facultat de Psicologia. Universitat Autònoma de Barcelona (UAB), Barcelona, Spain; 4 Department of Psychology. University of North Carolina at Greensboro, Greensboro, United States; 5 Sant Pere Claver - Fundació Sanitària, Barcelona, Spain Background: The neurodevelopmental vulnerability for schizophrenia is expressed across a dynamic continuum referred to as schizotypy that ranges from mild impairment to psychosis. The catechol-O-Methyltransferase (COMT) Val158Met polymorphism is a candidate susceptibility gene for schizophrenia because its involvement regulating dopamine in the prefrontal cortex. Diminished prefrontal dopamine availability is linked to negative symptom schizotypy and schizophrenia. The aim of the present study was to examine the association of COMT Val158Met (rs4680) and psychometrically assessed positive and negative schiztypy in a sample young healthy undergraduates. Methods: The sample consisted of 548 undergraduates enrolled in psychology courses at the UAB. The mean age was 20.6 years (SD=4.1). The sample was 17% male and 83% female. All participant were genotyped for COMT Val158Met polymorphism (rs4680) using Taqman 5’exonuclease assay. The distribution of all genotypes was in Hardy-Weinberg equilibrium All the individuals completed self-report questionnaires assessing schizotypy. These questionnaires included the Magical ideation (Eckblad & Chapman, 1983), Perceptual aberration (Chapman et al, 1978), Physical Anhedonia (Chapman et al., 1976) and Revised Social Anhedonia (Eckblad et al. 1982). Exploratory and confirmatory factor analyses of the four scales reliably produced two
S317
factors, positive and negative schizotypy, that account for 80% of the variance. Results: ANOVAs revealed a significant association of COMT Val158Met genotype with negative schizotypy (F(2,481)=4.34, p>0.05, but not positive schizotypy scores F(2,481)=1.96, ns. Our results indicated that the Val/Val group significantly exceeded the Val/Met and Met/Met groups on negative schizotypy scores. Discussion: These findings support the idea that a biological differentiation underlies positive and negative schizotypy, consistent with the multidimensional model of schizotypy. The results from the present study are consistent with recent work providing a connection for negative schizotypy and COMT (Kaczorowski et al. 2011).
Poster #102 FAMILY ASSOCIATION STUDY OF CANDIDATE GENES IN SCHIZOPHRENIA Pawel Kapelski, Maria Skibinska, Aleksandra Szczepankiewicz, Monika Dmitrzak-W˛eglarz, Piotr Czerski, Joanna Hauser University of Medical Sciences, Poznan, Poland Background: The aim of the study was to estimate the transmission of candidate genes alleles (according to neurodevelopment and glutamatergic hypothesis of schizophrenia) by parents to their children with schizophrenia. The genes under investigation were the following: Glycogen synthase kinase 3-beta (GSK3B) rs334558, BDNF (Brain-Derived Neurotrophic Factor) - polymorphism rs 6265, rs 988748, rs 2030324, NTRK2 (Neurotrophic Tyrosine Kinase Receptor Type 2) - polymorphism rs1187327, rs993315, rs1187326;Tyrosine protein kinase FYN (rs706895, rs3730353, rs6916861) and GRIN2B (rs1019385, rs890, rs7301328, rs1806201). Methods: There were 154 families in the group under investigation (sick person and his/her both parents). The patients and their parents were examined by two psychiatrists using SCID (Structured Clinical Interview for DSM-IV Axis I Disorders). No mental disturbances were found with all the patients’ parents. All the persons included in the study were of the Polish origin. The statistical analysis of the frequency of tansmission of alleles was carried out by TDT (Transmission Disequilibrium Test) method.To analyse the transmission disequilibrium of alleles Haploview v. 4.2. program was used. Results: Overtransmission of allel T of the rs334558 polymorphism of GSK3B was observed (transmitted:undertransmitted ratio was 83:59). There was significant statistical difference (p=0.044) in transmission of T allel from healthy heterozygous parents to schizophrenic children. In case of polymorphism rs6916861 of gene FYN a trend was observed towards a more frequent transmission of allel G by parents to their children with schizophrenia (p=0,067). Discussion: Our study indicates possible involvement of rs334558 (-50C>T) polymorphism of GSK3B gene and polymorphism rs6916861 of gene FYNin the pathogenesis of schizophrenia.
Poster #103 SEROTONIN TRANSPORTER GENE POLYMORPHISM (5-HTTLPR) AND DEPRESSIVE SYMPTOMS IN SCHIZOPHRENIA Dalibor Karlovic 1 , Ante Silic 1 , Ana Kovak-Mufic 1 , Mario Stefanovic 2 , Jelena Culej 2 , Nada Vrkic 2 1 Department of Psychiatry, University Clinical Center Sestre Milosrdnice, Zagreb, Croatia; 2 Department of Laboratory Medicine, University Clinical Center Sestre Milosrdnice, Zagreb, Croatia Background: A role for the serotonin transporter gene polymorphism in mental illnesses and anxiety/depression traits has been implicated. The contribution of genetic factors in personality traits and the manifestation of specific symptoms in psychiatric illnesses have yet to be elucidated. Depressive symptoms are a significant component in a pattern of schizophrenic symptoms. Methods: This study focused on the relation between 5-HTTLPR polymorphism and clinical presentations of schizophrenia, specifically those related to the depressive symptoms. Using clinical and psychological analyses, we tested the genetic association between the 5-HTTLPR polymorphism (5-HTT gene-linked polymorphic region) and depressive-related symptoms