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Poster #T149 LINE1 POLYMORPHIC RETROTRANSPOSITIONS IN SCHIZOPHRENIA
Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
Poster #T149 LINE1 POLYMORPHIC RETROTRANSPOSITIONS IN SCHIZOPHRENIA Fabio Macciardi 1 , Guia Guffanti 2 , James Fallon 3 , Theo G.M. van Erp 3 , Michele Pato 4 , Steven G. Potkin 3 , James A. Knowles 4 , Steven A. McCarroll 5 , Carlos N. Pato 4 , Simona Gaudi 6 1 UC Irvine; 2 Columbia University; 3 University of California, Irvine; 4 University of Southern California; 5 Broad Institute, MIT and Harvard University; 6 Istituto Superiore di Sanita’, Roma Background: Genome-wide association studies (GWAS) have produced a growing number of replicated Single Nucleotide Polymorphism (SNP) associations in complex psychiatric diseases, including schizophrenia, autism, and bipolar disorder. In most cases SNPs, Insertions/Deletions (Indels) and Copy Number Variants (CNVs) associated with complex psychiatric traits are mostly found in non-gene/non-coding regions and map predominantly in association with regulatory elements, which include both Transposable Elements (TEs) and TE-derived elements, like for example long intergenic non-coding RNAs (lincRNAs) or microRNA (miRNAs). Evidence is slowly accumulating that TEs could be involved in structural genomic variants and can contribute to the genetic component of vulnerability to psychiatric disorders. Although findings have been mostly anecdotal and despite our still initial and limited knowledge, active retrotransposition of LINEs, Alus and SVAs has been identified in several different human brain regions. The provocative hypothesis that we can derive is that active mobilization and differential expression of TEs can be essential in normal brain development (and adult physiology), and possibly in psychiatric disorders. Methods: We have sequenced the whole genome of ∼1,000 SZ cases ad matched controls from our large sample of cases and controls that we collected over several years and include some mid-size families where schizophrenia segregates. For both cases and controls we are characterizing their genomic architecture, with a special interest in non-coding regulatory regions that harbor the largest number of association signals with the disease. In addition to the already large number of positively associated SNPs that fall within already known TEs as we understand from the last release of the human genome annotation (hg19), we are also looking for new TE retrotranspositions. Building from our sequenced families and using the ad hoc pipeline we have developed, we can identify both retrotransposition polymorphisms (RIPs – Retrotransposon Insertion Polymorphisms, i.e. new TE insertions that are transmitted from parent to their children) and “de novo” TE insertions that can arise in affected children, but are not present in parents. Results: We found that more than 70% of SNP association signals fall within already known TEs or lincRNAs rather than within the boundaries of coding genes. Moreover, in many cases, the associated SNPs are far away from “genes”. Thus, using these associations as proxies for genes should be considered only a consequence of our current practice of binning the whole genome into “gene” regions rather than based on a carefully annotated gene-mapping procedure. When looking at RIPs in the few families that we have available from sequencing, we have observed that new TE insertions are more common than we previously thought, for all TE classes. Gene network analyses suggest predominant dysfunctions in Neurodevelopment, supporting a developmental hypothesis for Schizophrenia. Discussion: With next-generation whole-genome approaches, we expect that our understanding of the relationship between TEs and psychiatric disorders will greatly improve. Current technologies offer a unique opportunity to integrate DNA and RNA sequencing data to explain the potential effects of RIPs on gene expression. We believe that understanding the mechanisms that finely dysregulate the genome and transcriptome in psychiatric disorders is of pivotal relevance
Poster #T150 DEPERSONALIZATION IN THE SCHIZOPHRENIA SPECTRUM: LACK OF SENSE OF AGENCY AT THE CURRENT TIME OF ACTION DUE TO IMPAIRED PREDICTION Takaki Maeda 1 , Keisuke Takahata 2 , Tsukasa Okimura 1 , Akihiro Koreki 1 , Sho Moriguchi 1 , Masaru Mimura 1 , Motoichiro Kato 1 1 Department of Neuropsychiatry, Keio University School of Medicine; 2 Molecular Neuroimaging Program, Molecular Imaging Center, National Institute of Radiological Sciences
