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COMT GENOTYPE AND MEMORY PERFORMANCE IN SCHIZOPHRENIA
456
Abstracts
Poster 88 COMT GENOTYPE AND MEMORY PERFORMANCE IN SCHIZOPHRENIA Elizabeth W. Twamley1,2, Lea Vella1,3, Cynthia Z. Burton1,3, Gauri N. Savla1, Jami J. Guidry1, Arpi Minassian1, Robert M. Bilder4, John R. Kelsoe1,2 1 University of California, San Diego La Jolla, CA, USA; 2VA San Diego Healthcare System San Diego, CA, USA; 3San Diego State University San Diego, CA, USA; 4University of California, Los Angeles Los Angeles, CA, USA Background: The Val158Met single nucleotide polymorphism of the catechol-O-methyltransferase (COMT) gene on chromosome 22 influences dopamine catabolism and is related to cognitive impairment in schizophrenia. Previous research has found that the Met allele is associated in a dose-response fashion with better performance on most neuropsychological tests. Methods: We assessed 138 outpatients with schizophrenia-spectrum disorders (65% men; 59% Caucasian; mean age = 49; mean years of education = 13) with a blood draw and a comprehensive neuropsychological, functional, and clinical battery. Participants with the Val/Val (n = 49), Val/Met (n = 57), and Met/Met (n = 32) genotypes did not differ on demographic variables, diagnosis, type or dosage of antipsychotic medication, or duration of psychosis. Results: Spearman correlations between the "dose" of the Met allele (0, 1, or 2 Met alleles) and the neuropsychological, functional, and clinical variables demonstrated that a higher number of Met alleles was associated with better estimated premorbid intellectual functioning (r = .20, p = .020), verbal memory (r = .18, p = .036), visual memory (r = .17, p = .047), and working memory (r = .17, p = .045). Met carriers significantly outperformed noncarriers on measures of premorbid intellectual functioning (t = 2.25, df = 136, p = .026), verbal memory (t = 2.13, df = 136, p = .035), and visual memory (t = 2.09, df = 119.34, p = .028). Discussion: The Met allele appears to be associated with better performance in premorbid intellectual functioning, delayed verbal and visual recall, and working memory, explaining 3-4% of the variance in these abilities. Associations between COMT genotype and functional capacity or psychiatric symptom severity were not statistically significant. Because the Val158Met polymorphism typically explains a small amount of variance in cognitive performance and given the size of the current sample, these results need to be replicated with a larger sample and other variants should be considered to further understand genetic contributions to cognition.
doi:10.1016/j.schres.2010.02.849
Poster 89 DISRUPTED IN SCHIZOPHRENIA 1 GENOTYPE AND RESPONSE TO ANTIPSYCHOTICS IN FIRST EPISODE PSYCHOSIS Javier Vazquez-Bourgon1, Ignacio Mata1, Rocio Pérez-Iglesias1, Jose Manuel Rodríguez-Sánchez1, Eugenio Carrasco-Marín2, Jose Luis Vázquez-Barquero1, Benedicto Crespo-Facorro1 1 Department of Psychiatry. Hospital Universitario Marques de Valdecilla Santander, Cantabria, Spain; 2Department of Imnunology. Hospital Universitario Marques de Valdecilla Santander, Cantabria, Spain Background: Currently there is substantial evidence supporting DISC1 as one of the main candidate genes for schizophrenia. Moreover, variations in several DISC1 polymorphisms have been associated in schizophrenic patients to brain structure abnormalities, altered brain activation, cognitive impairment, and clinical
severity. The biological function of the DISC1 is not completely understood. However, there is strong evidence showing that DISC1 interacts with a range of proteins forming the DISC1-Interactome. Through its interactions with these proteins, DISC1 gets involved in neurodevelopment and neuronal signalling processes, but also in glutamate transmission. And since the glutamate system has been proposed as one of the mechanism of actions for antipsychotic drugs, the DISC1, through its interaction with proteins of the glutamate system might be involved itself in processes of treatment response. Recent studies support this hypothesis. Therefore it has been shown that chronic treatment with antipsychotics increased the expression of DISC1 mRNA in cortex and hippocampus. Moreover, some psychiatric drug target genes that display DISC1 pathway mediated differential expression. Therefore we aimed to study if variations in a DISC1 polymorphism were associated to variations in treatment response. Methods: We studied a sample of 213 Caucasian drug-naïve patients experiencing a first episode of non-affective psychosis (DSM-IV). Response to antipsychotics was defined according to three symptom scales. Response was asses at 6 weeks (short-term) and at 1 year (long-term) of entering the treatment program. BPRS Response was defined as a decrease of at least 40% in