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IMAGING GENETICS TOWARDS A NEW DIAGNOSIS OF SCHIZOPHRENIA
S872
Abstracts
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.164
SA93. IMAGING GENETICS TOWARDS A NEW DIAGNOSIS OF SCHIZOPHRENIA n
Wenhao Jiang , Jessica Turner Georgia State University
future effort. Firstly, more brain measures need to be introduced, and the criteria of intermediate phenotypes should be carefully checked. The specificity of brain alterations will need careful examination in clinical settings. Secondly, more genetic factors need to be collected. Polygenic risk scores, parallel independent component analysis and other clustering method may be promising. Factors other than SNPs, such as copy number variations and regulatory factors will need to be included. Finally, imaging genetics will need compatible phenomenological assessment scales which need not distinguish current diagnoses but provide a comprehensive scan of clinical features.
Background: Current diagnoses of Schizophrenia (SZ) and related psychiatric disorders are catalogued by phenomenological principles and clinical descriptions. Complicated gene and environmental factor interactions likely play an important role in the onset of SZ and induce great heterogeneity. This unclear etiology and heterogeneity prevent the establishing of accurate subgroups within SZ through clinical observation alone; simultaneously, the boundaries among psychiatric disorders previously drawn by phenomenological findings are merging because there is great overlap, especially in genetic variations and brain imaging findings. By characterizing and quantifying brain regions affected in psychiatric disorders, imaging genetics is a valuable research method to fulfill a new diagnostic system. We review contributions of imaging genetics to SZ diagnosis, limitations, and possible future directions. Methods: Among numerous imaging genetic studies, we reviewed recent studies with relatively clear and consistent findings. They were either done in task-phase imaging to indicate certain cognitive impairments of SZ, or the genes included were highlighted in SZ itself or an important cognitive domain related to SZ. Results: Some pioneering studies contribute to subtypes and disorder boundaries. The clustering study from Arnedo et al. formed correlations between disjoined networks of symptom groups and Single Nucleotide Polymorphism (SNP) sets, and it may be promising for future SZ subtypes. Bipolar-SZ Network on Intermediate Phenotypes studies combining various clinical biomarkers and brain imaging divided SZ, bipolar disorder and schizoaffective disorder into three different “biotypes” regardless original diagnoses, and it provided meaningful insight into the disorder boundaries. For imaging genetics research, large numbers of associations between functional imaging intermediate phenotypes and genes have been found in working memory, episodic memory, emotion, attention, cognitive control, and theory of mind in SZ or healthy risk allele carriers. Such associations were difficult to identify while using structural brains measures. Discussion: Imaging genetics will continue to shape the diagnosis of SZ and related disorders. However, there are still problems to solve. Most importantly, the logic behind imaging genetics has been questioned. Franke et al. reminds us the structural brain deficits believed to be important pathological alterations of SZ may reflect prenatal and later development environmental effects not specific to SZ, or the diagnostic category of SZ may not be uniformly organized. The following aspects need
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.165
SA94. A DIRECT REGULATORY LINK BETWEEN MICRORNA MIR-137 AND SHANK2 WITH IMPLICATIONS FOR NEUROPSYCHIATRIC DISORDERS n
Simone Berkel , Ana de Sena Cortabitarte, Flavia-Bianca Cristian, Christine Fischer, Gudrun Rappold Institute of Human Genetics Heidelberg
Background: The SHANK gene family encodes for postsynaptic scaffolding proteins with an important role at glutamatergic synapses in the brain and has been linked to a spectrum of neurodevelopmental disorders. The schizophrenia associated microRNA miR-137 and the SHANK genes converge on several levels, (a) both are expressed at the synapse, (b) both influence neuronal development, and (c) both have a strong link to neurodevelopmental and neuropsychiatric disorders like intellectual disability, autism and schizophrenia. This compiled evidence raised the question if the SHANKs might be targets of miR-137. Methods: The in silico analysis of all three SHANK genes identified a single, highly conserved binding site for miR-137 in the 3´UTR of SHANK2. Luciferase assays were carried out in a neuroblastoma cell line (SH-SY5Y) and in mouse primary hippocampal neurons to validate the putative binding site. MiR-137 was overexpressed or inhibited in hippocampal neurons and Shank2 expression was analyzed by qPCR and Western blot. In addition, we analyzed expression levels of experimentally validated miR-137 target genes in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia and control individuals using the RNA-seq data from the CommonMind Consortium. Results: We can show that miR-137 targets the 3´UTR of SHANK2 in a site-specific manner. Overexpression of miR137 significantly lowered endogenous Shank2 protein levels without detectable influence on mRNA level; conversely, the inhibition of miR-137 resulted in the increase of Shank2 protein in neuronal cells. To further support the link between miR-137 and schizophrenia, we compared the expression of mir-137 precursor and miR-137 target genes (including SHANK2) in the DLPFC of schizophrenia and control individuals. Almost one third (18/63; 29%) of validated miR-137 target genes showed significant
Abstracts
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.164
SA93. IMAGING GENETICS TOWARDS A NEW DIAGNOSIS OF SCHIZOPHRENIA n
Wenhao Jiang , Jessica Turner Georgia State University
future effort. Firstly, more brain measures need to be introduced, and the criteria of intermediate phenotypes should be carefully checked. The specificity of brain alterations will need careful examination in clinical settings. Secondly, more genetic factors need to be collected. Polygenic risk scores, parallel independent component analysis and other clustering method may be promising. Factors other than SNPs, such as copy number variations and regulatory factors will need to be included. Finally, imaging genetics will need compatible phenomenological assessment scales which need not distinguish current diagnoses but provide a comprehensive scan of clinical features.
