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. 2013 Jun;9(6):e1003523.
doi: 10.1371/journal.pgen.1003523. Epub 2013 Jun 6.

Network topologies and convergent aetiologies arising from deletions and duplications observed in individuals with autism

Hyun Ji Noh  1 , Chris P Ponting, Hannah C Boulding, Stephen Meader, Catalina Betancur, Joseph D Buxbaum, Dalila Pinto, Christian R Marshall, Anath C Lionel, Stephen W Scherer, Caleb Webber
Affiliations

Network topologies and convergent aetiologies arising from deletions and duplications observed in individuals with autism

Hyun Ji Noh et al. PLoS Genet. 2013 Jun.

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Relationships of mouse model phenotypic terms enriched among genes overlapped by de novo CNVs identified in individuals with ASD.
Relationships between phenotypic terms within the Mammalian Phenotype Ontology are indicated by a blue arrow running from the child term to the parent term. Terms are significant (BH-adjusted p<5%) in at least one of 4 sets of de novo CNVs identified in individuals with autism if they are shown with a coloured border (red, dark and light blue). Those terms whose significant enrichment is observed in three independent sets, and thus triplicated, are marked with a boxed letter “T”. Panels A–E show representative clusters of Behaviour/Neurological phenotypic category, while Panel F shows the enriched phenotypes from the Nervous System phenotypic category and Panel G shows representative enrichments from the Hearing/Vestibular/Ear phenotypic category. The number adjacent to the phenotypic terms indicates the rank of that phenotypic term among those phenotypes significantly enriched among a set of 22 disease genes previously implicated in ASD (see Results).
Figure 2
Figure 2. An ASD-associated interaction network.
The network is formed from direct protein-protein interactions between the products of ASD dn CNV genes that are associated with synaptic phenotypes (shown with thicker grey border), genes previously implicated in ASD (ASD-implicated genes), and other ASD dn CNV genes whose products directly interact with these gene's products. Physical interactions between two proteins are shown as an edge connecting two circles representing each gene. Genes found to be duplicated in autistic patients in this study are shown in green, deleted genes in blue, and ASD-implicated genes in red. An alternative and more detailed view of this network is shown in Figure S6.
Figure 3
Figure 3. Distinct duplications and deletions of genes whose proteins interact within the ASD-associated network perturb pathways in the same direction.
Genes duplicated within ASD dn CNVs are indicated with green upwards arrows while those deleted are denoted by blue downwards arrows. Previously identified ASD-Implicated genes found to be disrupted in autism patients are denoted with red downwards arrows. The nature of the interactions/regulations between proteins/molecules are shown with different edge types (see in-figure legend). The ASD-associated network (Figure 2) identifies several deletion/duplication pathway cascades, for example the MAPK3 pathway (see Discussion for additional examples). Here, deletions of the MAPK3 pathway components (i.e. SYNGAP1, SHANK2, KRAS, MAPK3, PAK2, and CREBBP) and duplications of their negative regulators (i.e. FMR1, GDI1, ARHGDIA, CAMK2B, and CAMKK2) found in autistic patients identify converging effects on the MAPK pathway, specifically reduced CREB-dependent transcription , , , . CREB-dependent transcription has been implicated in neuroadaptation . In addition, increased NO* production leads to the inhibition of MAPK1/3 activity , which fits well with the observed CNV duplications of both NOS1 and DLG4, the latter gene promoting recruitment of NOS1 . Similarly, duplication of PRKG1, which is up-regulated by NO* and expresses a product that inhibits IP3 production, is predicted to reduced activation of the calcium-releasing IP3-receptor ITPR1 , which is in turn found to be deleted.
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