BPRS. SANS response and SAPS Response: Patients had to fulfill the three following criteria: i) Decrease of at least 40%; ii) Total score below 8; iii) Non of the scale Items being equal or above 4. Genotyping was accomplished by automatic genotyping using ABI 3700 technology. All statistical analyses were carried out using the statistical software package SPSS 15.0 for Windows. When studying possible associations between Ser704Cys genotype and response to antipsychotic treatment, Chi square analyses were carried out. Statistical significance was established at p < 0.05. Results: Patients were in Hardy-Weinberg equilibrium. Rs821616 genotype and allelic frequencies were calculated, being as follows: AA = 6.6%; AT = 42.7%; TT= 50.7% and A = 0.28; T = 0.72 respectively. None of Ser704Cys DISC1 genotypes modulated significantly the risk of psychosis when comparing the sample of psychotic patients with the control group. Our results showed no statistical association between the Ser704Cys polymorphism and response to antipsychotic treatment using any of the response definitions, neither at short-term (6 weeks) nor at long-term (1 year). Discussion: Our study showed that Ser704Cys DISC1 genotype is not a marker of response in psychosis. However, this result is not completely unexpected as we can only understand the treatment response as a complex process in which multiple proteins are involved in multi-interactions. Therefore, it would be difficult to find a single polymorphism causing such a modulation on the treatment response to antipsychotics. It is more likely that the pharmacogenetic processes will be explained using more complex models such as the "Synaptic Theory of Schizophrenia" proposed by Harrison and Weinberger, in which the risk of psychosis –and why not, the response to antipsychotics- would be mediated by the convergence of several susceptibility genes' effects on synaptic processing in brain microcircuitries, mainly on the glutamate synapse.
doi:10.1016/j.schres.2010.02.850
Poster 90 AKT1 GENE IS ASSOCIATED WITH ATTENTION AND BRAIN MORPHOLOGY IN PATIENTS WITH SCHIZOPHRENIA Yuka Yasuda1,2,3, Ryota Hashimoto1,2,3, Hironori Takamura2,3,4, Kazutaka Ohi2,3, Motoyuki Fukumoto2,3, Kiyotaka Nemoto5, Takashi Ohnishi6, Hidenaga Yamamori2,7, Hidetoshi Takahashi2,3,
Abstracts
Poster 88 COMT GENOTYPE AND MEMORY PERFORMANCE IN SCHIZOPHRENIA Elizabeth W. Twamley1,2, Lea Vella1,3, Cynthia Z. Burton1,3, Gauri N. Savla1, Jami J. Guidry1, Arpi Minassian1, Robert M. Bilder4, John R. Kelsoe1,2 1 University of California, San Diego La Jolla, CA, USA; 2VA San Diego Healthcare System San Diego, CA, USA; 3San Diego State University San Diego, CA, USA; 4University of California, Los Angeles Los Angeles, CA, USA Background: The Val158Met single nucleotide polymorphism of the catechol-O-methyltransferase (COMT) gene on chromosome 22 influences dopamine catabolism and is related to cognitive impairment in schizophrenia. Previous research has found that the Met allele is associated in a dose-response fashion with better performance on most neuropsychological tests. Methods: We assessed 138 outpatients with schizophrenia-spectrum disorders (65% men; 59% Caucasian; mean age = 49; mean years of education = 13) with a blood draw and a comprehensive neuropsychological, functional, and clinical battery. Participants with the Val/Val (n = 49), Val/Met (n = 57), and Met/Met (n = 32) genotypes did not differ on demographic variables, diagnosis, type or dosage of antipsychotic medication, or duration of psychosis. Results: Spearman correlations between the "dose" of the Met allele (0, 1, or 2 Met alleles) and the neuropsychological, functional, and clinical variables demonstrated that a higher number of Met alleles was associated with better estimated premorbid intellectual functioning (r = .20, p = .020), verbal memory (r = .18, p = .036), visual memory (r = .17, p = .047), and working memory (r = .17, p = .045). Met carriers significantly outperformed noncarriers on measures of premorbid intellectual functioning (t = 2.25, df = 136, p = .026), verbal memory (t = 2.13, df = 136, p = .035), and visual memory (t = 2.09, df = 119.34, p = .028). Discussion: The Met allele appears to be associated with better performance in premorbid intellectual functioning, delayed verbal and visual recall, and working memory, explaining 3-4% of the variance in these abilities. Associations between COMT genotype and functional capacity or psychiatric symptom severity were not statistically significant. Because the Val158Met polymorphism typically explains a small amount of variance in cognitive performance and given the size of the current sample, these results need to be replicated with a larger sample and other variants should be considered to further understand genetic contributions to cognition.
