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Biomarkers In Schizophrenia: A Focus On Blood Based Theranostics
S398
Abstracts of the XXIV World Congress of Psychiatric Genetics (WCPG) 2016
5
Melbourne Neuropsychiatry Centre, The University of Melbourne & Melbourne Health, Melbourne, Australia 6 Monash Alfred Psychiatry Research Centre (MAPrc), The Alfred Hospital and Central Clinical School, Monash University, Melbourne, Australia; Brain and Psychological Sciences Research Centre (BPsyC), Faculty of Health, Arts and Design, School of Health Sciences, Swinburne University, Melbourne, Australia; St Vincent’s Mental Health, Melbourne, Australia Background: Despite cognitive deficits being recognised as a core feature of schizophrenia (Sz), comprehensive understanding of the underlying aetiology remains elusive. Evidence has implicated a dysfunctional muscarinic system in contributing to the executive functioning (EF) deficits prevalent in Sz. Two independent investigations have investigated a SNP at the M1 receptor gene c.267C (rs2067477) that reportedly spares EF capabilities in Sz. Both studies indicated that patients who were heterozygous at c.267C made less perseverative errors on the Wisconsin Card Sorting Test (WCST) as compared to the homozygous group. This SNP has not been investigated beyond the WCST nor has the influence on cognition been explored in a healthy population. In both a Sz and healthy control sample, the current study sought to determine whether the rs2067477 genotype influences EF outside of that documented using the WCST. To provide a more holistic understanding of the influence M1 receptor sequence variation is having in Sz, the present study explored if differences in the genotype is associated with differential changes in cortical thickness of a number of EF-critical brain regions. Methods: Study 1: Genotype and neuropsychological data were obtained from 70 Sz/schizoaffective (SzA) patients and 165 healthy controls. Participants completed the Mazes and Spatial Span Backwards sub-tests of the MATRICS consensus cognitive battery as part of an ongoing investigation. Study 2: Imaging and genotype data were obtained from 176 Sz/SzA patients and 109 healthy controls from the Australian Schizophrenia Research Bank. Image preprocessing and Surfaced-based morphometry was performed using the FreeSurfer analysis suite. Results: Study 1: For the Mazes, only a significant main effect of group was returned, with healthy controls outperforming patients. Furthermore, a significant main effect of group and significant group by genotype interaction was returned for Spatial Span Backwards performance. In contrast to previous findings patients who were homozygous outperformed the heterozygous group, whilst homozygous and heterozygous healthy controls both equally outperformed the patient group. Study 2: Group-based statistical analysis across left and right hemispheres for five brain regions (anterior cingulate, rostral middle frontal gyrus, pars opercularis/triangularis/
orbitalis) revealed no significant differences in grey matter thickness across genotype. Similarly, no significant group by genotype interactions were returned for any of the five brain regions included in the analysis. An additional exploratory analysis was performed using all 33 bilateral brain regions produced by the FreeSurfer analysis suite, with no significant results being returned. Discussion: These preliminary results suggest that our current understanding of the rs2067477 genotype variation is not comprehensive enough, revealing a conflicting pattern of EF-rs20767477 genotype in schizophrenia compared to that previously documented. Furthermore, whilst this is the first study to investigate M1 receptor gene variation effects on EF in healthy controls, it appears that the association is disease specific, however more comprehensive investigations are required and recommended. Additional studies are likewise required to examine if rs2067477 genotype variation is associated with differential changes in brain structure in schizophrenia, as the present study was unable to identify any changes in cortical grey matter thickness.