Background: Current diagnoses of Schizophrenia (SZ) and related psychiatric disorders are catalogued by phenomenological principles and clinical descriptions. Complicated gene and environmental factor interactions likely play an important role in the onset of SZ and induce great heterogeneity. This unclear etiology and heterogeneity prevent the establishing of accurate subgroups within SZ through clinical observation alone; simultaneously, the boundaries among psychiatric disorders previously drawn by phenomenological findings are merging because there is great overlap, especially in genetic variations and brain imaging findings. By characterizing and quantifying brain regions affected in psychiatric disorders, imaging genetics is a valuable research method to fulfill a new diagnostic system. We review contributions of imaging genetics to SZ diagnosis, limitations, and possible future directions. Methods: Among numerous imaging genetic studies, we reviewed recent studies with relatively clear and consistent findings. They were either done in task-phase imaging to indicate certain cognitive impairments of SZ, or the genes included were highlighted in SZ itself or an important cognitive domain related to SZ. Results: Some pioneering studies contribute to subtypes and disorder boundaries. The clustering study from Arnedo et al. formed correlations between disjoined networks of symptom groups and Single Nucleotide Polymorphism (SNP) sets, and it may be promising for future SZ subtypes. Bipolar-SZ Network on Intermediate Phenotypes studies combining various clinical biomarkers and brain imaging divided SZ, bipolar disorder and schizoaffective disorder into three different “biotypes” regardless original diagnoses, and it provided meaningful insight into the disorder boundaries. For imaging genetics research, large numbers of associations between functional imaging intermediate phenotypes and genes have been found in working memory, episodic memory, emotion, attention, cognitive control, and theory of mind in SZ or healthy risk allele carriers. Such associations were difficult to identify while using structural brains measures. Discussion: Imaging genetics will continue to shape the diagnosis of SZ and related disorders. However, there are still problems to solve. Most importantly, the logic behind imaging genetics has been questioned. Franke et al. reminds us the structural brain deficits believed to be important pathological alterations of SZ may reflect prenatal and later development environmental effects not specific to SZ, or the diagnostic category of SZ may not be uniformly organized. The following aspects need
Disclosure: Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.08.165
SA94. A DIRECT REGULATORY LINK BETWEEN MICRORNA MIR-137 AND SHANK2 WITH IMPLICATIONS FOR NEUROPSYCHIATRIC DISORDERS n
Simone Berkel , Ana de Sena Cortabitarte, Flavia-Bianca Cristian, Christine Fischer, Gudrun Rappold Institute of Human Genetics Heidelberg
Background: The SHANK gene family encodes for postsynaptic scaffolding proteins with an important role at glutamatergic synapses in the brain and has been linked to a spectrum of neurodevelopmental disorders. The schizophrenia associated microRNA miR-137 and the SHANK genes converge on several levels, (a) both are expressed at the synapse, (b) both influence neuronal development, and (c) both have a strong link to neurodevelopmental and neuropsychiatric disorders like intellectual disability, autism and schizophrenia. This compiled evidence raised the question if the SHANKs might be targets of miR-137. Methods: The in silico analysis of all three SHANK genes identified a single, highly conserved binding site for miR-137 in the 3´UTR of SHANK2. Luciferase assays were carried out in a neuroblastoma cell line (SH-SY5Y) and in mouse primary hippocampal neurons to validate the putative binding site. MiR-137 was overexpressed or inhibited in hippocampal neurons and Shank2 expression was analyzed by qPCR and Western blot. In addition, we analyzed expression levels of experimentally validated miR-137 target genes in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia and control individuals using the RNA-seq data from the CommonMind Consortium. Results: We can show that miR-137 targets the 3´UTR of SHANK2 in a site-specific manner. Overexpression of miR137 significantly lowered endogenous Shank2 protein levels without detectable influence on mRNA level; conversely, the inhibition of miR-137 resulted in the increase of Shank2 protein in neuronal cells. To further support the link between miR-137 and schizophrenia, we compared the expression of mir-137 precursor and miR-137 target genes (including SHANK2) in the DLPFC of schizophrenia and control individuals. Almost one third (18/63; 29%) of validated miR-137 target genes showed significant