S343
Background: Depersonalization refers to phenomena in which subjects complains that their mental activities, bodies, and/or surrounding environments are changed in their quality, so as to be unreal and strange. The pathophysiologic mechanisms underlying depersonalization have long been historically discussed from various standpoints, however, the theory for core pathophysiology is still controversial. In the present study, we investigated the nature of depersonalization especially in the schizophrenia spectrum. Regarding depersonalization in schizophrenia, the phenomena is one of characteristic symptoms in early stages of the illness, and is regarded as the prototype of self-disturbances in schizophrenia. Neurobiological research of depersonalization recently focused on a profound disruption of self-awareness mainly characterized by feeling of subjective emotional numbing and feeling of disembodiment including sense of body-ownership and agency (Sierra 2011). We investigated the cognitive mechanisms of depersonalization from the perspective of sense of agency (SoA). SoA is defined as a feeling that a person causes and controls his/her own actions and their effects on the outside world, and it is one of the essential aspects of self-consciousness). Moreover, SoA has been recognized as an operational measure for evaluating self-disturbances in schizophrenia (Frith et al., 2000; Lindner et al., 2005; Maeda et al., 2012; 2013), and aberrant SoA in schizophrenia has been physiologically explained based on the forward model in self-monitoring for intentional actions. Methods: We investigated patterns of SoA in the schizotypal subjects with depersonalization by means of our original task: sense of agency task (Keio method) (Maeda et al., 2012; 2013) which is a agency attribution task that evaluates explicit experience of the temporal causal relation between an intentional action (Key press) and an external event on the PC screen. Various temporal delays of 0 to 1,000 ms were randomly introduced in the computer manipulation. Results: We demonstrated the specific patterns of strikingly attenuated SoA in no-delay condition in subjects with depersonalization, i.e., the lack of SoA in the current time of actions. This means that agentic “cleft” between self and the external world could exist during intentional actions. This could never be found in chronic schizophrenia in our previous studies. Therefore, these curious findings are supposed to be specific findings in subjects characterized with depersonalization in early stage of schizophrenia spectrum disorders. Discussion: From the perspective of the Forward model, the lack of SoA in the current time of action could be due to delayed prediction signals. We hypothesized the delayed prediction signal would be the core pathophysiological mechanisms for the schizophrenia spectrum, and pure form of the inadequate predictions could be seen without any compensatory processes in the early stage of the illness. Clinically, clarifying the specific nature of the depersonalization in early stage of the schizophrenia spectrum disorders could have significant implications for a profound understanding of pathophysiology of schizophrenia and could have critical role in its precise diagnosis in early intervention.
Poster #T151 CHILDHOOD AND ADOLESCENCE SYMPTOMS PRECEDING FIRST EPISODE PSYCHOSIS IN A GENERAL POPULATION BASED NORTHERN FINLAND 1986 BIRTH COHORT Pirjo H. Mäki 1,2 , Tatu-Pekka Laakso 1 , Marika Kaakinen 3 , Jouko Miettunen 1 , Graham Murray 4 , Irma Moilanen 5 , Tuula Hurtig 6 , Matti Joukamaa 7 , Markus Heinimaa 8 , Sebastian Therman 9 , Juha M. Veijola 10 1 University of Oulu, Finland; 2 Department of Psychiatry, Oulu University Hospital, Finland; 3 Institute of Health Sciences, University of Oulu, Finland; 4 University of Cambridge; 5 Department of Psychiatry, University of Oulu and Clinic of Child Psychiatry, University of Oulu, Finland; 6 Institute of Health Sciences, University of Oulu and Clinic of Child Psychiatry, University of Oulu, Finland; 7 Department of Psychiatry, Tampere University Hospital, Tampere, Finland; 8 Department of Psychiatry, University of Turku; 9 Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland; 10 Department of Psychiatry, University of Oulu and Oulu University Hospital, Finland Background: The onset for psychotic disorder is often in adolescence. At least some of them are neurodevelopmental disorders. Prospective general population based reports are lacking on specific symptoms in childhood and adolescence predicting clinically treated first episode psychosis in youth
