- Email: [email protected]
A NOVEL DOPAMINE D2 RECEPTOR GENE POLYMORPHISM AFFECTS EMOTIONAL BEHAVIOR AND PHYSIOLOGY IN HEALTHY SUBJECTS
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Abstracts / Schizophrenia Research 102/1–3, Supplement 2 (2008) 1–279
of increased stress-reactivity. Furthermore, increased stress-reactivity levels in the siblings were associated with increased positive symptom intensity in the patients. These results thus suggest a genetic contribution to increased stress-sensitivity, which is specifically underlyingthe positive dimension of psychosis. References [1] Myin-Germeys I, van Os J. Stress-reactivity in psychosis: evidence for an affective pathway to psychosis. Clin Psychol Rev 2007;27:409-424. [2] Myin-Germeys I, Van Os J, Schwartz JE, Stone AA, Delespaul PA. Emotional reactivity to daily life stress in psychosis. Arch Gen Psychiatry Dec 2001;58(12):1137-1144. [3] Myin-Germeys I, Delespaul PA, Van Os J. Behavioral sensitization to daily life stress in psychosis. Psychological Medicine 2005;35:733-741.
373 – HTR3A AND HTR3B SUBUNITS OF SEROTONIN IONOTROPIC RECEPTOR IN SUICIDAL BEHAVIOR AND SCHIZOPHRENIA: HAPLOTYPE ANALYSIS VERSUS GENOTYPE-GENOTYPE INTERACTION Vincenzo De Luca CAMH, Toronto, Canada [email protected] Introduction: Up to ten percent of patients affected with schizophrenia commit suicide and thus suicide represents the major contributor to the increased mortality of people suffering from schizophrenia. Alterations in the serotonin (5-HT) system have been related to impulsive aggression and suicidal behavior. Genetic variations in the serotonin ionotropic receptor subunits (HTR3A and HTR3B) genes, positioned in tandem on chromosome 11q23.2, have been shown to be associated with psychiatric disorders. Methods: To determine the association between suicide attempt in 231 schizophrenia patients, we performed haplotype analysis in the genomic regions of HTR3A and HTR3B using 16 polymorphisms. Results: The SNP rs1176744 Ser129Tyr yielded evidence of association with suicide attempts in schizophrenia (p=0.0107) employing a multidimensionality reduction analysis. On the other hand the haplotype analysis was not significant. Conclusions: Our results suggest an important role for HTR3B in suicide attempts in schizophrenia and also exclude the interaction between these two subunits in conferring risk for suicide attempts using two different statistical strategies
374 – FUNCTIONAL INTERACTION BETWEEN DOPAMINE REGULATING GENES: EFFECTS OF DAT AND DRD2 POLYMORPHISMS ON WORKING MEMORY ACTIVITY IN HUMAN BRAIN Leonardo Fazio 1 , Giuseppe Blasi 1 , Antonio Rampino 1 , Raffaella Romano 1 , Annabella di Giorgio 1 , Grazia Caforio 1 , Paolo Taurisano 1 , Apostolos Papazacharias 1 , Ying Zang 2 , Audrey Papp 2 , Wolfgang Sadée 2 , Alessandro Bertolino 1 1 Psychiatric Neuroscience Group, Department of Psychiatry and Neurology, University of Bari, Bari, Italy; 2 Program in Pharmacogenomics, Department of Pharmacology, College of Medicine, and Division of Biostatistics, College of Public Health, The Ohio State University, Columbus, USA [email protected] Introduction: Dopamine neurotransmission has been shown to be critically involved in the pathophysiology of schizophrenia. Recent studies provide evidence for a direct protein-protein interaction between D2 dopamine receptor (DRD2) and the dopamine transporter (DAT). Both DRD2 and DAT have functional polymorphisms that seems to modulate working memory related brain activity in humans. The purpose of the present study with fMRI was to evaluate in healthy subjects the association between a genetically-based dose effect of
dopamine signaling as determined by DRD2 and DAT polymorphism with activity of prefrontal cortex and striatum during working memory. Methods: 149 healthy subjects, genotyped for DAT 3’VNTR and DRD2 rs1076 560 polymorphisms (DAT: 10/10=59, 9-repeat carriers=89; DRD2: GG=117, GT=32) underwent BOLD-fMRI at 3T while performing a version of the N-Back working memory task. SPM5 random-effects models were used for statistical analyses (all p<0.005). Results: Genotype groups did not differ for a series of sociodemographic variables. fMRI data analysis showed a main effect of DAT and DRD2 polymorphisms and their interaction in the striatum, cingulate and dorsolateral prefrontal cortex. A factorial ANOVA performed on BOLD signal change in caudate and prefrontal cortex revealed a non-linear interaction between DAT and DRD2 genotype. Conclusions: These results demonstrate an interaction between two genes regulating dopamine signaling on specific neuronal network subserving working memory. Our data can be helpful in studying complex genetics interactions in central nervous system phenotypes associated with dopamine signaling and with schizophrenia.
