Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism

Simone Gupta; Shannon E. Ellis; Foram N. Ashar; Anna Moes; Joel S. Bader; Jianan Zhan; Andrew B. West; Dan E. Arking

doi:10.1038/ncomms6748

Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism

Simone Gupta, Shannon E. Ellis, Foram N. Ashar, Anna Moes, Joel S. Bader, Jianan Zhan, Andrew B. West, Dan E. Arking

School of Medicine

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

249 Scopus citations

Abstract

Recent studies of genomic variation associated with autism have suggested the existence of extreme heterogeneity. Large-scale transcriptomics should complement these results to identify core molecular pathways underlying autism. Here we report results from a large-scale RNA sequencing effort, utilizing region-matched autism and control brains to identify neuronal and microglial genes robustly dysregulated in autism cortical brain. Remarkably, we note that a gene expression module corresponding to M2-activation states in microglia is negatively correlated with a differentially expressed neuronal module, implicating dysregulated microglial responses in concert with altered neuronal activity-dependent genes in autism brains. These observations provide pathways and candidate genes that highlight the interplay between innate immunity and neuronal activity in the aetiology of autism.

Original language	English (US)
Article number	5748
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms6748
State	Published - 2014

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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title = "Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism",

abstract = "Recent studies of genomic variation associated with autism have suggested the existence of extreme heterogeneity. Large-scale transcriptomics should complement these results to identify core molecular pathways underlying autism. Here we report results from a large-scale RNA sequencing effort, utilizing region-matched autism and control brains to identify neuronal and microglial genes robustly dysregulated in autism cortical brain. Remarkably, we note that a gene expression module corresponding to M2-activation states in microglia is negatively correlated with a differentially expressed neuronal module, implicating dysregulated microglial responses in concert with altered neuronal activity-dependent genes in autism brains. These observations provide pathways and candidate genes that highlight the interplay between innate immunity and neuronal activity in the aetiology of autism.",

author = "Simone Gupta and Ellis, {Shannon E.} and Ashar, {Foram N.} and Anna Moes and Bader, {Joel S.} and Jianan Zhan and West, {Andrew B.} and Arking, {Dan E.}",

note = "Funding Information: This work was supported by a grant from the Simons Foundation (SFARI 137603 to D.E.A.) and by the National Institute of Mental Health Autism Centers of Excellence Network Grant 5R01MH081754. Tissue was provided to A.B.W. by the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, the Autism Tissue Program (ATP) and the Harvard Brain Tissue Resource Center (supported in part by PHS grant R24 MH068855). We thank Rebecca Tomlinson and Cristina Harmelink for contributing to the generation of the RNAseq libraries. We thank Rita Cowell for critical review of the manuscript. We thank Jane Pickett, Carolyn Komich Hare and Ellen Xiu from the ATP for tissue coordination. Publisher Copyright: {\textcopyright} 2014 Macmillan Publishers Limited. All rights reserved.",

year = "2014",

doi = "10.1038/ncomms6748",

language = "English (US)",

volume = "5",

journal = "Nature Communications",

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AU - Gupta, Simone

AU - Ellis, Shannon E.

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AU - Moes, Anna

AU - Bader, Joel S.

AU - Zhan, Jianan

AU - West, Andrew B.

AU - Arking, Dan E.

N1 - Funding Information: This work was supported by a grant from the Simons Foundation (SFARI 137603 to D.E.A.) and by the National Institute of Mental Health Autism Centers of Excellence Network Grant 5R01MH081754. Tissue was provided to A.B.W. by the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, the Autism Tissue Program (ATP) and the Harvard Brain Tissue Resource Center (supported in part by PHS grant R24 MH068855). We thank Rebecca Tomlinson and Cristina Harmelink for contributing to the generation of the RNAseq libraries. We thank Rita Cowell for critical review of the manuscript. We thank Jane Pickett, Carolyn Komich Hare and Ellen Xiu from the ATP for tissue coordination. Publisher Copyright: © 2014 Macmillan Publishers Limited. All rights reserved.

PY - 2014

Y1 - 2014

N2 - Recent studies of genomic variation associated with autism have suggested the existence of extreme heterogeneity. Large-scale transcriptomics should complement these results to identify core molecular pathways underlying autism. Here we report results from a large-scale RNA sequencing effort, utilizing region-matched autism and control brains to identify neuronal and microglial genes robustly dysregulated in autism cortical brain. Remarkably, we note that a gene expression module corresponding to M2-activation states in microglia is negatively correlated with a differentially expressed neuronal module, implicating dysregulated microglial responses in concert with altered neuronal activity-dependent genes in autism brains. These observations provide pathways and candidate genes that highlight the interplay between innate immunity and neuronal activity in the aetiology of autism.

AB - Recent studies of genomic variation associated with autism have suggested the existence of extreme heterogeneity. Large-scale transcriptomics should complement these results to identify core molecular pathways underlying autism. Here we report results from a large-scale RNA sequencing effort, utilizing region-matched autism and control brains to identify neuronal and microglial genes robustly dysregulated in autism cortical brain. Remarkably, we note that a gene expression module corresponding to M2-activation states in microglia is negatively correlated with a differentially expressed neuronal module, implicating dysregulated microglial responses in concert with altered neuronal activity-dependent genes in autism brains. These observations provide pathways and candidate genes that highlight the interplay between innate immunity and neuronal activity in the aetiology of autism.

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Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism

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