학술논문
Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder
Document Type
article
Author
Gandal, Michael J; Zhang, Pan; Hadjimichael, Evi; Walker, Rebecca L; Chen, Chao; Liu, Shuang; Won, Hyejung; van Bakel, Harm; Varghese, Merina; Wang, Yongjun; Shieh, Annie W; Haney, Jillian; Parhami, Sepideh; Belmont, Judson; Kim, Minsoo; Moran Losada, Patricia; Khan, Zenab; Mleczko, Justyna; Xia, Yan; Dai, Rujia; Wang, Daifeng; Yang, Yucheng T; Xu, Min; Fish, Kenneth; Hof, Patrick R; Warrell, Jonathan; Fitzgerald, Dominic; White, Kevin; Jaffe, Andrew E; Peters, Mette A; Gerstein, Mark; Liu, Chunyu; Iakoucheva, Lilia M; Pinto, Dalila; Geschwind, Daniel H; Ashley-Koch, Allison E; Crawford, Gregory E; Garrett, Melanie E; Song, Lingyun; Safi, Alexias; Johnson, Graham D; Wray, Gregory A; Reddy, Timothy E; Goes, Fernando S; Zandi, Peter; Bryois, Julien; Price, Amanda J; Ivanov, Nikolay A; Collado-Torres, Leonardo; Hyde, Thomas M; Burke, Emily E; Kleiman, Joel E; Tao, Ran; Shin, Joo Heon; Akbarian, Schahram; Girdhar, Kiran; Jiang, Yan; Kundakovic, Marija; Brown, Leanne; Kassim, Bibi S; Park, Royce B; Wiseman, Jennifer R; Zharovsky, Elizabeth; Jacobov, Rivka; Devillers, Olivia; Flatow, Elie; Hoffman, Gabriel E; Lipska, Barbara K; Lewis, David A; Haroutunian, Vahram; Hahn, Chang-Gyu; Charney, Alexander W; Dracheva, Stella; Kozlenkov, Alexey; DelValle, Diane; Francoeur, Nancy; Roussos, Panos; Fullard, John F; Bendl, Jaroslav; Hauberg, Mads E; Mangravite, Lara M; Chae, Yooree; Peng, Junmin; Niu, Mingming; Wang, Xusheng; Webster, Maree J; Beach, Thomas G; Jiang, Yi; Grennan, Kay S
Source
Science. 362(6420)
Subject
Language
Abstract
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.