375 – A NOVEL DOPAMINE D2 RECEPTOR GENE POLYMORPHISM AFFECTS EMOTIONAL BEHAVIOR AND PHYSIOLOGY IN HEALTHY SUBJECTS Luciana Lo Bianco, Giuseppe Blasi, Paolo Taurisano, Barbara Gelao, Raffaella Romano, Leonardo Fazio, Apostolos Papazacharias, Annabella Di Giorgio, Grazia Caforio, Antonio Rampino, Rita Masellis, Audrey Papp, Marcello Nardini, Wolfgang Sadee, Alessandro Bertolino University of Bari, Bari, Italy [email protected] Introduction: Previous studies have shown that dopamine modulates emotional behavior as well as amygdala and prefrontal cortex activity during emotion processing. Furthermore, other evidence has revealed that a single nucleotide polymorphism (SNP - rs1076560) in the D2 dopaminergic receptor (DRD2) gene affects splicing and is associated with differential cortical and subcortical activity during cognition. The aim of this study was to investigate if DRD2 rs1076560 affects emotional behavior as well as prefrontal and amygdala activity during implicit and explicit emotional processing. Methods: 127 healthy subjects were genotyped for the DRD2 SNP rs1076560 (101 were homozygous for the G allele, GG, and 26 were heterozygous, GT). The Big Five Questionnaire (BFQ) was administered to all subjects enrolled in the study. Furthermore, fMRI data from 12 GG and 12 GT matched for a series of demographic and neuropsychological variableswere also compared. During the fMRI session, subjects performed a task requiring implicit or explicit processing of emotional facial stimuli. Results: Behavioral data showed higher scores at the Emotion Control scale of the BFQ for GT relative to GG subjects (p=0.05). Furthermore, imaging data revealed an interaction between genotype and task on amygdala and prefrontal activity (p<0.05, small volume corrected). In particular, GG subjects showed greater amygdala activity during implicit processing and greater left dorsolateral prefrontal BOLD responses during explicit processing when compared with the GT individuals. Conclusions: These results suggest that DRD2 rs1076560 modulates emotional behavior as well as amygdala and PFC activity during emotional processing. Acknowledgements: DRD2 rs1076560 modulates emotional behavior as well as amygdala and PFC activity during emotion processing. References [1] Zhang Y. et al. Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory. PNAS 2007; 104(51):20552-20557. [2] Salgado-Pineda P. et al. Dopaminergic Contribution to the Regulation of Emotional Perception. Clin Neuropharmacol 2005; 28(5):228-237.
Abstracts / Schizophrenia Research 102/1–3, Supplement 2 (2008) 1–279 [3] Rosenkranz J.A. and Grace A.A. Modulation of Basolateral Amygdala Neuronal Firing and Afferent Drive by Dopamine Receptor Activation In Vivo. The Journal of Neuroscience, 1999; 19(24):11027–1 1039.
