Integrated systems analysis reveals a molecular network underlying autism spectrum disorders

Molecular Systems Biology

Jingjing Li¹  Minyi Shi¹  Zhihai Ma¹  Shuchun Zhao³  Ghia Euskirchen¹  Jennifer Ziskin³  Alexander Urban²  Joachim Hallmayer² 

[1] Department of Genetics, Stanford Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, CA, USA;Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA;Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA

关键词: autism spectrum disorders;    corpus callosum;    functional modules;    oligodendrocytes;    protein interaction network;   

DOI  :  10.15252/msb.20145487

来源: Wiley

【 摘 要 】

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.

Synopsis

An integrative analysis of the interactome, gene expression and genome sequencing data identifies protein interaction modules implicated in autism spectrum disorders and reveals the corpus callosum as a potential tissue of origin in ASD.

• Topological clustering of the human protein-protein interaction network reveals two modules implicated in ASD, module #2 for chromatin remodeling proteins and transcription factors and #13 for proteins involved in brain function.
• Module #13 has dichotomized expression with one sub-component ubiquitously expressed in the brain, and the other enriched in the corpus callosum.
• Module #13 is involved in oligodendrocyte development and axon myelination in the corpus callosum.
• This study suggests interhemispheric disconnectivity in the brain as a potential cause underlying autism.

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.