Poster #T149 LINE1 POLYMORPHIC RETROTRANSPOSITIONS IN SCHIZOPHRENIA Fabio Macciardi 1 , Guia Guffanti 2 , James Fallon 3 , Theo G.M. van Erp 3 , Michele Pato 4 , Steven G. Potkin 3 , James A. Knowles 4 , Steven A. McCarroll 5 , Carlos N. Pato 4 , Simona Gaudi 6 1 UC Irvine; 2 Columbia University; 3 University of California, Irvine; 4 University of Southern California; 5 Broad Institute, MIT and Harvard University; 6 Istituto Superiore di Sanita’, Roma Background: Genome-wide association studies (GWAS) have produced a growing number of replicated Single Nucleotide Polymorphism (SNP) associations in complex psychiatric diseases, including schizophrenia, autism, and bipolar disorder. In most cases SNPs, Insertions/Deletions (Indels) and Copy Number Variants (CNVs) associated with complex psychiatric traits are mostly found in non-gene/non-coding regions and map predominantly in association with regulatory elements, which include both Transposable Elements (TEs) and TE-derived elements, like for example long intergenic non-coding RNAs (lincRNAs) or microRNA (miRNAs). Evidence is slowly accumulating that TEs could be involved in structural genomic variants and can contribute to the genetic component of vulnerability to psychiatric disorders. Although findings have been mostly anecdotal and despite our still initial and limited knowledge, active retrotransposition of LINEs, Alus and SVAs has been identified in several different human brain regions. The provocative hypothesis that we can derive is that active mobilization and differential expression of TEs can be essential in normal brain development (and adult physiology), and possibly in psychiatric disorders. Methods: We have sequenced the whole genome of ∼1,000 SZ cases ad matched controls from our large sample of cases and controls that we collected over several years and include some mid-size families where schizophrenia segregates. For both cases and controls we are characterizing their genomic architecture, with a special interest in non-coding regulatory regions that harbor the largest number of association signals with the disease. In addition to the already large number of positively associated SNPs that fall within already known TEs as we understand from the last release of the human genome annotation (hg19), we are also looking for new TE retrotranspositions. Building from our sequenced families and using the ad hoc pipeline we have developed, we can identify both retrotransposition polymorphisms (RIPs – Retrotransposon Insertion Polymorphisms, i.e. new TE insertions that are transmitted from parent to their children) and “de novo” TE insertions that can arise in affected children, but are not present in parents. Results: We found that more than 70% of SNP association signals fall within already known TEs or lincRNAs rather than within the boundaries of coding genes. Moreover, in many cases, the associated SNPs are far away from “genes”. Thus, using these associations as proxies for genes should be considered only a consequence of our current practice of binning the whole genome into “gene” regions rather than based on a carefully annotated gene-mapping procedure. When looking at RIPs in the few families that we have available from sequencing, we have observed that new TE insertions are more common than we previously thought, for all TE classes. Gene network analyses suggest predominant dysfunctions in Neurodevelopment, supporting a developmental hypothesis for Schizophrenia. Discussion: With next-generation whole-genome approaches, we expect that our understanding of the relationship between TEs and psychiatric disorders will greatly improve. Current technologies offer a unique opportunity to integrate DNA and RNA sequencing data to explain the potential effects of RIPs on gene expression. We believe that understanding the mechanisms that finely dysregulate the genome and transcriptome in psychiatric disorders is of pivotal relevance
Poster #T150 DEPERSONALIZATION IN THE SCHIZOPHRENIA SPECTRUM: LACK OF SENSE OF AGENCY AT THE CURRENT TIME OF ACTION DUE TO IMPAIRED PREDICTION Takaki Maeda 1 , Keisuke Takahata 2 , Tsukasa Okimura 1 , Akihiro Koreki 1 , Sho Moriguchi 1 , Masaru Mimura 1 , Motoichiro Kato 1 1 Department of Neuropsychiatry, Keio University School of Medicine; 2 Molecular Neuroimaging Program, Molecular Imaging Center, National Institute of Radiological Sciences
S343
