- Email: [email protected]
Novel Implications For RNA In Psychiatric Genetics
Abstracts Results: We propose that 1) as has been advocated for genomic studies of other medical conditions PG researchers should, at a minimum, offer findings generated in the course of research that are clinically valid, medically important, and medically actionable. When resources allow, PG researchers should also offer non-medically actionable findings, that we argue are “clinically valuable” such as: 2) clinically valid findings that help corroborate or reject a psychiatric diagnosis; 3) clinically valid findings that provide information about important health risks; and 4) “likely clinically valuable” findings such as variants of unknown significance that are rare, missense or nonsense variants in genomic loci known to be associated with a psychiatric or other disorder that may help explain a participant’s symptoms. Conclusions: Genomic testing raises complex challenges for investigators, such as how to manage the increasing amount of Clinically Relevant Findings (CRFs) emerging knowledge and novel technologies can generate. CRFs could impact participants’ health care by facilitating prevention, diagnosis, treatment selection, or a better understanding of the pathogenesis of a participant’s symptoms. Offering some CRFs could maximize the social utility of PG research by not only generating generalizable knowledge, but potentially directly benefiting those individuals who contribute to science by participating in these studies. We aim to spark a discussion about which CRFs should be offered considering the particularities of PG research and the potential risks and benefits to participants. Harmonizing RoR policies should help promote the benefits of responsible RoR.
Disclosure Nothing to disclose.
S719 Methods: Here we will show the ongoing projects on psychiatric genetics in the Paisa Population in both genetics of severe mental illness and pharmacogenetics of lithium response in bipolar disorder. Results: We will discuss the importance of genetic studies in a genetically isolated and how this potentially more homogeneous population may help to detect common and rare genetic variants underpinning severe mental illness and traits like lithium response. Conclusions: Genetics studies in isolated populations represent an important strategy in the mapping and understanding of genetic basis of complex disorders as bipolar disorder and other mental illnesses. We will show and discuss the ongoing psychiatric genetics studies in the Paisa Population from Colombia.
Disclosure Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.06.032
Saturday, October 14, 2017 10:00 a.m. - 11:30 a.m. Symposia Sessions NOVEL IMPLICATIONS FOR RNA IN PSYCHIATRIC GENETICS Carrie Wright (Chair)1, Murray Cairns (Co-chair)2, Daniel Weinberger (Discussant)1 1 2
http://dx.doi.org/10.1016/j.euroneuro.2017.06.031
RESEARCH EXPERIENCE IN PSYCHIATRIC GENETICS IN COLOMBIA: ONGOING STUDIES Ana María Díaz Zuluaga Universidad de Antioquia Abstract
Background: The “Paisa Population” is a genetically and culturally homogeneous population of Colombia which has been focus of genetics studies in neuropsychiatric disorders in the last decade. This population is highly affected by major mental disorders, especially bipolar disorder. Several studies have been performed trying to understand the genetic basis underlying the disease by evaluating extended pedigrees. Also, the first pharmacogenetic study in this special population is being carried out with the aim to identify genetic variants associated with lithium response in the treatment of bipolar disorder.
