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Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder

by Hadjimichael, Evi , Ivanov, Nikolay A. , Niu, Mingming , Varghese, Merina , Kundakovic, Marija , Webster, Maree J. , Xu, Min , Ashley-Koch, Allison E. , Jaffe, Andrew E. , Park, Royce B. , Haney, Jillian , Fish, Kenneth , Moran Losada, Patricia , Fitzgerald, Dominic , Dracheva, Stella , Khan, Zenab , Won, Hyejung , Bendl, Jaroslav , Goes, Fernando S. , Kozlenkov, Alexey , Chen, Chao , Warrell, Jonathan , Gandal, Michael J. , Bryois, Julien , Wray, Gregory A. , Flatow, Elie , Haroutunian, Vahram , Zhang, Pan , Fullard, John F. , Safi, Alexias , DelValle, Diane , Hoffman, Gabriel E. , Zandi, Peter , Peng, Junmin , Gerstein, Mark , Mangravite, Lara M , Kleiman, Joel E. , Chae, Yooree , Collado-Torres, Leonardo , Xia, Yan , Mleczko, Justyna , Francoeur, Nancy , Hahn, Chang-Gyu , Reddy, Timothy E , Wiseman, Jennifer R , Wang, Yongjun , Geschwind, Daniel H. , Lewis, David A. , Belmont, Judson , Zharovsky, Elizabeth , Walker, Rebecca L. , Garrett, Melanie E. , Brown, Leanne , Johnson, Graham D. , Hyde, Thomas M. , Tao, Ran , Devillers, Olivia , Hauberg, Mads E. , Akbarian, Schahram , Girdhar, Kiran , Wang, Xusheng , Burke, Emily E. , Crawford, Gregory E. , Hof, Patrick R. , van Ba

in Autism / Autism Spectrum Disorder - genetics / Autism Spectrum Disorders / Behavior disorders / Bipolar disorder / Bipolar Disorder - genetics / Blood-brain barrier / Brain / Brain - metabolism / Coding / Data processing / Disorders / Disruption / Effect Size / Enrichment / Gene expression / Gene regulation / Gene sequencing / Genes / Genetic analysis / Genetic Predisposition to Disease / Genetics / Genomes / Genotypes / Health risks / Humans / Integration / Interferon / Literary Devices / Mental disorders / Modules / NF-κB protein / Non-coding RNA / Pathology / Pathophysiology / Phenotypes / Protein Isoforms - genetics / Proteins / Psychiatry / Regulatory mechanisms (biology) / Regulatory sequences / Ribonucleic acid / Risk / RNA / RNA Splicing / Schizophrenia / Schizophrenia - genetics / Sequence Analysis, RNA / Splicing / Transcription / Transcriptome

2018

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Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder

2018

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2018

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Journal Article

Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder

Hadjimichael, Evi,

Ivanov, Nikolay A.,

Niu, Mingming,

Varghese, Merina,

Kundakovic, Marija,

Webster, Maree J.,

Xu, Min,

Ashley-Koch, Allison E.,

Jaffe, Andrew E.,

Park, Royce B.,

Haney, Jillian,

Fish, Kenneth,

Moran Losada, Patricia,

Fitzgerald, Dominic,

Dracheva, Stella,

Khan, Zenab,

Won, Hyejung,

Bendl, Jaroslav,

Goes, Fernando S.,

Kozlenkov, Alexey,

Chen, Chao,

Warrell, Jonathan,

Gandal, Michael J.,

Bryois, Julien,

Wray, Gregory A.,

Flatow, Elie,

Haroutunian, Vahram,

Zhang, Pan,

Fullard, John F.,

Safi, Alexias,

DelValle, Diane,

Hoffman, Gabriel E.,

Zandi, Peter,

Peng, Junmin,

Gerstein, Mark,

Mangravite, Lara M,

Kleiman, Joel E.,

Chae, Yooree,

Collado-Torres, Leonardo,

Xia, Yan,

Mleczko, Justyna,

Francoeur, Nancy,

Hahn, Chang-Gyu,

Reddy, Timothy E,

Wiseman, Jennifer R,

Wang, Yongjun,

Geschwind, Daniel H.,

Lewis, David A.,

Belmont, Judson,

Zharovsky, Elizabeth,

Walker, Rebecca L.,

Garrett, Melanie E.,

Brown, Leanne,

Johnson, Graham D.,

Hyde, Thomas M.,

Tao, Ran,

Devillers, Olivia,

Hauberg, Mads E.,

Akbarian, Schahram,

Girdhar, Kiran,

Wang, Xusheng,

Burke, Emily E.,

Crawford, Gregory E.,

Hof, Patrick R.,

van Ba

2018

Overview

Most genetic risk for psychiatric disease lies in regulatory regions, implicating pathogenic dysregulation of gene expression and splicing. However, comprehensive assessments of transcriptomic organization in diseased brains are limited. In this work, we integrated genotypes and RNA sequencing in brain samples from 1695 individuals with autism spectrum disorder (ASD), schizophrenia, and bipolar disorder, as well as controls. More than 25% of the transcriptome exhibits differential splicing or expression, with isoform-level changes capturing the largest disease effects and genetic enrichments. Coexpression networks isolate disease-specific neuronal alterations, as well as microglial, astrocyte, and interferon-response modules defining previously unidentified neural-immune mechanisms. We integrated genetic and genomic data to perform a transcriptome-wide association study, prioritizing disease loci likely mediated by cis effects on brain expression. This transcriptome-wide characterization of the molecular pathology across three major psychiatric disorders provides a comprehensive resource for mechanistic insight and therapeutic development.

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Publisher

The American Association for the Advancement of Science

Subject

Autism

/ Autism Spectrum Disorder - genetics

/ Autism Spectrum Disorders

/ Behavior disorders

/ Bipolar disorder

/ Bipolar Disorder - genetics

/ Blood-brain barrier