Background: Depersonalization refers to phenomena in which subjects complains that their mental activities, bodies, and/or surrounding environments are changed in their quality, so as to be unreal and strange. The pathophysiologic mechanisms underlying depersonalization have long been historically discussed from various standpoints, however, the theory for core pathophysiology is still controversial. In the present study, we investigated the nature of depersonalization especially in the schizophrenia spectrum. Regarding depersonalization in schizophrenia, the phenomena is one of characteristic symptoms in early stages of the illness, and is regarded as the prototype of self-disturbances in schizophrenia. Neurobiological research of depersonalization recently focused on a profound disruption of self-awareness mainly characterized by feeling of subjective emotional numbing and feeling of disembodiment including sense of body-ownership and agency (Sierra 2011). We investigated the cognitive mechanisms of depersonalization from the perspective of sense of agency (SoA). SoA is defined as a feeling that a person causes and controls his/her own actions and their effects on the outside world, and it is one of the essential aspects of self-consciousness). Moreover, SoA has been recognized as an operational measure for evaluating self-disturbances in schizophrenia (Frith et al., 2000; Lindner et al., 2005; Maeda et al., 2012; 2013), and aberrant SoA in schizophrenia has been physiologically explained based on the forward model in self-monitoring for intentional actions. Methods: We investigated patterns of SoA in the schizotypal subjects with depersonalization by means of our original task: sense of agency task (Keio method) (Maeda et al., 2012; 2013) which is a agency attribution task that evaluates explicit experience of the temporal causal relation between an intentional action (Key press) and an external event on the PC screen. Various temporal delays of 0 to 1,000 ms were randomly introduced in the computer manipulation. Results: We demonstrated the specific patterns of strikingly attenuated SoA in no-delay condition in subjects with depersonalization, i.e., the lack of SoA in the current time of actions. This means that agentic “cleft” between self and the external world could exist during intentional actions. This could never be found in chronic schizophrenia in our previous studies. Therefore, these curious findings are supposed to be specific findings in subjects characterized with depersonalization in early stage of schizophrenia spectrum disorders. Discussion: From the perspective of the Forward model, the lack of SoA in the current time of action could be due to delayed prediction signals. We hypothesized the delayed prediction signal would be the core pathophysiological mechanisms for the schizophrenia spectrum, and pure form of the inadequate predictions could be seen without any compensatory processes in the early stage of the illness. Clinically, clarifying the specific nature of the depersonalization in early stage of the schizophrenia spectrum disorders could have significant implications for a profound understanding of pathophysiology of schizophrenia and could have critical role in its precise diagnosis in early intervention.
Poster #T151 CHILDHOOD AND ADOLESCENCE SYMPTOMS PRECEDING FIRST EPISODE PSYCHOSIS IN A GENERAL POPULATION BASED NORTHERN FINLAND 1986 BIRTH COHORT Pirjo H. Mäki 1,2 , Tatu-Pekka Laakso 1 , Marika Kaakinen 3 , Jouko Miettunen 1 , Graham Murray 4 , Irma Moilanen 5 , Tuula Hurtig 6 , Matti Joukamaa 7 , Markus Heinimaa 8 , Sebastian Therman 9 , Juha M. Veijola 10 1 University of Oulu, Finland; 2 Department of Psychiatry, Oulu University Hospital, Finland; 3 Institute of Health Sciences, University of Oulu, Finland; 4 University of Cambridge; 5 Department of Psychiatry, University of Oulu and Clinic of Child Psychiatry, University of Oulu, Finland; 6 Institute of Health Sciences, University of Oulu and Clinic of Child Psychiatry, University of Oulu, Finland; 7 Department of Psychiatry, Tampere University Hospital, Tampere, Finland; 8 Department of Psychiatry, University of Turku; 9 Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland; 10 Department of Psychiatry, University of Oulu and Oulu University Hospital, Finland Background: The onset for psychotic disorder is often in adolescence. At least some of them are neurodevelopmental disorders. Prospective general population based reports are lacking on specific symptoms in childhood and adolescence predicting clinically treated first episode psychosis in youth