Lieber Institute for Brain Development University of Newcastle
Overall Abstract Over the past few decades our understanding of the complexity of both psychiatric genetics and gene expression has expanded exponentially. It is now understood that multiple genes and various genetic factors contribute to the risk for psychiatric disorders. It is also now understood that a variety of non-coding RNA species and RNA-modifying proteins work in concert to modulate gene expression with unexpectedly high levels of nuance. Challenging how we think about gene expression, our awareness of the influence of RNA continues to evolve and build as new non-coding RNA species are discovered, novel functions are attributed to the more characterized non-coding RNAs, and additional interactions between non-coding and coding RNAs are elucidated. The involvement of such RNA based mechanisms in regulating pathways contributing to brain function and disease continues to be uncovered and may provide avenues for critical breakthroughs in our understanding and treatment of psychiatric disorders. This symposium will explore the implications of a variety of novel RNA contributions to psychiatric illnesses. Each
S720
Abstracts
presentation will describe the potential influence of a different RNA mechanism of gene regulation in brain function and disease. Dr. Wright will discuss recent findings for isomiRNA, isoforms of canonical microRNAs, in schizophrenia. Dr. Mellios will present his recent work on circRNA in schizophrenia and bipolar disorder. Dr. Perrone-Bizzozero will explore the influence of RNA-binding proteins KSRP and HuD on gene expression in schizophrenia, bipolar disorder, Huntington’s disease, and Parkinson’s disease. Finally, Dr. Cairns will describe his work on understanding the influence of coding and non-coding RNA-interaction networks in a variety of psychiatric disorders, including schizophrenia, and how they are modulated and perturbed by genomic and epigenetic variation associated with these syndromes. His work suggests that while small non-coding RNA, particularly miRNA, are important, long non-coding RNA may also play a significant role in complex regulatory networks. The topics in this symposium shine light on the additional layers of complexity that RNA biology lends to neurodevelopment and function. The symposium will close with a discussion about how current research in this sphere may influence the trajectory of furthering our understanding of psychiatric disease and our ability to treat and prevent such disorders.
Disclosure AstraZeneca – Employee, Self. http://dx.doi.org/10.1016/j.euroneuro.2017.06.033
CHARACTERIZATION OF MIRNA ISOFORM EXPRESSION IN SCHIZOPHRENIA USING POSTMORTEM HUMAN BRAIN TISSUE n
Carrie Wright ,1, Joo Heon Shin1, Anandita Rajpurohit1, Courtney Williams1, Andrew Jaffe1, Nicholas Brandon2, Thomas Hyde1, Joel Kleinman1, Alan Cross2, Daniel Weinberger1 1 2
canonically described miRNA sequences was coined in 2008. Research demonstrates that these miRNA variants have altered stability and in some cases distinct functions from their close sequence relatives. Recent findings also indicate that altered isomiR expression is associated with disease states. To date little research has characterized the expression of isomiRs in the brain, however alterations in canonical miRNA expression and miRNA biogenesis have been reproducibly associated with schizophrenia, suggesting that the biogenesis of isomiRs may also be altered. Therefore, we characterized isomiR expression in 92 postmortem dorsolateral prefrontal cortex (DLPFC) human brain samples, including 30 samples from patients with schizophrenia and 62 from healthy controls. Using small RNA sequencing, we profiled the expression of both canonical miRNAs and isomiRs. We utilized the BIOO Scientific NextFlex small RNA sequencing kit, with 500 ng of starting total RNA and ran 50 base pair sequencing on the HiSeq 3000. We achieved a sequencing depth of over 20 million reads per sample. Reads were aligned to miRNA and isomiR sequences using miRge. First, we assessed the overall magnitude and diversity of isomiR expression, however no differences were found between cases and controls. We then assessed the influence of diagnosis on the expression of individual miRNAs and isomiRs. Seven canonical miRNAs and 52 isomiRs, derived from 22 canonically described miRNA sequences, were identified to be differentially expressed between cases and controls. Importantly many of these isomiRs had alterations in the 5 prime portion of their sequence. Such alterations have been shown to shift the repertoire of binding partners to be distinct from that of the canonical sequence. Therefore, altered expression of these isomiRs may especially indicate modifications in gene expression regulation in schizophrenia. More research is necessary to decipher the role of these miRNA variants in schizophrenia and the brain. However, our study suggests that such variation should not be ignored.
Disclosure AstraZeneca – Employee, Self http://dx.doi.org/10.1016/j.euroneuro.2017.06.034
Lieber Institute for Brain Development AstraZeneca
Abstract The nuances of small non-coding RNA biology continue to be discovered. The most characterized species of non-coding RNAs are microRNA (miRNA). miRNA largely function to modulate gene expression by repressing the translation of mRNA into protein. It is now known that miRNA participate in regulating nearly every type of cellular process and their importance in brain development, function, and disease continues to be uncovered. Recently RNA sequencing revealed that miRNA are often produced in detectable levels with slight sequence variations. Several steps are involved in the biogenesis of miRNA and slight changes in these processes can lead to a variety of extensions, deletions, or alterations in the final mature sequence. The name isomiR for these isoforms of
DYSREGULATED IN PSYCHIATRIC DISORDERS CIRCULAR RNAS INTERACT WITH RNA BINDING PROTEINS TO REGULATE SYNAPTIC PLASTICITY Jason Weick2, Brian Rodriguez2, Stephen Amoah2, Michela DellOrco2, Alexander Hafez2, Brigham Hartley3, Kristen Brennand3, Stephen Haggarty4, Nora Perrone-Bizzozero2, n Nikolaos Mellios ,1 1
University of New Mexico School of Medicine University of New Mexico 3 Mount Sinai 4 MGH (Harvard Medical School) 2
Disclosure Nothing to disclose.