376 – POLYMORPHISMS OF THE DOPAMINE D2 RECEPTOR GENE AFFECT ASPECTS OF COGNITION IN HUMANS Barbara Gelao, B. Gelao, R. Romano, P. Taurisano, G. Caforio, A. Di Giorgio, A. Rampino, A. Porcelli, L. Fazio, L. Lo Bianco, M. Nardini, G. Blasi, A. Bertolino University of Study of Bari, Bari, Italy [email protected] Introduction: Cortical and subcortical dopamine D2 receptor (DRD2) signaling has been implicated in cognitive processes, including working memory, attention and executive functions. The aim of this study was to investigate the association of cognition with three frequent DRD2 SNPs, two intronic SNPs, respectively SNP19 (rs#1076560)(G/T) and SNP17 (rs#2283265)(G/T), which affect mRNA splicing, and SNP2 in the promoter region (rs#12364283)(T/C) affecting total mRNA expression. Methods: We recruited a large sample of healthy subjects (N=77119) matched for socio-demographic variables across the three DRD2 SNPs. All subjects underwent a set of neuropsychological tests assessing working memory (N-back), sustained attention (CPT), executive function (WCST), cognitive flexibility (TMT A-B), and memory (WMS). Behavioral performance was evaluated in terms of accuracy and reaction time. Moreover, all raw scores were transformed to z scores to calculate the composite score using the mean of z scores for each subject. Results: ANOVA demonstrated a significant main effect of DRD2 SNP19 on composite score (p<0.05). ANOVAs of the different tests indicated that G/G homozygotes perform better than T allele carriers at 1back and 2back. We also observed a significant association between DRD2 SNP2 and cognitive flexibility (p<0.05). Homozygotes T/T were faster than T/C while performing the TMT B. No significant effect was found for SNP17. Conclusions: Genetic variation in DRD2 seems to affect several cognitive processes, including working memory and cognitive flexibility. Our results may suggest that these variants provide risk to psychiatric disorders associated with these cognitive deficits. References [1] Y.Zhang,A.Bertolino, L.Fazio, G.Blasi, A.Rampino, R.Romano, ML Lee, T. Xiao, A.Papp, D. Wang, W. Sadee: "Polymorphisms in human dopamine D2 receptor gene expression, splicing and neuronal activity during working memory". Proceedinggs of National Academy o f Science, USA, 2007 Dec 18; 104(51): 20552-7
377 – IDENTIFYING GENES FOR SCHIZOPHRENIA IN A LARGE PEDIGREE FROM A NORTHERN SWEDISH ISOLATED POPULATION Maaike Alaerts 1 , Diego Forero 1 , Shana Ceulemans 1 , Sonia De Zutter 1 , Karl-Fredrik Norrback 2 , Dirk Goossens 1 , Peter De Rijk 1 , Rolf Adolfsson 2 , Jurgen Del-Favero 1 1 VIB Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium; 2 Department of Clinical Science, University of Umeå, Umeå, Sweden [email protected] Introduction: Schizophrenia is a severe psychiatric disorder affecting about 1% of the population worldwide. With the pathophysiology of this disease being unknown and genetic heterogeneity being a fact, the search for SZ risk genes has proven very difficult. Therefore we opted to undertake this task with a positional cloning approach in a huge pedigree from a geographically isolated and thus genetically more homogeneous population, living in the Skellefteå area in the Northern Swedish province of Västerbotten. The complex 14-generation
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pedigree under study consists of about 21500 members and was constructed top down from 3 ancestors with a psychiatric disorder born around 1650. Methods: We performed a genome-wide scan in 81 SZ patients and 100 close relatives belonging to the enormous pedigree. 409 STR-markers with a mean inter-marker distance of about 8 cM were genotyped. Parametric and nonparametric tests of linkage were performe d on specifically constructed sub-pedigrees,preserving the maximum genealogical information. Results: Statistically significant linkage was found on chromosome 11p14 and four other regions showed suggestive linkage. Conclusions: Candidate regions containing risk genes contributing to the etiology of schizophrenia were identified in a large pedigree from an isolated Northern Swedish population. Fine-mapping of the regions and segregation analysis are being performed and further detailed genetic analysis will be done applying a linkage disequilibrium mapping approach. Acknowledgements: We would especially like to thank the patients and family members from Skellefteå for their cooperation. References [1] Sanders J, Gill M. (2007) Unravelling the genome: a review of molecular genetic research in schizophrenia. Ir J Med Sci 176(1):5-9.