Disclosure Nothing to Disclose. http://dx.doi.org/10.1016/j.euroneuro.2016.09.436
M46. BIOMARKERS IN SCHIZOPHRENIA: A FOCUS ON BLOOD BASED THERANOSTICS
Sosin Dmitriy1, Nasyrova Regina1, Taraskina Anastasia2, Ershov Evgeny3, Sosina Kristina1, Zabotina Anna4, Grunina Maria5, Pchelina Maria6, Krupitsky Evgeny1 1
Saint Petersburg Bekhterev Research Psychoneurological Institute 2 Saint Petersburg Bekhterev Research Psychoneurological Institute; First Saint Petersburg Pavlov State medical University; National Research Centre “Kurchatov Institute” B.P. Konstantinov Petersburg Nuclear Physics Institute 3 Saint Petersburg Psychiatric Hospital №1 named after P.P. Kaschenko 4 First Saint Petersburg Pavlov State medical University; National Research Centre “Kurchatov Institute” B.P. Konstantinov Petersburg Nuclear Physics Institute 5 National Research Centre “Kurchatov Institute” B.P. Konstantinov Petersburg Nuclear Physics Institute 6 First Saint Petersburg Pavlov State medical University
Abstracts of the XXIV World Congress of Psychiatric Genetics (WCPG) 2016 Background: Identification of biomarkers that can be used as predictors of treatment response in schizophrenic patients might be an important step towards development of personalized treatment approach to this disease. Currently, there is a growing body of research on blood-based biomarkers to monitor the effects of pharmacological treatment of the neuropsychiatric diseases (including schizophrenia). However, studies on the longitudinal changes in peripheral monoamine related molecules necessary to address this hypothesis are scarce. The dominant «dopamine hyperfunction hypothesis» has been supported by molecular, pharmacological and clinical evidence for over 40 years. Dopamine receptors are key elements of the dopaminergic system. Serotonin 5-HT2 receptors modulate the dopamine function. Moreover, most antipsychotics have an affinity for these receptors. Therefore, the purpose of this study was to explore the relations between mRNA levels of genes of dopamine D4 receptors and 5-hydroxytryptamine receptor 2A in peripheral blood mononuclear cells on the one hand, and treatment effect of antipsychotics in schizophrenic patients on the other hand. Methods: Study sample: 52 men with first episode of schizophrenia according to ICD-10 treated with olanzapine or haloperidol (monotherapy) (mean age 26,4 7 6,2 and 29,4 7 8,1, respectively). Total mRNA was isolated from unfractionated PBMCs and was performed to cDNA by using kits Qiagen. mRNA expression was determined by the fluorogenic TaqMan approach. The efficacy of treatment was assessed with PANSS. Assessments were done before treatment (V1) as well as by days 14 and 28 after administration of antipsychotic (V2, V3). Statistical analysis was performed using statistical software SPSS version 21 (IBM, USA). As the data on mRNA levels was not normally distributed, non-parametric tests were employed. The Kruskal-Wallis or Mann-Whitney tests were performed to compare expression levels of DRD4, 5HTR2A mRNA among the both groups of patients and various visits. Spearman`s correlation analysis was used to analyze the relationship between the mRNA levels of the two target genes and the five factor scores of the PANSS. The data is show as the mean 7 SEM. Results: Positive response to treatment (reduction of general assessment on PANSS, po0.001) was registered in both groups – regardless of the medication. No significant differences in mRNA expression levels of DRD4 and 5HTR2A in PBMCs were found between patients treated with olanzapine and on haloperidol at V1: 8,31 7 2,39 vs 10,34 7 2,85, p= 0,74 and 4,69 7 1,64 vs 4,6 7 1,22, p= 0,25, respectively. Against the background of antipsychotic therapy a significant positive correlation between baseline (V1) 5HTR2A mRNA levels on the one hand and score of the PANSS on the other hand were found only in patients treated with olanzapine (r= 0,375, p=0,049 and r=0,442, p=0,024, for V2, V3, respectively). Discussion: These finding suggest that 5HTR2A mRNA levels in PBMCs of schizophrenic patients before treatment might be a potential diagnostic biomarker of the efficacy of olanzapine therapy. The study was supported with the grant of Russian Science Foundation (14-15-00904).
