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

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

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

Author(s) -

Michael J. Gandal,

Pan Zhang,

Evi Hadjimichael,

Rebecca L. Walker,

Chao Chen,

Shuang Liu,

Hyejung Won,

Harm van Bakel,

Merina Varghese,

Yongjun Wang,

Annie W. Shieh,

Jillian R. Haney,

Sepideh Parhami,

Judson Belmont,

Minsoo Kim,

Patricia Morán Losada,

Zenab Khan,

Justyna Mleczko,

Yan Xia,

Rujia Dai,

Daifeng Wang,

Yucheng Yang,

Min Xu,

Kenneth Fish,

Patrick R. Hof,

Jonathan Warrell,

Dominic Fitzgerald,

Kevin P. White,

Andrew E. Jaffe,

Mette A. Peters,

Mark Gerstein,

Chunyu Liu,

Lilia M. Iakoucheva,

Dalila Pinto,

Daniel H. Geschwind,

Allison E. AshleyKoch,

Gregory E. Crawford,

Melanie E. Garrett,

Lingyun Song,

Alexias Safi,

Graham D. Johnson,

Gregory A. Wray,

Timothy E. Reddy,

Fernando S. Goes,

Peter P. Zandi,

Julien Bryois,

Amanda J. Price,

Nikolay A. Ivanov,

Leonardo ColladoTorres,

Thomas M. Hyde,

Emily E. Burke,

Joel E. Kleiman,

Ran Tao,

Joo Heon 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 E. Hoffman,

Barbara K. Lipska,

David A. Lewis,

Vahram Haroutunian,

Chang-Gyu Hahn,

Alexander W. Charney,

Stella Dracheva,

Alexey Kozlenkov,

Diane M. Del Valle,

Nancy Francoeur,

Panos Roussos,

John F. Fullard,

Jaroslav Bendl,

Mads E. Hauberg,

Lara M. Mangravite,

Yooree Chae,

Junmin Peng,

Mingming Niu,

Xusheng Wang,

Maree J. Webster,

Thomas G. Beach,

Yi Jiang,

Kay Grennan,

Ramu Vadukapuram,

Lijun Cheng,

Miguel Brown,

Mimi Brown,

Tonya M. Brunetti,

Thomas Goodman,

Majd Alsayed,

Damon Polioudakis,

Brie Wamsley,

Jiani Yin,

Tarik Hadžić,

Luis de la Torre-Ubieta,

Vivek Swarup,

Stephan Sanders,

Matthew W. State,

Donna M. Werling,

JoonYong An,

Brooke Sheppard,

A. Jeremy Willsey,

Mohana Ray,

Gina Giase,

Amira Kefi,

Eugenio Mattei,

Michael Purcaro,

Zhiping Weng,

Jill E. Moore,

Henry Pratt,

Jack Huey,

Tyler Borrman,

Patrick F. Sullivan,

Paola GiustiRodríguez,

Yunjung Kim,

Patrick Sullivan,

Jin Szatkiewicz,

Suhn K. Rhie,

Christoper Armoskus,

Adrian Camarena,

Peggy Farnham,

Valeria N. Spitsyna,

Heather Witt,

Shan Schreiner,

Oleg V. Evgrafov,

James A. Knowles,

Fábio C. P. Navarro,

Declan Clarke,

Prashant S. Emani,

Mengting Gu,

Xu Shi,

Robert R. Kitchen,

Gamze Gürsoy,

Jing Zhang,

Becky C. Carlyle,

Angus C. Nairn,

Mingfeng Li,

Sirisha Pochareddy,

Nenad Šestan,

Mario Škarica,

Zhen Li,

André M. M. Sousa,

Gabriel Santpere,

Jinmyung Choi,

Ying Zhu,

Tianliuyun Gao,

Daniel J. Miller,

Adriana Cherskov,

Mo Yang,

Anahita Amiri,

Gianfilippo Coppola,

Jessica Mariani,

Soraya Scuderi,

Anna Szekely,

Flora M. Vaccarino,

Feinan Wu,

Sherman M. Weissman,

Tanmoy Roychowdhury,

Alexej Abyzov

Publication year - 2018

Publication title -

science

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 12.556

H-Index - 1186

eISSN - 1095-9203

pISSN - 0036-8075

DOI - 10.1126/science.aat8127

Subject(s) - transcriptome , biology , schizophrenia (object oriented programming) , alternative splicing , autism spectrum disorder , disease , neuroscience , bipolar disorder , immune dysregulation , rna splicing , genetics , rna seq , gene , autism , gene expression , computational biology , gene isoform , medicine , rna , immune system , psychiatry , pathology , cognition

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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