title: Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.
abstract: Autism is a complex disease whose etiology remains elusive. We integrated previously and newly generated data and developed a systems framework involving the interactome, gene expression and genome sequencing to identify a protein interaction module with members strongly enriched for autism candidate genes. Sequencing of 25 patients confirmed the involvement of this module in autism, which was subsequently validated using an independent cohort of over 500 patients. Expression of this module was dichotomized with a ubiquitously expressed subcomponent and another subcomponent preferentially expressed in the corpus callosum, which was significantly affected by our identified mutations in the network center. RNA-sequencing of the corpus callosum from patients with autism exhibited extensive gene mis-expression in this module, and our immunochemical analysis showed that the human corpus callosum is predominantly populated by oligodendrocyte cells. Analysis of functional genomic data further revealed a significant involvement of this module in the development of oligodendrocyte cells in mouse brain. Our analysis delineates a natural network involved in autism, helps uncover novel candidate genes for this disease and improves our understanding of its molecular pathology.
authors.affiliation: Department of Genetics, Stanford Center for Genomics and Personalized Medicine Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Genetics, Stanford Center for Genomics and Personalized Medicine Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Minyi
authors.initials: M
authors.lastname: Shi
authors.affiliation: Department of Genetics, Stanford Center for Genomics and Personalized Medicine Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Zhihai
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Shuchun
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Genetics, Stanford Center for Genomics and Personalized Medicine Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Ghia
authors.initials: G
authors.lastname: Euskirchen
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ziskin
authors.affiliation: Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Urban
authors.affiliation: Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Joachim
authors.initials: J
authors.lastname: Hallmayer
authors.affiliation: Department of Genetics, Stanford Center for Genomics and Personalized Medicine Stanford University School of Medicine, Stanford, CA, USA mpsnyder@stanford.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Snyder
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D003337:Corpus Callosum / Q000502:physiology; D015870:Gene Expression; D053263:Gene Regulatory Networks; D015894:Genome, Human; D006801:Humans; D008297:Male; D051379:Mice; D009836:Oligodendroglia / Q000502:physiology; D060066:Protein Interaction Maps; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D049490:Systems Biology
keywords: autism spectrum disorders; corpus callosum; functional modules; oligodendrocytes; protein interaction network