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.

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…Utrophin was originally identified as an ASD candidate based on its enrichment in an autism-associated protein interaction module. Sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene, confirming the involvement of this module in autism; this finding was further validated by exome sequencing of an independent cohort of 505 ASD cases and 491 controls 10 .…”

“…Multiple ASD susceptibility genes converge on cellular pathways that intersect at the postsynaptic site of glutamatergic synapses 7,8 , the development and maturation of synaptic contacts 9 or synaptic transmission 10 . The majority of excitatory glutamatergic synapses are located in small dendritic protrusions known as spines.…”

An integrative analysis of non-coding regulatory DNA variations associated with autism spectrum disorder

“…To test for a general association of the regulatory SNVs with ASD, enrichment was calculated against several ASDassociated gene sets from different sources; the Simons Foundation Autism Research Initiative (SFARI) AutDB database (December 2015 update, Scores indicating any support: S,1-4) [47], our previously developed ASD protein-protein interaction network (AXAS-ASD), which uses 'seed' genes from public resources and their firstdegree neighbors [30] and Module 13 (M13-Li2014)-a module of protein-protein interactions from Li, Shi [48]which is associated with ASD risk. In addition three control datasets were retrieved from the GWAS catalog (https://www.ebi.ac.uk/gwas): (1) coronary artery disease (GWAS-CAD), (2) Crohn's disease (GWAS-Crohn), (3) and autism spectrum disorders (GWAS-ASD).…”

“…MRE miRNA regulatory elements Fig. 2 Enrichment of the filtered regulatory variants and the proteincoding variants from ASD cases in different ASD-associated datasets AXAS-ASD (n = 2664) [30], SFARI (n = 397) [47], M13 -Li 2014 (n = 115) [48], and GWAS-ASD (ASD associated genes as described in the NHGRI-EBI GWAS Catalog). Two unrelated disease control datasets, coronary artery disease (GWAS-CAD), and Crohn's disease (GWAS-Crohn) were also retrieved from the NHGRI-EBI GWAS Catalog.…”

Translational Research in Pediatrics IV: Solid Tissue Collection and Processing

“…233 The AFS has the practical limitation of its inability to assess each anatomic region separately, resulting in the development of an agonal stress rating system that evaluates the degree of stress based on gene expression data. 237 The agonal stress rating can reduce the number of false-positive findings by allowing a quantitative 113 • PPT1, caspase-3, cleaved-PARP, caspase-9, ROS, and SOD-2 113 • Infi ltrative glioma and gliosis 53 • EGFR 53 • Autism [197][198][199] • Neuronal microexons, 197 • Infantile X-linked dilated cardiomyopathy 200 • Saturated fatty acids, mitochondria structure 200 • Dilated cardiomyopathy and congenital heart disease 137…”