- Email: [email protected]
157 – Catechol-O-methyltransferase polymorphism and antisaccade eye movements in schizophrenia
ABSTRACTS / Schizophrenia Research 98 (2008) 3–199 adult ADHD and schizophrenia. Our sample consisted of 78 DSM-IV patients affected by adult ADHD from the Toronto area. All patients were white European Caucasian, the mean age was 33 ± 9.58 years (SD) and there were 54 men and 24 women. Current smoking status was assessed by a medical history questionnaire, and there were 29 current smokers and 49 non-smokers. We analyze the single marker association by chi-square and the CHRNA7–CHRFAM7A interaction by logistic regression, considering the 113 bp and the − 2 bp deletion dominant. Results: In our sample the 113 bp allele in CHRNA7 does not confer risk for smoking in the ADHD (χ2 = 0.47, df = 1, p = 0.492). The − 2 bp in the α7like does not confer risk for smoking (χ2 = 0.00, df = 1, p = 0.984). Age, gender, IQ and Temperament Character Inventory (TCI) scores are important factors in determining smoking in special populations therefore we incorporate these factors in a logistic regression assuming dominant effect for these two genetic variants (113 bp and − 2 bp). Finally, since the two genes are supposed to interact, we employed logistic regression also for the interaction model. Conclusions: The analysis of α7 genes in ADHD showed no association with smoking. The molecular hypothesis of α7/α7like interaction and the number of α7like copy variation remains very interesting for psychiatric phenotype and nicotine addiction even though the α7/α7like showed no interaction in conferring risk for smoking in this sample.
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Studies; patients met criteria for schizophrenia or schizoaffective disorder (DSM-IV). Danish samples included 322 schizophrenia patients (ICD-10) from the Danish Psychiatric Biobank and 331 healthy control subjects. Genotyping, GCLC GAG TNR polymorphism was assessed by PCR amplification as described by Walsh et al. (2001). Results: We report evidence that patients have a decreased capacity to synthesize GSH that is most likely of genetic origin: (a) the activity of the GSH key synthesizing enzyme glutamate–cysteine–ligase (GCL) in patients was impaired in skin fibroblast cultures under conditions of oxidative stress. (b) This reduced GCL activity correlated with decreased GCL catalytic subunit (GCLC) protein expression. (c) Two independent case–control studies showed a significant association between schizophrenia and a GAG trinucleotide repeat (TNR) polymorphism in the GCLC gene. The most common TNR genotype 7/7 was more frequent in controls, whereas the rarest TNR genotype 8/ 8 was three times more frequent in patients. (d) The disease-associated genotypes correlated with a decrease in GCLC protein expression, GCL activity and GSH content. Conclusions: These results combined with observations that GSHdeficient models reveal morphological (GABA interneurones), electrophysiological (NMDA hypofunction) and behavioral (cognitive functions) anomalies analogous to those observed in patients, suggest that glutathione synthesis dysfunction may represent a causal mechanism leading to redox dysregulation and oxidative stress in schizophrenia.
doi:10.1016/j.schres.2007.12.222 doi:10.1016/j.schres.2007.12.223
156 – REDOX DYSREGULATION AND OXIDATIVE STRESS IN SCHIZOPHRENIA: GENETIC AND FUNCTIONAL ANOMALIES IN GLUTATHIONE SYNTHESIS
157 – CATECHOL-O-METHYLTRANSFERASE POLYMORPHISM AND ANTISACCADE EYE MOVEMENTS IN SCHIZOPHRENIA
R. Gysin 1, R. Kraftsik 2, J. Sandell 1, P. Bovet 3, C. Chapuis 1, P. Conus 3, P. Deppen 1, M. Preisig 3, V. Ruiz 1, P. Steullet 1, M. Tosic 1, T. Werge 4, M. Cuenod 1, K.Q. Do 1.
H.M. Haraldsson 1, U. Ettinger 2, B.B. Magnusdottir 1,2, T. Sigmundsson 1, E. Sigurdsson 1, H. Petursson 1.
