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

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 Haney; Sepideh Parhami; Judson Belmont; Minsoo Kim; Patricia Moran Losada; Zenab Khan; Justyna Mleczko; Yan Xia; Rujia Dai; Daifeng Wang; Yucheng T. Yang; Min Xu; Kenneth Fish; Patrick R. Hof; Jonathan Warrell; Dominic Fitzgerald; Kevin White; Andrew E. Jaffe; Mette A. Peters; Mark Gerstein; Chunyu Liu; Lilia M. Iakoucheva; Dalila Pinto; Daniel H. Geschwind

doi:10.1126/science.aat8127

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

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 Haney, Sepideh Parhami, Judson Belmont, Minsoo Kim, Patricia Moran Losada, Zenab Khan, Justyna Mleczko, Yan Xia, Rujia DaiDaifeng Wang, Yucheng T. Yang, Min Xu, Kenneth Fish, Patrick R. Hof, Jonathan Warrell, Dominic Fitzgerald, Kevin White, Andrew E. Jaffe, Mette A. Peters, Mark Gerstein, Chunyu Liu, Lilia M. Iakoucheva, Dalila Pinto, Daniel H. Geschwind

Bloomberg School of Public Health

Research output: Contribution to journal › Article › peer-review

240 Scopus citations

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 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.

Original language	English (US)
Article number	1265
Journal	Science
Volume	362
Issue number	6420
DOIs	https://doi.org/10.1126/science.aat8127
State	Published - Dec 14 2018

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Gandal, M. J., Zhang, P., Hadjimichael, E., Walker, R. L., Chen, C., Liu, S., Won, H., Van Bakel, H., Varghese, M., Wang, Y., Shieh, A. W., Haney, J., Parhami, S., Belmont, J., Kim, M., Losada, P. M., Khan, Z., Mleczko, J., Xia, Y., ... Geschwind, D. H. (2018). Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science, 362(6420), Article 1265. https://doi.org/10.1126/science.aat8127

Gandal, MJ, Zhang, P, Hadjimichael, E, Walker, RL, Chen, C, Liu, S, Won, H, Van Bakel, H, Varghese, M, Wang, Y, Shieh, AW, Haney, J, Parhami, S, Belmont, J, Kim, M, Losada, PM, Khan, Z, Mleczko, J, Xia, Y, Dai, R, Wang, D, Yang, YT, Xu, M, Fish, K, Hof, PR, Warrell, J, Fitzgerald, D, White, K, Jaffe, AE, Peters, MA, Gerstein, M, Liu, C, Iakoucheva, LM, Pinto, D & Geschwind, DH 2018, 'Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder', Science, vol. 362, no. 6420, 1265. https://doi.org/10.1126/science.aat8127

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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 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.",

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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.

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

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