doi:10.1016/j.schres.2010.02.849
Poster 89 DISRUPTED IN SCHIZOPHRENIA 1 GENOTYPE AND RESPONSE TO ANTIPSYCHOTICS IN FIRST EPISODE PSYCHOSIS Javier Vazquez-Bourgon1, Ignacio Mata1, Rocio Pérez-Iglesias1, Jose Manuel Rodríguez-Sánchez1, Eugenio Carrasco-Marín2, Jose Luis Vázquez-Barquero1, Benedicto Crespo-Facorro1 1 Department of Psychiatry. Hospital Universitario Marques de Valdecilla Santander, Cantabria, Spain; 2Department of Imnunology. Hospital Universitario Marques de Valdecilla Santander, Cantabria, Spain Background: Currently there is substantial evidence supporting DISC1 as one of the main candidate genes for schizophrenia. Moreover, variations in several DISC1 polymorphisms have been associated in schizophrenic patients to brain structure abnormalities, altered brain activation, cognitive impairment, and clinical
severity. The biological function of the DISC1 is not completely understood. However, there is strong evidence showing that DISC1 interacts with a range of proteins forming the DISC1-Interactome. Through its interactions with these proteins, DISC1 gets involved in neurodevelopment and neuronal signalling processes, but also in glutamate transmission. And since the glutamate system has been proposed as one of the mechanism of actions for antipsychotic drugs, the DISC1, through its interaction with proteins of the glutamate system might be involved itself in processes of treatment response. Recent studies support this hypothesis. Therefore it has been shown that chronic treatment with antipsychotics increased the expression of DISC1 mRNA in cortex and hippocampus. Moreover, some psychiatric drug target genes that display DISC1 pathway mediated differential expression. Therefore we aimed to study if variations in a DISC1 polymorphism were associated to variations in treatment response. Methods: We studied a sample of 213 Caucasian drug-naïve patients experiencing a first episode of non-affective psychosis (DSM-IV). Response to antipsychotics was defined according to three symptom scales. Response was asses at 6 weeks (short-term) and at 1 year (long-term) of entering the treatment program. BPRS Response was defined as a decrease of at least 40% in BPRS. SANS response and SAPS Response: Patients had to fulfill the three following criteria: i) Decrease of at least 40%; ii) Total score below 8; iii) Non of the scale Items being equal or above 4. Genotyping was accomplished by automatic genotyping using ABI 3700 technology. All statistical analyses were carried out using the statistical software package SPSS 15.0 for Windows. When studying possible associations between Ser704Cys genotype and response to antipsychotic treatment, Chi square analyses were carried out. Statistical significance was established at p < 0.05. Results: Patients were in Hardy-Weinberg equilibrium. Rs821616 genotype and allelic frequencies were calculated, being as follows: AA = 6.6%; AT = 42.7%; TT= 50.7% and A = 0.28; T = 0.72 respectively. None of Ser704Cys DISC1 genotypes modulated significantly the risk of psychosis when comparing the sample of psychotic patients with the control group. Our results showed no statistical association between the Ser704Cys polymorphism and response to antipsychotic treatment using any of the response definitions, neither at short-term (6 weeks) nor at long-term (1 year). Discussion: Our study showed that Ser704Cys DISC1 genotype is not a marker of response in psychosis. However, this result is not completely unexpected as we can only understand the treatment response as a complex process in which multiple proteins are involved in multi-interactions. Therefore, it would be difficult to find a single polymorphism causing such a modulation on the treatment response to antipsychotics. It is more likely that the pharmacogenetic processes will be explained using more complex models such as the "Synaptic Theory of Schizophrenia" proposed by Harrison and Weinberger, in which the risk of psychosis –and why not, the response to antipsychotics- would be mediated by the convergence of several susceptibility genes' effects on synaptic processing in brain microcircuitries, mainly on the glutamate synapse.
doi:10.1016/j.schres.2010.02.850
Poster 90 AKT1 GENE IS ASSOCIATED WITH ATTENTION AND BRAIN MORPHOLOGY IN PATIENTS WITH SCHIZOPHRENIA Yuka Yasuda1,2,3, Ryota Hashimoto1,2,3, Hironori Takamura2,3,4, Kazutaka Ohi2,3, Motoyuki Fukumoto2,3, Kiyotaka Nemoto5, Takashi Ohnishi6, Hidenaga Yamamori2,7, Hidetoshi Takahashi2,3,