1
1
Center for Psychiatric Neuroscience, Department of Psychiatry, University Hospital Center and University of Lausanne, Switzerland 2 Department of Cellular Biology and Morphology, University of Lausanne, Switzerland 3 Service of General Psychiatry, Department of Psychiatry, University Hospital Center and University of Lausanne, Switzerland 4 Research Institute of Biological Psychiatry, Copenhagen University Hospital, Sct. Hans Hospital, Roskilde, Denmark Presenting Author details: [email protected] Site de Cery, CH-1008 Prilly-Lausanne, Switzerland, Tel.: +41 21 643 65 65; fax: +41 21 6436562. Background: Converging evidence speak in favor of an abnormal susceptibility to oxidative stress in schizophrenia. It is however unclear if this is a primary cause, due to a defect of the redox regulation system, or a secondary effect due to unknown processes including excessive production of reactive oxygen species. A decreased level of glutathione (GSH), the principal non-protein antioxidant and redox regulator, was observed both in cerebrospinal fluid and prefrontal cortex of schizophrenia patients. Methods: All subjects of the Swiss sample (66 patients and 48 controls) were assessed using Diagnostic Interview for Genetic
Division of Psychiatry, Landspitali University Hospital, Reykjavik, Iceland 2 Institute of Psychiatry, King's College London, London, UK Presenting Author details: [email protected] Hringbraut, 101 Reykjavik, Iceland, Tel.: +354 543 4067; fax: +354 543 4816. Background: The catechol-O-methyltransferase (COMT) enzyme catabolizes dopamine. The Val158Met single nucleotide polymorphism (rs4680) in the COMT gene has received considerable attention as a candidate gene for schizophrenia. A recent theoretical analysis of COMT data suggests that genotype affects performance as a function of task characteristics, with the Val and Met alleles being associated with better performance on measures of plasticity and stability, respectively (Bilder et al., 2004). The antisaccade (AS) eye movement task relies heavily on processes of plasticity, such as cognitive flexibility and error monitoring. AS deficits are promising endophenotypes in genetic studies of schizophrenia. The aim was to investigate the effects of COMT Val158Met polymorphism on AS in schizophrenics and healthy controls. Methods: Schizophrenia patients (N = 118) and controls (N = 109) underwent infrared oculographic assessment of AS. Subjects were
98
ABSTRACTS / Schizophrenia Research 98 (2008) 3–199
genotyped for COMT Val158Met and divided into two groups according to Val allele carrier status (Val carriers vs. non-carriers). Results: Patients displayed more reflexive errors, longer latency and lower amplitude gain than controls (all p b 0.004). Val allele carriers made significantly fewer reflexive errors than non-carriers (p = 0.03). AS latency, amplitude gain and spatial error did not differ by genotype and there were no group-by-genotype interactions (p N 0.1). Conclusions: The results suggest that Met homozygotes have more frequent AS reflexive errors than Val carriers. This finding is consistent with the hypothesis that the Val allele is advantageous in the performance on measures of cognitive plasticity. Acknowledgement: The study was supported by a grant from the Icelandic Research Fund (RANNIS). Ulrich Ettinger is supported by an ESRC/MRC Fellowship. Reference: Bilder, RM., Volavka, J., et al. The catechol-O-methyltransferase polymorphism: relations to the tonic–phasic dopamine hypothesis and neuropsychiatric phenotypes, 2004, Neuropsychopharmacology, 29, 1943–1961. doi:10.1016/j.schres.2007.12.224
158 – LACK OF ASSOCIATION BETWEEN VAL158MET POLYMORPHISM OF CATECHOL-O-METHYLTRANSFERASE GENE AND COGNITIVE FUNCTIONS IN SCHIZOPHRENIA PATIENTS AND CONTROLS K.S. Hong 1, H.J. Park 1, D.Y. Park 1, E.Y. Cho 1, H.O. Jeun 1, N. Kim 1, Y.-S. Lee 2, D. Lee 1. 1
Department of Psychiatry, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea 2 Yong-In Mental Hospital, Yong-In, Kyunggi-Do, Republic of Korea Presenting Author details: [email protected] #50, Ilwon-dong, Kangnam-Gu, 135-710 Seoul, Republic of Korea, Tel.: +82 2 34103584; fax: +82 2 34100050. Background: Catechol-O-methyltransferase (COMT) gene has been identified as a positional and functional candidate gene of schizophrenia. Although specific mechanism of increasing schizophrenia susceptibility by this gene has not well described yet, recent studies suggest that the Valine allele of COMT Val158Met polymorphism may contribute to cognitive decline in schizophrenia. The present study investigated the association between this polymorphism of COMT gene and cognitive markers related to schizophrenia in both schizophrenia patients and control groups. Methods: The subjects were 78 DSM-IV schizophrenia patients and 97 normal controls. Comprehensive neurocognitive tests for which performance deficits have been reported in schizophrenia were administered. Genotyping for COMT Val158Met polymorphism was done with SNapShot method. Association analyses between genotype and cognitive functions were performed using ANCOVA and regression analysis. Results: In the comparison of allele frequencies between patient and control groups, no significant association between the polymorphism and schizophrenia was observed. In both patients and control groups, significant differences of cognitive performances among genotype groups were not identified.