S399
Disclosure Nothing to Disclose. http://dx.doi.org/10.1016/j.euroneuro.2016.09.437
M47. WHOLE EXOME SEQUENCING OF AFFECTED INDIVIDUALS FROM LARGE CONSANGUINEOUS PEDIGREES WITH PSYCHOTIC/AFFECTIVE DISORDERS FROM PAKISTAN
Qin He1, Ilyass Hajji2, Daniel Jimenez2, Souhila Benbetka2, Amelie Johnson2, Alexandre Dionne-Laporte3, Dan Spiegelman3, Ridha Joober4, Marie-Pierre Dubé5, Lynn DeLisi6, Guy A. Rouleau3, Lan Xiong7 1
University of Montreal, Canada Centre de recherche, Institut universitaire en santé mentale de Montréal, University of Montreal, Canada 3 Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada 4 Douglas Mental Health University Institute, McGill University, Montreal, Canada 5 Statistical Genetics Research Group, Montreal Heart Institute, Montreal, Canada 6 VA Boston Healthcare 7 Centre de recherche, Institut universitaire en santé mentale de Montréal, Montréal, Canada, Département de psychiatrie, Université de Montréal, Montreal, Canada 2
Background: For historical, religious, cultural, and social reasons, Pakistan has the highest rate of consanguineous marriage in the world, which have generated some large multiplex pedigrees clustering severely affected individuals with major psychiatric disorders. Such large consanguineous unions may offer a unique opportunity to identify, and characterize genetic risk factors associated with severe psychotic/affective disorders, as well as the mode of inheritance and underlying genetic mechanisms. Methods: 10 multiplex pedigrees aggregated with psychotic/affective disorders were included in the study. Exome capturing was performed using Agilent SureSelect™ Human All Exon Kits for 118 affected individuals, and sequenced by HiSeq2000 at McGill University and Génome Québec Innovation Centre. Sequence data was processed, aligned and variants called using standard bioinformatic pipeline, with extensive relevant annotations, including the functional effects and deleteriousness of the variants, population frequencies, and relevant phenotypic information. Results: I. Selection of potential candidate variants/genes: (1) In total, 846,266 variants were identified in 118 exomes
Abstracts of the XXIV World Congress of Psychiatric Genetics (WCPG) 2016
5
Melbourne Neuropsychiatry Centre, The University of Melbourne & Melbourne Health, Melbourne, Australia 6 Monash Alfred Psychiatry Research Centre (MAPrc), The Alfred Hospital and Central Clinical School, Monash University, Melbourne, Australia; Brain and Psychological Sciences Research Centre (BPsyC), Faculty of Health, Arts and Design, School of Health Sciences, Swinburne University, Melbourne, Australia; St Vincent’s Mental Health, Melbourne, Australia Background: Despite cognitive deficits being recognised as a core feature of schizophrenia (Sz), comprehensive understanding of the underlying aetiology remains elusive. Evidence has implicated a dysfunctional muscarinic system in contributing to the executive functioning (EF) deficits prevalent in Sz. Two independent investigations have investigated a SNP at the M1 receptor gene c.267C (rs2067477) that reportedly spares EF capabilities in Sz. Both studies indicated that patients who were heterozygous at c.267C made less perseverative errors on the Wisconsin Card Sorting Test (WCST) as compared to the homozygous group. This SNP has not been investigated beyond the WCST nor has the influence on cognition been explored in a healthy population. In both a Sz and healthy control sample, the current study sought to determine whether the rs2067477 genotype influences EF outside of that documented using the WCST. To provide a more holistic understanding of the influence M1 receptor sequence variation is having in Sz, the present study explored if differences in the genotype is associated with differential changes in cortical thickness of a number of EF-critical brain regions. Methods: Study 1: Genotype and neuropsychological data were obtained from 70 Sz/schizoaffective (SzA) patients and 165 healthy controls. Participants completed the Mazes and Spatial Span Backwards sub-tests of the MATRICS consensus cognitive battery as part of an ongoing investigation. Study 2: Imaging and genotype data were obtained