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

Authors
Michael Gandal,Pan Zhang
Evi Hadjimichael,Rebecca Walker,Chao Chen,Shuang Liu,Hyejung Won,Harm Bakel,Merina Varghese,Yongjun Wang,Annie Shieh,Jillian Haney,Sepideh Parhami,Judson Belmont,Minsoo Kim,Patricia Losada,Zenab Khan,Justyna Mleczko,Yan Xia,Rujia Dai,Daifeng Wang,Yucheng Yang,Min Xu,Kenneth Fish,Patrick Hof,Jonathan Warrell,Dominic Fitzgerald,Kevin White,Andrew Jaffe,Mette Peters,Mark Gerstein,Chunyu Liu,Lilia Iakoucheva,Dalila Pinto,Daniel Geschwind,Allison Ashley‐Koch,Gregory Crawford,Melanie Garrett,Lingyun Song,Alexias Safi,Graham Johnson,Gregory Wray,Timothy Reddy,Fernando Goes,Peter Zandi,Julien Bryois,Amanda Price,Nikolay Ivanov,Leonardo Collado‐Torres,Thomas Hyde,Emily Burke,Joel Kleiman,Ran Tao,Joo Shin,Schahram Akbarian,Kiran Girdhar,Yan Jiang,Marija Kundaković,Leanne Brown,Bibi Kassim,Royce Park,Jennifer Wiseman,Elizabeth Zharovsky,Rivka Jacobov,Olivia Devillers,Elie Flatow,Gabriel Hoffman,Barbara Lipska,David Lewis,Vahram Haroutunian,Chang-Gyu Hahn,Alexander Charney,Stella Dracheva,Alexey Kozlenkov,Diane Valle,Nancy Francoeur,Panos Roussos,John Fullard,Jaroslav Bendl,Mads Hauberg,Lara Mangravite,Younbyoung Chae,Junmin Peng,Mingming Niu,Xusheng Wang,Maree Webster,Thomas Beach,Yi Jiang,Kay Grennan,Ramu Vadukapuram,Lijun Cheng,Miguel Brown,Mimi Brown,Tonya Brunetti,Thomas Goodman,Majd Alsayed,Damon Polioudakis,Brie Wamsley,Jiani Yin,Tarik Hadžić,Luis Torre-Ubieta,Vivek Swarup,Stephan Sanders,Matthew State,Donna Werling,Joon‐Yong An,Brooke Sheppard,A. Willsey,Mohana Ray,Gina Giase,Amira Kefi,Eugenio Mattei,Michael Purcaro,Zhiping Weng,Jill Moore,Henry Pratt,Jack Huey,Tyler Borrman,Patrick Sullivan,Paola Giusti‐Rodríguez,Yunjung Kim,Jin Szatkiewicz,Suhn Rhie,Christoper Armoskus,Adrian Camarena,Peggy Farnham,Valeria Spitsyna,Heather Witt,Shannon Schreiner,Oleg Evgrafov,James Knowles,Fábio Navarro,Declan Clarke,Prashant Emani,Mengting Gu,Xu Shi,Robert Kitchen,Gamze Gürsoy,Jing Zhang,Becky Carlyle,Angus Nairn,Mingfeng Li,Sirisha Pochareddy,Nenad Šestan,Mario Škarica,Zhen Li,André Sousa,Gabriel Santpere,Jinmyung Choi,Ying Zhu,Tianliuyun Gao,Daniel Miller,Adriana Cherskov,Mo Yang,Anahita Amiri,Gianfilippo Coppola,Jessica Mariani,Soraya Scuderi,Anna Szekely,Flora Vaccarino,Feinan Wu,Sherman Weissman,Tanmoy Roychowdhury
+161 authors
,Alexej Abyzov
Journal
Published
Dec 13, 2018
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Abstract

INTRODUCTION Our understanding of the pathophysiology of psychiatric disorders, including autism spectrum disorder (ASD), schizophrenia (SCZ), and bipolar disorder (BD), lags behind other fields of medicine. The diagnosis and study of these disorders currently depend on behavioral, symptomatic characterization. Defining genetic contributions to disease risk allows for biological, mechanistic understanding but is challenged by genetic complexity, polygenicity, and the lack of a cohesive neurobiological model to interpret findings. RATIONALE The transcriptome represents a quantitative phenotype that provides biological context for understanding the molecular pathways disrupted in major psychiatric disorders. RNA sequencing (RNA-seq) in a large cohort of cases and controls can advance our knowledge of the biology disrupted in each disorder and provide a foundational resource for integration with genomic and genetic data. RESULTS Analysis across multiple levels of transcriptomic organization—gene expression, local splicing, transcript isoform expression, and coexpression networks for both protein-coding and noncoding genes—provides an in-depth view of ASD, SCZ, and BD molecular pathology. More than 25% of the transcriptome exhibits differential splicing or expression in at least one disorder, including hundreds of noncoding RNAs (ncRNAs), most of which have unexplored functions but collectively exhibit patterns of selective constraint. Changes at the isoform level, as opposed to the gene level, show the largest effect sizes and genetic enrichment and the greatest disease specificity. We identified coexpression modules associated with each disorder, many with enrichment for cell type–specific markers, and several modules significantly dysregulated across all three disorders. These enabled parsing of down-regulated neuronal and synaptic components into a variety of cell type– and disease-specific signals, including multiple excitatory neuron and distinct interneuron modules with differential patterns of disease association, as well as common and rare genetic risk variant enrichment. The glial-immune signal demonstrates shared disruption of the blood-brain barrier and up-regulation of NFkB-associated genes, as well as disease-specific alterations in microglial-, astrocyte-, and interferon-response modules. A coexpression module associated with psychiatric medication exposure in SCZ and BD was enriched for activity-dependent immediate early gene pathways. To identify causal drivers, we integrated polygenic risk scores and performed a transcriptome-wide association study and summary-data–based Mendelian randomization. Candidate risk genes—5 in ASD, 11 in BD, and 64 in SCZ, including shared genes between SCZ and BD—are supported by multiple methods. These analyses begin to define a mechanistic basis for the composite activity of genetic risk variants. CONCLUSION Integration of RNA-seq and genetic data from ASD, SCZ, and BD provides a quantitative, genome-wide resource for mechanistic insight and therapeutic development at Resource.PsychENCODE.org. These data inform the molecular pathways and cell types involved, emphasizing the importance of splicing and isoform-level gene regulatory mechanisms in defining cell type and disease specificity, and, when integrated with genome-wide association studies, permit the discovery of candidate risk genes. The PsychENCODE cross-disorder transcriptomic resource. Human brain RNA-seq was integrated with genotypes across individuals with ASD, SCZ, BD, and controls, identifying pervasive dysregulation, including protein-coding, noncoding, splicing, and isoform-level changes. Systems-level and integrative genomic analyses prioritize previously unknown neurogenetic mechanisms and provide insight into the molecular neuropathology of these disorders.

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