Conclusions: These findings do not support a major role of COMT gene in the regulation of the cognitive processes of schizophrenia. doi:10.1016/j.schres.2007.12.225
159 – GENETIC VARIATIONS OF THE HUMAN NEUROPSIN GENE AND PSYCHIATRIC DISORDERS: POLYMORPHISM SCREENING AND POSSIBLE ASSOCIATION WITH BIPOLAR DISORDER AND COGNITIVE FUNCTIONS A. Izumi 1,2, Y. Iijima 1, H. Noguchi 1, T. Numakawa 1, T. Okada 1, H. Hori 1, T. Kato 3, M. Tatsumi 4,5, A. Kosuga 4, K. Kamijima 4, T. Asada 6, K. Arima 7, O. Saitoh 7, S. Shiosaka 2, H. Kunugi 1. 1 Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan 2 Division of Structural Cell Biology, Nara Institute of Science and Technology, Nara Japan 3 Laboratory for Molecular Dynamics of Mental Disorders, Brain Science Institute, RIKEN, Saitama Japan 4 Department of Psychiatry, Showa University School of Medicine, Tokyo, Japan 5 Yokohama Shinryo Clinic, Kanagawa, Japan 6 Department of Psychiatry, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan 7 Department of Psychiatry, Musashi Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan
Presenting Author details: [email protected] 4-1-1 Ogawa-Higashi, Kodaira, 1878502 Tokyo, Japan, Tel.: +81 42 3461714; fax: +81 42 3461744. Background: Human NP (hNP) has been implicated in the progressive change of cognitive abilities during primate evolution. The hNP gene maps to chromosome 19q13, a region reportedly linked to schizophrenia and bipolar disorder. Therefore, hNP is a functional and positional candidate gene for association with schizophrenia, mood disorders and cognitive ability. Methods: Polymorphism screening was performed for the entire hNP gene. Core promoter region was determined and whether transcriptional activity alters in an allele-dependent manner was examined by using the dual-luciferase system. Allelic and genotypic distributions of 5 single nucleotide polymorphisms (SNPs) were compared between patients with schizophrenia (n = 439), major depression (n = 409), bipolar disorder (n = 207) and controls (n = 727). The possible association of hNP genotype with memory index (assessed with Wechsler Memory Scale, revised; WMS-R) and intelligence quotient (IQ assessed with Wechsler Adult Intelligence Scale, revised; WAISR) was examined in healthy controls (n = 176). Results: A total of 28 SNPs, including 9 novel SNPs, were identified. No significant effects on transcriptional activity were observed for SNPs in the promoter region. A significant allelic association was found between several SNPs and bipolar disorder (for SNP23 at the 3′ regulatory region: odds ratio 1.48, 95% confidential interval 1.16– 1.88, p = 0.0015). However, such an association was not detected for schizophrenia or depression. Significant differences were observed of SNP23 with attention/concentration subscale score of WMS-R (p = 0.016) and verbal IQ (p b 0.001).
97
Studies; patients met criteria for schizophrenia or schizoaffective disorder (DSM-IV). Danish samples included 322 schizophrenia patients (ICD-10) from the Danish Psychiatric Biobank and 331 healthy control subjects. Genotyping, GCLC GAG TNR polymorphism was assessed by PCR amplification as described by Walsh et al. (2001). Results: We report evidence that patients have a decreased capacity to synthesize GSH that is most likely of genetic origin: (a) the activity of the GSH key synthesizing enzyme glutamate–cysteine–ligase (GCL) in patients was impaired in skin fibroblast cultures under conditions of oxidative stress. (b) This reduced GCL activity correlated with decreased GCL catalytic subunit (GCLC) protein expression. (c) Two independent case–control studies showed a significant association between schizophrenia and a GAG trinucleotide repeat (TNR) polymorphism in the GCLC gene. The most common TNR genotype 7/7 was more frequent in controls, whereas the rarest TNR genotype 8/ 8 was three times more frequent in patients. (d) The disease-associated genotypes correlated with a decrease in GCLC protein expression, GCL activity and GSH content. Conclusions: These results combined with observations that GSHdeficient models reveal morphological (GABA interneurones), electrophysiological (NMDA hypofunction) and behavioral (cognitive functions) anomalies analogous to those observed in patients, suggest that glutathione synthesis dysfunction may represent a causal mechanism leading to redox dysregulation and oxidative stress in schizophrenia.