378 – EXPRESSIONS OF mRNA FOR GDNF IN SCHIZOPHRENIA Köksal Alptekin 1 , Simge Aykan 2 , Berna B.K. Akdede 1 , Halis Ulas 1 , Ahmet Aktaner 1 , Ceyhun Can 1 , Nese Cengizcetin 1 , Seda Mertol 1 , Meral Oguz 1 , Serhat Taslýca 3 1 Department of Psychiatry, Dokuz Eylül University School of Medicine, Izmir; 2 Department of Neuroscience, Izmir; 3 Department of Biophysics, Dokuz Eylül University School of Medicine, Izmir, Turkey [email protected] Introduction: Glial cell line-derived neurotrophic factor (GDNF) may play an important role in development and maintenance of dopamine neurons and support a neurodevelopmental hypothesis of schizophrenia. This study aimed to determine the relationship between GDNF mRNA expression levels and negative, positive subtypes of schizophrenia. Methods: Thirty-five DSM-IV schizophrenia patients, rated with PANSS and 33 healthy volunteers were included. Negative subtype was defined as having dominant negative symptoms without positive symptoms since one-year. Lymphocytes were isolated from periphe ral blood. Total RNA extracted from lymphocytes of individuals was amplified by RT-PCR. Quantitative real time PCR using SYBR Green I was used to quantify the expression of the GDNF gene. Relative expression of GDNF was normalized with beta-actin as a housekeeping gene.The DeltaDeltaCt method was used for the analysis of relative expression. Results: No significant differences in expressions of mRNA for GDNF between schizophrenia patients and healthy subjects were observed. GDNF mRNA levels negatively correlated to duration of schizophrenia, and positively correlated to PANSS Negative sub-syndromes, such as emotional withdrawal, poor report, and passive/apathetic social withdrawal. We did not find any relation between GDNF mRNA levels and positive symptoms of schizophrenia. Conclusions: This study has enhanced a relationship between GDNF gene expression on lymphocytes and negative symptoms of schizophrenia. There are few studies indicating a possible involvement of GDNF in schizophrenia. However this is the first study to show the association between GDNF and negative symptoms of schizophrenia that may support a neurodevelopmental etiology for schizophrenia, especially related to the negative subtype. References [1] Williams HJ, Norton N, Peirce T, Dwyer S, Williams NM, Moskvina V, Owen MJ, O’Donovan MC, 2007. Association analysis of
Abstracts / Schizophrenia Research 102/1–3, Supplement 2 (2008) 1–279
of increased stress-reactivity. Furthermore, increased stress-reactivity levels in the siblings were associated with increased positive symptom intensity in the patients. These results thus suggest a genetic contribution to increased stress-sensitivity, which is specifically underlyingthe positive dimension of psychosis. References [1] Myin-Germeys I, van Os J. Stress-reactivity in psychosis: evidence for an affective pathway to psychosis. Clin Psychol Rev 2007;27:409-424. [2] Myin-Germeys I, Van Os J, Schwartz JE, Stone AA, Delespaul PA. Emotional reactivity to daily life stress in psychosis. Arch Gen Psychiatry Dec 2001;58(12):1137-1144. [3] Myin-Germeys I, Delespaul PA, Van Os J. Behavioral sensitization to daily life stress in psychosis. Psychological Medicine 2005;35:733-741.