from 176 Sz/SzA patients and 109 healthy controls from the Australian Schizophrenia Research Bank. Image preprocessing and Surfaced-based morphometry was performed using the FreeSurfer analysis suite. Results: Study 1: For the Mazes, only a significant main effect of group was returned, with healthy controls outperforming patients. Furthermore, a significant main effect of group and significant group by genotype interaction was returned for Spatial Span Backwards performance. In contrast to previous findings patients who were homozygous outperformed the heterozygous group, whilst homozygous and heterozygous healthy controls both equally outperformed the patient group. Study 2: Group-based statistical analysis across left and right hemispheres for five brain regions (anterior cingulate, rostral middle frontal gyrus, pars opercularis/triangularis/
orbitalis) revealed no significant differences in grey matter thickness across genotype. Similarly, no significant group by genotype interactions were returned for any of the five brain regions included in the analysis. An additional exploratory analysis was performed using all 33 bilateral brain regions produced by the FreeSurfer analysis suite, with no significant results being returned. Discussion: These preliminary results suggest that our current understanding of the rs2067477 genotype variation is not comprehensive enough, revealing a conflicting pattern of EF-rs20767477 genotype in schizophrenia compared to that previously documented. Furthermore, whilst this is the first study to investigate M1 receptor gene variation effects on EF in healthy controls, it appears that the association is disease specific, however more comprehensive investigations are required and recommended. Additional studies are likewise required to examine if rs2067477 genotype variation is associated with differential changes in brain structure in schizophrenia, as the present study was unable to identify any changes in cortical grey matter thickness.
Disclosure Nothing to Disclose. http://dx.doi.org/10.1016/j.euroneuro.2016.09.436
M46. BIOMARKERS IN SCHIZOPHRENIA: A FOCUS ON BLOOD BASED THERANOSTICS
Sosin Dmitriy1, Nasyrova Regina1, Taraskina Anastasia2, Ershov Evgeny3, Sosina Kristina1, Zabotina Anna4, Grunina Maria5, Pchelina Maria6, Krupitsky Evgeny1 1
Saint Petersburg Bekhterev Research Psychoneurological Institute 2 Saint Petersburg Bekhterev Research Psychoneurological Institute; First Saint Petersburg Pavlov State medical University; National Research Centre “Kurchatov Institute” B.P. Konstantinov Petersburg Nuclear Physics Institute 3 Saint Petersburg Psychiatric Hospital №1 named after P.P. Kaschenko 4 First Saint Petersburg Pavlov State medical University; National Research Centre “Kurchatov Institute” B.P. Konstantinov Petersburg Nuclear Physics Institute 5 National Research Centre “Kurchatov Institute” B.P. Konstantinov Petersburg Nuclear Physics Institute 6 First Saint Petersburg Pavlov State medical University
Abstracts of the XXIV World Congress of Psychiatric Genetics (WCPG) 2016 Background: Identification of biomarkers that can be used as predictors of treatment response in schizophrenic patients might be an important step towards development of personalized treatment approach to this disease. Currently, there is a growing body of research on blood-based biomarkers to monitor the effects of pharmacological treatment of the neuropsychiatric diseases (including schizophrenia). However, studies on the longitudinal changes in peripheral monoamine related molecules necessary to address this hypothesis are scarce. The dominant «dopamine hyperfunction hypothesis» has been supported by molecular, pharmacological and clinical evidence for over 40 years. Dopamine receptors are key elements of the dopaminergic system. Serotonin 5-HT2 receptors modulate the dopamine function. Moreover, most antipsychotics have an affinity for these receptors. Therefore, the purpose of this study was to explore the relations between mRNA levels of genes of dopamine D4 receptors and 5-hydroxytryptamine receptor 2A in peripheral blood mononuclear cells on the one hand, and treatment effect of antipsychotics in schizophrenic patients on