doi:10.1016/j.schres.2007.12.222 doi:10.1016/j.schres.2007.12.223
156 – REDOX DYSREGULATION AND OXIDATIVE STRESS IN SCHIZOPHRENIA: GENETIC AND FUNCTIONAL ANOMALIES IN GLUTATHIONE SYNTHESIS
157 – CATECHOL-O-METHYLTRANSFERASE POLYMORPHISM AND ANTISACCADE EYE MOVEMENTS IN SCHIZOPHRENIA
R. Gysin 1, R. Kraftsik 2, J. Sandell 1, P. Bovet 3, C. Chapuis 1, P. Conus 3, P. Deppen 1, M. Preisig 3, V. Ruiz 1, P. Steullet 1, M. Tosic 1, T. Werge 4, M. Cuenod 1, K.Q. Do 1.
H.M. Haraldsson 1, U. Ettinger 2, B.B. Magnusdottir 1,2, T. Sigmundsson 1, E. Sigurdsson 1, H. Petursson 1.
1
1
Center for Psychiatric Neuroscience, Department of Psychiatry, University Hospital Center and University of Lausanne, Switzerland 2 Department of Cellular Biology and Morphology, University of Lausanne, Switzerland 3 Service of General Psychiatry, Department of Psychiatry, University Hospital Center and University of Lausanne, Switzerland 4 Research Institute of Biological Psychiatry, Copenhagen University Hospital, Sct. Hans Hospital, Roskilde, Denmark Presenting Author details: [email protected] Site de Cery, CH-1008 Prilly-Lausanne, Switzerland, Tel.: +41 21 643 65 65; fax: +41 21 6436562. Background: Converging evidence speak in favor of an abnormal susceptibility to oxidative stress in schizophrenia. It is however unclear if this is a primary cause, due to a defect of the redox regulation system, or a secondary effect due to unknown processes including excessive production of reactive oxygen species. A decreased level of glutathione (GSH), the principal non-protein antioxidant and redox regulator, was observed both in cerebrospinal fluid and prefrontal cortex of schizophrenia patients. Methods: All subjects of the Swiss sample (66 patients and 48 controls) were assessed using Diagnostic Interview for Genetic
Division of Psychiatry, Landspitali University Hospital, Reykjavik, Iceland 2 Institute of Psychiatry, King's College London, London, UK Presenting Author details: [email protected] Hringbraut, 101 Reykjavik, Iceland, Tel.: +354 543 4067; fax: +354 543 4816. Background: The catechol-O-methyltransferase (COMT) enzyme catabolizes dopamine. The Val158Met single nucleotide polymorphism (rs4680) in the COMT gene has received considerable attention as a candidate gene for schizophrenia. A recent theoretical analysis of COMT data suggests that genotype affects performance as a function of task characteristics, with the Val and Met alleles being associated with better performance on measures of plasticity and stability, respectively (Bilder et al., 2004). The antisaccade (AS) eye movement task relies heavily on processes of plasticity, such as cognitive flexibility and error monitoring. AS deficits are promising endophenotypes in genetic studies of schizophrenia. The aim was to investigate the effects of COMT Val158Met polymorphism on AS in schizophrenics and healthy controls. Methods: Schizophrenia patients (N = 118) and controls (N = 109) underwent infrared oculographic assessment of AS. Subjects were
98
ABSTRACTS / Schizophrenia Research 98 (2008) 3–199
genotyped for COMT Val158Met and divided into two groups according to Val allele carrier status (Val carriers vs. non-carriers). Results: Patients displayed more reflexive errors, longer latency and lower amplitude gain than controls (all p b 0.004). Val allele carriers made significantly fewer reflexive errors than non-carriers (p = 0.03). AS latency, amplitude gain and spatial error did not differ by genotype and there were no group-by-genotype interactions (p N 0.1). Conclusions: The results suggest that Met homozygotes have more frequent AS reflexive errors than Val carriers. This finding is consistent with the hypothesis that the Val allele is advantageous in the performance on measures of cognitive plasticity. Acknowledgement: The study was supported by a grant from the Icelandic Research Fund (RANNIS). Ulrich Ettinger is supported by an ESRC/MRC Fellowship. Reference: Bilder, RM., Volavka, J., et al. The catechol-O-methyltransferase polymorphism: relations to the tonic–phasic dopamine hypothesis and neuropsychiatric phenotypes, 2004, Neuropsychopharmacology, 29, 1943–1961. doi:10.1016/j.schres.2007.12.224
158 – LACK OF ASSOCIATION BETWEEN VAL158MET POLYMORPHISM OF CATECHOL-O-METHYLTRANSFERASE GENE AND COGNITIVE FUNCTIONS IN SCHIZOPHRENIA PATIENTS AND CONTROLS K.S. Hong 1, H.J. Park 1, D.Y. Park 1, E.Y. Cho 1, H.O. Jeun 1, N. Kim 1, Y.-S. Lee 2, D. Lee 1. 1