S719 Methods: Here we will show the ongoing projects on psychiatric genetics in the Paisa Population in both genetics of severe mental illness and pharmacogenetics of lithium response in bipolar disorder. Results: We will discuss the importance of genetic studies in a genetically isolated and how this potentially more homogeneous population may help to detect common and rare genetic variants underpinning severe mental illness and traits like lithium response. Conclusions: Genetics studies in isolated populations represent an important strategy in the mapping and understanding of genetic basis of complex disorders as bipolar disorder and other mental illnesses. We will show and discuss the ongoing psychiatric genetics studies in the Paisa Population from Colombia.
Disclosure Nothing to disclose. http://dx.doi.org/10.1016/j.euroneuro.2017.06.032
Saturday, October 14, 2017 10:00 a.m. - 11:30 a.m. Symposia Sessions NOVEL IMPLICATIONS FOR RNA IN PSYCHIATRIC GENETICS Carrie Wright (Chair)1, Murray Cairns (Co-chair)2, Daniel Weinberger (Discussant)1 1 2
http://dx.doi.org/10.1016/j.euroneuro.2017.06.031
RESEARCH EXPERIENCE IN PSYCHIATRIC GENETICS IN COLOMBIA: ONGOING STUDIES Ana María Díaz Zuluaga Universidad de Antioquia Abstract
Background: The “Paisa Population” is a genetically and culturally homogeneous population of Colombia which has been focus of genetics studies in neuropsychiatric disorders in the last decade. This population is highly affected by major mental disorders, especially bipolar disorder. Several studies have been performed trying to understand the genetic basis underlying the disease by evaluating extended pedigrees. Also, the first pharmacogenetic study in this special population is being carried out with the aim to identify genetic variants associated with lithium response in the treatment of bipolar disorder.
Lieber Institute for Brain Development University of Newcastle
Overall Abstract Over the past few decades our understanding of the complexity of both psychiatric genetics and gene expression has expanded exponentially. It is now understood that multiple genes and various genetic factors contribute to the risk for psychiatric disorders. It is also now understood that a variety of non-coding RNA species and RNA-modifying proteins work in concert to modulate gene expression with unexpectedly high levels of nuance. Challenging how we think about gene expression, our awareness of the influence of RNA continues to evolve and build as new non-coding RNA species are discovered, novel functions are attributed to the more characterized non-coding RNAs, and additional interactions between non-coding and coding RNAs are elucidated. The involvement of such RNA based mechanisms in regulating pathways contributing to brain function and disease continues to be uncovered and may provide avenues for critical breakthroughs in our understanding and treatment of psychiatric disorders. This symposium will explore the implications of a variety of novel RNA contributions to psychiatric illnesses. Each
S720
Abstracts
presentation will describe the potential influence of a different RNA mechanism of gene regulation in brain function and disease. Dr. Wright will discuss recent findings for isomiRNA, isoforms of canonical microRNAs, in schizophrenia. Dr. Mellios will present his recent work on circRNA in schizophrenia and bipolar disorder. Dr. Perrone-Bizzozero will explore the influence of RNA-binding proteins KSRP and HuD on gene expression in schizophrenia, bipolar disorder, Huntington’s disease, and Parkinson’s disease. Finally, Dr. Cairns will describe his work on understanding the influence of coding and non-coding RNA-interaction networks in a variety of psychiatric disorders, including schizophrenia, and how they are modulated and perturbed by genomic and epigenetic variation associated with these syndromes. His work suggests that while small non-coding RNA, particularly miRNA, are important, long non-coding RNA may also play a significant role in complex regulatory networks. The topics in this symposium shine light on the additional layers of complexity that RNA biology lends to neurodevelopment and function. The symposium will close with a discussion about how current research in this sphere may influence the trajectory of furthering our understanding of psychiatric disease and our ability to treat and prevent such disorders.
