title: Network topologies and convergent aetiologies arising from deletions and duplications observed in individuals with autism.
abstract: Autism Spectrum Disorders (ASD) are highly heritable and characterised by impairments in social interaction and communication, and restricted and repetitive behaviours. Considering four sets of de novo copy number variants (CNVs) identified in 181 individuals with autism and exploiting mouse functional genomics and known protein-protein interactions, we identified a large and significantly interconnected interaction network. This network contains 187 genes affected by CNVs drawn from 45% of the patients we considered and 22 genes previously implicated in ASD, of which 192 form a single interconnected cluster. On average, those patients with copy number changed genes from this network possess changes in 3 network genes, suggesting that epistasis mediated through the network is extensive. Correspondingly, genes that are highly connected within the network, and thus whose copy number change is predicted by the network to be more phenotypically consequential, are significantly enriched among patients that possess only a single ASD-associated network copy number changed gene (p = 0.002). Strikingly, deleted or disrupted genes from the network are significantly enriched in GO-annotated positive regulators (2.3-fold enrichment, corrected p = 2×10(-5)), whereas duplicated genes are significantly enriched in GO-annotated negative regulators (2.2-fold enrichment, corrected p = 0.005). The direction of copy change is highly informative in the context of the network, providing the means through which perturbations arising from distinct deletions or duplications can yield a common outcome. These findings reveal an extensive ASD-associated molecular network, whose topology indicates ASD-relevant mutational deleteriousness and that mechanistically details how convergent aetiologies can result extensively from CNVs affecting pathways causally implicated in ASD.
authors.affiliation: MRC Functional Genomics Unit, University of Oxford, Department of Physiology, Anatomy, and Genetics, Oxford, United Kingdom.
authors.forename: Hyun Ji
authors.initials: HJ
authors.lastname: Noh
authors.forename: Chris P
authors.initials: CP
authors.lastname: Ponting
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Boulding
authors.forename: Stephen
authors.initials: S
authors.lastname: Meader
authors.forename: Catalina
authors.initials: C
authors.lastname: Betancur
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Dalila
authors.initials: D
authors.lastname: Pinto
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.forename: Anath C
authors.initials: AC
authors.lastname: Lionel
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.forename: Caleb
authors.initials: C
authors.lastname: Webber
mesh_terms: D000818:Animals; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D017353:Gene Deletion; D018628:Gene Dosage; D020440:Gene Duplication; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D051379:Mice; D060066:Protein Interaction Maps / Q000235:genetics*