TY - JOUR
T1 - Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder
AU - Gandal, Michael J.
AU - Zhang, Pan
AU - Hadjimichael, Evi
AU - Walker, Rebecca L.
AU - Chen, Chao
AU - Liu, Shuang
AU - Won, Hyejung
AU - Van Bakel, Harm
AU - Varghese, Merina
AU - Wang, Yongjun
AU - Shieh, Annie W.
AU - Haney, Jillian
AU - Parhami, Sepideh
AU - Belmont, Judson
AU - Kim, Minsoo
AU - Losada, Patricia Moran
AU - Khan, Zenab
AU - Mleczko, Justyna
AU - Xia, Yan
AU - Dai, Rujia
AU - Wang, Daifeng
AU - Yang, Yucheng T.
AU - Xu, Min
AU - Fish, Kenneth
AU - Hof, Patrick R.
AU - Warrell, Jonathan
AU - Fitzgerald, Dominic
AU - White, Kevin
AU - Jaffe, Andrew E.
AU - Peters, Mette A.
AU - Gerstein, Mark
AU - Liu, Chunyu
AU - Iakoucheva, Lilia M.
AU - Pinto, Dalila
AU - Geschwind, Daniel H.
N1 - Publisher Copyright:
© 2018 American Association for the Advancement of Science. All rights reserved.
PY - 2018/12/14
Y1 - 2018/12/14
N2 - 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 likelymediated 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.
AB - 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 likelymediated 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.
UR - http://www.scopus.com/inward/record.url?scp=85058422390&partnerID=8YFLogxK
U2 - 10.1126/science.aat8127
DO - 10.1126/science.aat8127
M3 - Article
C2 - 30545856
AN - SCOPUS:85058422390
SN - 0036-8075
VL - 362
JO - Science
JF - Science
IS - 6420
M1 - 1265
ER -