Disclosure AstraZeneca – Employee, Self. http://dx.doi.org/10.1016/j.euroneuro.2017.06.033
CHARACTERIZATION OF MIRNA ISOFORM EXPRESSION IN SCHIZOPHRENIA USING POSTMORTEM HUMAN BRAIN TISSUE n
Carrie Wright ,1, Joo Heon Shin1, Anandita Rajpurohit1, Courtney Williams1, Andrew Jaffe1, Nicholas Brandon2, Thomas Hyde1, Joel Kleinman1, Alan Cross2, Daniel Weinberger1 1 2
canonically described miRNA sequences was coined in 2008. Research demonstrates that these miRNA variants have altered stability and in some cases distinct functions from their close sequence relatives. Recent findings also indicate that altered isomiR expression is associated with disease states. To date little research has characterized the expression of isomiRs in the brain, however alterations in canonical miRNA expression and miRNA biogenesis have been reproducibly associated with schizophrenia, suggesting that the biogenesis of isomiRs may also be altered. Therefore, we characterized isomiR expression in 92 postmortem dorsolateral prefrontal cortex (DLPFC) human brain samples, including 30 samples from patients with schizophrenia and 62 from healthy controls. Using small RNA sequencing, we profiled the expression of both canonical miRNAs and isomiRs. We utilized the BIOO Scientific NextFlex small RNA sequencing kit, with 500 ng of starting total RNA and ran 50 base pair sequencing on the HiSeq 3000. We achieved a sequencing depth of over 20 million reads per sample. Reads were aligned to miRNA and isomiR sequences using miRge. First, we assessed the overall magnitude and diversity of isomiR expression, however no differences were found between cases and controls. We then assessed the influence of diagnosis on the expression of individual miRNAs and isomiRs. Seven canonical miRNAs and 52 isomiRs, derived from 22 canonically described miRNA sequences, were identified to be differentially expressed between cases and controls. Importantly many of these isomiRs had alterations in the 5 prime portion of their sequence. Such alterations have been shown to shift the repertoire of binding partners to be distinct from that of the canonical sequence. Therefore, altered expression of these isomiRs may especially indicate modifications in gene expression regulation in schizophrenia. More research is necessary to decipher the role of these miRNA variants in schizophrenia and the brain. However, our study suggests that such variation should not be ignored.
Disclosure AstraZeneca – Employee, Self http://dx.doi.org/10.1016/j.euroneuro.2017.06.034
Lieber Institute for Brain Development AstraZeneca
Abstract The nuances of small non-coding RNA biology continue to be discovered. The most characterized species of non-coding RNAs are microRNA (miRNA). miRNA largely function to modulate gene expression by repressing the translation of mRNA into protein. It is now known that miRNA participate in regulating nearly every type of cellular process and their importance in brain development, function, and disease continues to be uncovered. Recently RNA sequencing revealed that miRNA are often produced in detectable levels with slight sequence variations. Several steps are involved in the biogenesis of miRNA and slight changes in these processes can lead to a variety of extensions, deletions, or alterations in the final mature sequence. The name isomiR for these isoforms of
DYSREGULATED IN PSYCHIATRIC DISORDERS CIRCULAR RNAS INTERACT WITH RNA BINDING PROTEINS TO REGULATE SYNAPTIC PLASTICITY Jason Weick2, Brian Rodriguez2, Stephen Amoah2, Michela DellOrco2, Alexander Hafez2, Brigham Hartley3, Kristen Brennand3, Stephen Haggarty4, Nora Perrone-Bizzozero2, n Nikolaos Mellios ,1 1
University of New Mexico School of Medicine University of New Mexico 3 Mount Sinai 4 MGH (Harvard Medical School) 2