373 – HTR3A AND HTR3B SUBUNITS OF SEROTONIN IONOTROPIC RECEPTOR IN SUICIDAL BEHAVIOR AND SCHIZOPHRENIA: HAPLOTYPE ANALYSIS VERSUS GENOTYPE-GENOTYPE INTERACTION Vincenzo De Luca CAMH, Toronto, Canada [email protected] Introduction: Up to ten percent of patients affected with schizophrenia commit suicide and thus suicide represents the major contributor to the increased mortality of people suffering from schizophrenia. Alterations in the serotonin (5-HT) system have been related to impulsive aggression and suicidal behavior. Genetic variations in the serotonin ionotropic receptor subunits (HTR3A and HTR3B) genes, positioned in tandem on chromosome 11q23.2, have been shown to be associated with psychiatric disorders. Methods: To determine the association between suicide attempt in 231 schizophrenia patients, we performed haplotype analysis in the genomic regions of HTR3A and HTR3B using 16 polymorphisms. Results: The SNP rs1176744 Ser129Tyr yielded evidence of association with suicide attempts in schizophrenia (p=0.0107) employing a multidimensionality reduction analysis. On the other hand the haplotype analysis was not significant. Conclusions: Our results suggest an important role for HTR3B in suicide attempts in schizophrenia and also exclude the interaction between these two subunits in conferring risk for suicide attempts using two different statistical strategies
374 – FUNCTIONAL INTERACTION BETWEEN DOPAMINE REGULATING GENES: EFFECTS OF DAT AND DRD2 POLYMORPHISMS ON WORKING MEMORY ACTIVITY IN HUMAN BRAIN Leonardo Fazio 1 , Giuseppe Blasi 1 , Antonio Rampino 1 , Raffaella Romano 1 , Annabella di Giorgio 1 , Grazia Caforio 1 , Paolo Taurisano 1 , Apostolos Papazacharias 1 , Ying Zang 2 , Audrey Papp 2 , Wolfgang Sadée 2 , Alessandro Bertolino 1 1 Psychiatric Neuroscience Group, Department of Psychiatry and Neurology, University of Bari, Bari, Italy; 2 Program in Pharmacogenomics, Department of Pharmacology, College of Medicine, and Division of Biostatistics, College of Public Health, The Ohio State University, Columbus, USA [email protected] Introduction: Dopamine neurotransmission has been shown to be critically involved in the pathophysiology of schizophrenia. Recent studies provide evidence for a direct protein-protein interaction between D2 dopamine receptor (DRD2) and the dopamine transporter (DAT). Both DRD2 and DAT have functional polymorphisms that seems to modulate working memory related brain activity in humans. The purpose of the present study with fMRI was to evaluate in healthy subjects the association between a genetically-based dose effect of
dopamine signaling as determined by DRD2 and DAT polymorphism with activity of prefrontal cortex and striatum during working memory. Methods: 149 healthy subjects, genotyped for DAT 3’VNTR and DRD2 rs1076 560 polymorphisms (DAT: 10/10=59, 9-repeat carriers=89; DRD2: GG=117, GT=32) underwent BOLD-fMRI at 3T while performing a version of the N-Back working memory task. SPM5 random-effects models were used for statistical analyses (all p<0.005). Results: Genotype groups did not differ for a series of sociodemographic variables. fMRI data analysis showed a main effect of DAT and DRD2 polymorphisms and their interaction in the striatum, cingulate and dorsolateral prefrontal cortex. A factorial ANOVA performed on BOLD signal change in caudate and prefrontal cortex revealed a non-linear interaction between DAT and DRD2 genotype. Conclusions: These results demonstrate an interaction between two genes regulating dopamine signaling on specific neuronal network subserving working memory. Our data can be helpful in studying complex genetics interactions in central nervous system phenotypes associated with dopamine signaling and with schizophrenia.
375 – A NOVEL DOPAMINE D2 RECEPTOR GENE POLYMORPHISM AFFECTS EMOTIONAL BEHAVIOR AND PHYSIOLOGY IN HEALTHY SUBJECTS Luciana Lo Bianco, Giuseppe Blasi, Paolo Taurisano, Barbara Gelao, Raffaella Romano, Leonardo Fazio, Apostolos Papazacharias, Annabella Di Giorgio, Grazia Caforio, Antonio Rampino, Rita Masellis, Audrey Papp, Marcello Nardini, Wolfgang Sadee, Alessandro Bertolino University of Bari, Bari, Italy [email protected] Introduction: Previous studies have shown that dopamine modulates emotional behavior as well as amygdala and prefrontal cortex activity during emotion processing. Furthermore, other evidence has revealed that a single nucleotide polymorphism (SNP - rs1076560) in the D2 dopaminergic receptor (DRD2) gene affects splicing and is associated with differential cortical and subcortical activity during cognition. The aim of this study was to investigate if DRD2 rs1076560 affects emotional behavior as well as prefrontal and amygdala activity during implicit and explicit emotional processing. Methods: 127 healthy subjects were genotyped for the DRD2 SNP rs1076560 (101 were homozygous for the G allele, GG, and 26 were heterozygous, GT). The Big Five Questionnaire (BFQ) was administered to all subjects enrolled in the study. Furthermore, fMRI data from 12 GG and 12 GT matched for a series of demographic and neuropsychological variableswere also compared. During the fMRI session, subjects performed a task requiring implicit or explicit processing of emotional facial stimuli. Results: Behavioral data showed higher scores at the Emotion Control scale of the BFQ for GT relative to GG subjects (p=0.05). Furthermore, imaging data revealed an interaction between genotype and task on amygdala and prefrontal activity (p<0.05, small volume corrected). In particular, GG subjects showed greater amygdala activity during implicit processing and greater left dorsolateral prefrontal BOLD responses during explicit processing when compared with the GT individuals. Conclusions: These results suggest that DRD2 rs1076560 modulates emotional behavior as well as amygdala and PFC activity during emotional processing. Acknowledgements: DRD2 rs1076560 modulates emotional behavior as well as amygdala and PFC activity during emotion processing. References [1] Zhang Y. et al. Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory. PNAS 2007; 104(51):20552-20557. [2] Salgado-Pineda P. et al. Dopaminergic Contribution to the Regulation of Emotional Perception. Clin Neuropharmacol 2005; 28(5):228-237.