Department of Psychiatry, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea 2 Yong-In Mental Hospital, Yong-In, Kyunggi-Do, Republic of Korea Presenting Author details: [email protected] #50, Ilwon-dong, Kangnam-Gu, 135-710 Seoul, Republic of Korea, Tel.: +82 2 34103584; fax: +82 2 34100050. Background: Catechol-O-methyltransferase (COMT) gene has been identified as a positional and functional candidate gene of schizophrenia. Although specific mechanism of increasing schizophrenia susceptibility by this gene has not well described yet, recent studies suggest that the Valine allele of COMT Val158Met polymorphism may contribute to cognitive decline in schizophrenia. The present study investigated the association between this polymorphism of COMT gene and cognitive markers related to schizophrenia in both schizophrenia patients and control groups. Methods: The subjects were 78 DSM-IV schizophrenia patients and 97 normal controls. Comprehensive neurocognitive tests for which performance deficits have been reported in schizophrenia were administered. Genotyping for COMT Val158Met polymorphism was done with SNapShot method. Association analyses between genotype and cognitive functions were performed using ANCOVA and regression analysis. Results: In the comparison of allele frequencies between patient and control groups, no significant association between the polymorphism and schizophrenia was observed. In both patients and control groups, significant differences of cognitive performances among genotype groups were not identified.
Conclusions: These findings do not support a major role of COMT gene in the regulation of the cognitive processes of schizophrenia. doi:10.1016/j.schres.2007.12.225
159 – GENETIC VARIATIONS OF THE HUMAN NEUROPSIN GENE AND PSYCHIATRIC DISORDERS: POLYMORPHISM SCREENING AND POSSIBLE ASSOCIATION WITH BIPOLAR DISORDER AND COGNITIVE FUNCTIONS A. Izumi 1,2, Y. Iijima 1, H. Noguchi 1, T. Numakawa 1, T. Okada 1, H. Hori 1, T. Kato 3, M. Tatsumi 4,5, A. Kosuga 4, K. Kamijima 4, T. Asada 6, K. Arima 7, O. Saitoh 7, S. Shiosaka 2, H. Kunugi 1. 1 Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan 2 Division of Structural Cell Biology, Nara Institute of Science and Technology, Nara Japan 3 Laboratory for Molecular Dynamics of Mental Disorders, Brain Science Institute, RIKEN, Saitama Japan 4 Department of Psychiatry, Showa University School of Medicine, Tokyo, Japan 5 Yokohama Shinryo Clinic, Kanagawa, Japan 6 Department of Psychiatry, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan 7 Department of Psychiatry, Musashi Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan
Presenting Author details: [email protected] 4-1-1 Ogawa-Higashi, Kodaira, 1878502 Tokyo, Japan, Tel.: +81 42 3461714; fax: +81 42 3461744. Background: Human NP (hNP) has been implicated in the progressive change of cognitive abilities during primate evolution. The hNP gene maps to chromosome 19q13, a region reportedly linked to schizophrenia and bipolar disorder. Therefore, hNP is a functional and positional candidate gene for association with schizophrenia, mood disorders and cognitive ability. Methods: Polymorphism screening was performed for the entire hNP gene. Core promoter region was determined and whether transcriptional activity alters in an allele-dependent manner was examined by using the dual-luciferase system. Allelic and genotypic distributions of 5 single nucleotide polymorphisms (SNPs) were compared between patients with schizophrenia (n = 439), major depression (n = 409), bipolar disorder (n = 207) and controls (n = 727). The possible association of hNP genotype with memory index (assessed with Wechsler Memory Scale, revised; WMS-R) and intelligence quotient (IQ assessed with Wechsler Adult Intelligence Scale, revised; WAISR) was examined in healthy controls (n = 176). Results: A total of 28 SNPs, including 9 novel SNPs, were identified. No significant effects on transcriptional activity were observed for SNPs in the promoter region. A significant allelic association was found between several SNPs and bipolar disorder (for SNP23 at the 3′ regulatory region: odds ratio 1.48, 95% confidential interval 1.16– 1.88, p = 0.0015). However, such an association was not detected for schizophrenia or depression. Significant differences were observed of SNP23 with attention/concentration subscale score of WMS-R (p = 0.016) and verbal IQ (p b 0.001).