the other hand. Methods: Study sample: 52 men with first episode of schizophrenia according to ICD-10 treated with olanzapine or haloperidol (monotherapy) (mean age 26,4 7 6,2 and 29,4 7 8,1, respectively). Total mRNA was isolated from unfractionated PBMCs and was performed to cDNA by using kits Qiagen. mRNA expression was determined by the fluorogenic TaqMan approach. The efficacy of treatment was assessed with PANSS. Assessments were done before treatment (V1) as well as by days 14 and 28 after administration of antipsychotic (V2, V3). Statistical analysis was performed using statistical software SPSS version 21 (IBM, USA). As the data on mRNA levels was not normally distributed, non-parametric tests were employed. The Kruskal-Wallis or Mann-Whitney tests were performed to compare expression levels of DRD4, 5HTR2A mRNA among the both groups of patients and various visits. Spearman`s correlation analysis was used to analyze the relationship between the mRNA levels of the two target genes and the five factor scores of the PANSS. The data is show as the mean 7 SEM. Results: Positive response to treatment (reduction of general assessment on PANSS, po0.001) was registered in both groups – regardless of the medication. No significant differences in mRNA expression levels of DRD4 and 5HTR2A in PBMCs were found between patients treated with olanzapine and on haloperidol at V1: 8,31 7 2,39 vs 10,34 7 2,85, p= 0,74 and 4,69 7 1,64 vs 4,6 7 1,22, p= 0,25, respectively. Against the background of antipsychotic therapy a significant positive correlation between baseline (V1) 5HTR2A mRNA levels on the one hand and score of the PANSS on the other hand were found only in patients treated with olanzapine (r= 0,375, p=0,049 and r=0,442, p=0,024, for V2, V3, respectively). Discussion: These finding suggest that 5HTR2A mRNA levels in PBMCs of schizophrenic patients before treatment might be a potential diagnostic biomarker of the efficacy of olanzapine therapy. The study was supported with the grant of Russian Science Foundation (14-15-00904).
S399
Disclosure Nothing to Disclose. http://dx.doi.org/10.1016/j.euroneuro.2016.09.437
M47. WHOLE EXOME SEQUENCING OF AFFECTED INDIVIDUALS FROM LARGE CONSANGUINEOUS PEDIGREES WITH PSYCHOTIC/AFFECTIVE DISORDERS FROM PAKISTAN
Qin He1, Ilyass Hajji2, Daniel Jimenez2, Souhila Benbetka2, Amelie Johnson2, Alexandre Dionne-Laporte3, Dan Spiegelman3, Ridha Joober4, Marie-Pierre Dubé5, Lynn DeLisi6, Guy A. Rouleau3, Lan Xiong7 1
University of Montreal, Canada Centre de recherche, Institut universitaire en santé mentale de Montréal, University of Montreal, Canada 3 Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada 4 Douglas Mental Health University Institute, McGill University, Montreal, Canada 5 Statistical Genetics Research Group, Montreal Heart Institute, Montreal, Canada 6 VA Boston Healthcare 7 Centre de recherche, Institut universitaire en santé mentale de Montréal, Montréal, Canada, Département de psychiatrie, Université de Montréal, Montreal, Canada 2
Background: For historical, religious, cultural, and social reasons, Pakistan has the highest rate of consanguineous marriage in the world, which have generated some large multiplex pedigrees clustering severely affected individuals with major psychiatric disorders. Such large consanguineous unions may offer a unique opportunity to identify, and characterize genetic risk factors associated with severe psychotic/affective disorders, as well as the mode of inheritance and underlying genetic mechanisms. Methods: 10 multiplex pedigrees aggregated with psychotic/affective disorders were included in the study. Exome capturing was performed using Agilent SureSelect™ Human All Exon Kits for 118 affected individuals, and sequenced by HiSeq2000 at McGill University and Génome Québec Innovation Centre. Sequence data was processed, aligned and variants called using standard bioinformatic pipeline, with extensive relevant annotations, including the functional effects and deleteriousness of the variants, population frequencies, and relevant phenotypic information. Results: I. Selection of potential candidate variants/genes: (1) In total, 846,266 variants were identified in 118 exomes