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Science. 2018 Dec 14;362(6420). pii: eaat8127. doi: 10.1126/science.aat8127.

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

Gandal MJ1,2,3,4, Zhang P5, Hadjimichael E6,7,8,9, Walker RL2,3,4, Chen C10,11, Liu S12, Won H2,3,4,13,14, van Bakel H7, Varghese M9,15, Wang Y16, Shieh AW17, Haney J18,2,3, Parhami S18,2,3, Belmont J6,7,8,9, Kim M18,4, Moran Losada P5, Khan Z7, Mleczko J19, Xia Y10,17, Dai R10,17, Wang D20, Yang YT12, Xu M12, Fish K19, Hof PR9,15,21, Warrell J12, Fitzgerald D22, White K22,23,24, Jaffe AE25,26; PsychENCODE Consortium, Peters MA27, Gerstein M12, Liu C28,17,29, Iakoucheva LM30, Pinto D31,7,8,9, Geschwind DH1,2,3,4.

Author information

1
Department of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA. mgandal@mednet.ucla.edu liuch@upstate.edu lilyak@ucsd.edu dalila.pinto@mssm.edu dhg@mednet.ucla.edu.
2
Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
3
Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA.
4
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
5
Department of Psychiatry, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA.
6
Department of Psychiatry, and Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
7
Department of Genetics and Genomic Sciences, and Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
8
The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
9
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
10
The School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
11
National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, Hunan 410078, China.
12
Program in Computational Biology and Bioinformatics, Departments of Molecular Biophysics and Biochemistry, Computer Science, and Statistics & Data Science, Yale University, New Haven, CT 06520, USA.
13
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
14
UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
15
Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
16
The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
17
Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
18
Department of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA 90095, USA.
19
Departments of Medicine and Cardiology, Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
20
Department of Biomedical Informatics, Stony Brook University, Stony Brook, NY 11794, USA.
21
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
22
Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
23
Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL 60637, USA.
24
Tempus Labs, Chicago, IL 60654, USA.
25
Lieber Institute for Brain Development, Baltimore, MD 21205, USA.
26
Departments of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
27
CNS Data Coordination Group, Sage Bionetworks, Seattle, WA 98109, USA.
28
The School of Life Sciences, Central South University, Changsha, Hunan 410078, China. mgandal@mednet.ucla.edu liuch@upstate.edu lilyak@ucsd.edu dalila.pinto@mssm.edu dhg@mednet.ucla.edu.
29
School of Psychology, Shaanxi Normal University, Xian, Shaanxi 710000, China.
30
Department of Psychiatry, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA. mgandal@mednet.ucla.edu liuch@upstate.edu lilyak@ucsd.edu dalila.pinto@mssm.edu dhg@mednet.ucla.edu.
31
Department of Psychiatry, and Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. mgandal@mednet.ucla.edu liuch@upstate.edu lilyak@ucsd.edu dalila.pinto@mssm.edu dhg@mednet.ucla.edu.

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.

PMID:
30545856
DOI:
10.1126/science.aat8127
[Indexed for MEDLINE]

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