Integrated systems analysis reveals a molecular network underlying autism spectrum disorders

被引：99

作者：

Li, Jingjing ^{[1
]}

Shi, Minyi ^{[1
]}

Ma, Zhihai ^{[1
]}

Zhao, Shuchun ^{[2
]}

Euskirchen, Ghia ^{[1
]}

Ziskin, Jennifer ^{[2
]}

Urban, Alexander ^{[3
]}

Hallmayer, Joachim ^{[3
]}

Snyder, Michael ^{[1
]}

机构：

[1] Stanford Univ, Sch Med, Dept Genet, Stanford Ctr Genom & Personalized Med, Stanford, CA 94305 USA

[2] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA

[3] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA

来源：

MOLECULAR SYSTEMS BIOLOGY | 2014年 / 10卷 / 12期

关键词：

autism spectrum disorders; corpus callosum; functional modules; oligodendrocytes; protein interaction network; COPY-NUMBER VARIATION; DE-NOVO MUTATIONS; CORPUS-CALLOSUM; BRAIN-DEVELOPMENT; GENE; IMPLICATE; VARIANTS; YEAST; ASSOCIATION; RESOURCE;

D O I：

10.15252/msb.20145487

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：17

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