Abstracts / Schizophrenia Research 102/1–3, Supplement 2 (2008) 1–279 [3] Rosenkranz J.A. and Grace A.A. Modulation of Basolateral Amygdala Neuronal Firing and Afferent Drive by Dopamine Receptor Activation In Vivo. The Journal of Neuroscience, 1999; 19(24):11027–1 1039.
376 – POLYMORPHISMS OF THE DOPAMINE D2 RECEPTOR GENE AFFECT ASPECTS OF COGNITION IN HUMANS Barbara Gelao, B. Gelao, R. Romano, P. Taurisano, G. Caforio, A. Di Giorgio, A. Rampino, A. Porcelli, L. Fazio, L. Lo Bianco, M. Nardini, G. Blasi, A. Bertolino University of Study of Bari, Bari, Italy [email protected] Introduction: Cortical and subcortical dopamine D2 receptor (DRD2) signaling has been implicated in cognitive processes, including working memory, attention and executive functions. The aim of this study was to investigate the association of cognition with three frequent DRD2 SNPs, two intronic SNPs, respectively SNP19 (rs#1076560)(G/T) and SNP17 (rs#2283265)(G/T), which affect mRNA splicing, and SNP2 in the promoter region (rs#12364283)(T/C) affecting total mRNA expression. Methods: We recruited a large sample of healthy subjects (N=77119) matched for socio-demographic variables across the three DRD2 SNPs. All subjects underwent a set of neuropsychological tests assessing working memory (N-back), sustained attention (CPT), executive function (WCST), cognitive flexibility (TMT A-B), and memory (WMS). Behavioral performance was evaluated in terms of accuracy and reaction time. Moreover, all raw scores were transformed to z scores to calculate the composite score using the mean of z scores for each subject. Results: ANOVA demonstrated a significant main effect of DRD2 SNP19 on composite score (p<0.05). ANOVAs of the different tests indicated that G/G homozygotes perform better than T allele carriers at 1back and 2back. We also observed a significant association between DRD2 SNP2 and cognitive flexibility (p<0.05). Homozygotes T/T were faster than T/C while performing the TMT B. No significant effect was found for SNP17. Conclusions: Genetic variation in DRD2 seems to affect several cognitive processes, including working memory and cognitive flexibility. Our results may suggest that these variants provide risk to psychiatric disorders associated with these cognitive deficits. References [1] Y.Zhang,A.Bertolino, L.Fazio, G.Blasi, A.Rampino, R.Romano, ML Lee, T. Xiao, A.Papp, D. Wang, W. Sadee: "Polymorphisms in human dopamine D2 receptor gene expression, splicing and neuronal activity during working memory". Proceedinggs of National Academy o f Science, USA, 2007 Dec 18; 104(51): 20552-7
377 – IDENTIFYING GENES FOR SCHIZOPHRENIA IN A LARGE PEDIGREE FROM A NORTHERN SWEDISH ISOLATED POPULATION Maaike Alaerts 1 , Diego Forero 1 , Shana Ceulemans 1 , Sonia De Zutter 1 , Karl-Fredrik Norrback 2 , Dirk Goossens 1 , Peter De Rijk 1 , Rolf Adolfsson 2 , Jurgen Del-Favero 1 1 VIB Department of Molecular Genetics, University of Antwerp, Antwerpen, Belgium; 2 Department of Clinical Science, University of Umeå, Umeå, Sweden [email protected] Introduction: Schizophrenia is a severe psychiatric disorder affecting about 1% of the population worldwide. With the pathophysiology of this disease being unknown and genetic heterogeneity being a fact, the search for SZ risk genes has proven very difficult. Therefore we opted to undertake this task with a positional cloning approach in a huge pedigree from a geographically isolated and thus genetically more homogeneous population, living in the Skellefteå area in the Northern Swedish province of Västerbotten. The complex 14-generation
181
pedigree under study consists of about 21500 members and was constructed top down from 3 ancestors with a psychiatric disorder born around 1650. Methods: We performed a genome-wide scan in 81 SZ patients and 100 close relatives belonging to the enormous pedigree. 409 STR-markers with a mean inter-marker distance of about 8 cM were genotyped. Parametric and nonparametric tests of linkage were performe d on specifically constructed sub-pedigrees,preserving the maximum genealogical information. Results: Statistically significant linkage was found on chromosome 11p14 and four other regions showed suggestive linkage. Conclusions: Candidate regions containing risk genes contributing to the etiology of schizophrenia were identified in a large pedigree from an isolated Northern Swedish population. Fine-mapping of the regions and segregation analysis are being performed and further detailed genetic analysis will be done applying a linkage disequilibrium mapping approach. Acknowledgements: We would especially like to thank the patients and family members from Skellefteå for their cooperation. References [1] Sanders J, Gill M. (2007) Unravelling the genome: a review of molecular genetic research in schizophrenia. Ir J Med Sci 176(1):5-9.
378 – EXPRESSIONS OF mRNA FOR GDNF IN SCHIZOPHRENIA Köksal Alptekin 1 , Simge Aykan 2 , Berna B.K. Akdede 1 , Halis Ulas 1 , Ahmet Aktaner 1 , Ceyhun Can 1 , Nese Cengizcetin 1 , Seda Mertol 1 , Meral Oguz 1 , Serhat Taslýca 3 1 Department of Psychiatry, Dokuz Eylül University School of Medicine, Izmir; 2 Department of Neuroscience, Izmir; 3 Department of Biophysics, Dokuz Eylül University School of Medicine, Izmir, Turkey [email protected] Introduction: Glial cell line-derived neurotrophic factor (GDNF) may play an important role in development and maintenance of dopamine neurons and support a neurodevelopmental hypothesis of schizophrenia. This study aimed to determine the relationship between GDNF mRNA expression levels and negative, positive subtypes of schizophrenia. Methods: Thirty-five DSM-IV schizophrenia patients, rated with PANSS and 33 healthy volunteers were included. Negative subtype was defined as having dominant negative symptoms without positive symptoms since one-year. Lymphocytes were isolated from periphe ral blood. Total RNA extracted from lymphocytes of individuals was amplified by RT-PCR. Quantitative real time PCR using SYBR Green I was used to quantify the expression of the GDNF gene. Relative expression of GDNF was normalized with beta-actin as a housekeeping gene.The DeltaDeltaCt method was used for the analysis of relative expression. Results: No significant differences in expressions of mRNA for GDNF between schizophrenia patients and healthy subjects were observed. GDNF mRNA levels negatively correlated to duration of schizophrenia, and positively correlated to PANSS Negative sub-syndromes, such as emotional withdrawal, poor report, and passive/apathetic social withdrawal. We did not find any relation between GDNF mRNA levels and positive symptoms of schizophrenia. Conclusions: This study has enhanced a relationship between GDNF gene expression on lymphocytes and negative symptoms of schizophrenia. There are few studies indicating a possible involvement of GDNF in schizophrenia. However this is the first study to show the association between GDNF and negative symptoms of schizophrenia that may support a neurodevelopmental etiology for schizophrenia, especially related to the negative subtype. References [1] Williams HJ, Norton N, Peirce T, Dwyer S, Williams NM, Moskvina V, Owen MJ, O’Donovan MC, 2007. Association analysis of