Abstract
Autism spectrum disorder (ASD) is marked by a strong genetic heterogeneity, which is underlined by the low overlap between ASD risk gene lists proposed in different studies. In this context, molecular networks can be used to analyze the results of several genome-wide studies in order to underline those network regions harboring genetic variations associated with ASD, the so-called “disease modules.” In this work, we used a recent network diffusion-based approach to jointly analyze multiple ASD risk gene lists. We defined genome-scale prioritizations of human genes in relation to ASD genes from multiple studies, found significantly connected gene modules associated with ASD and predicted genes functionally related to ASD risk genes. Most of them play a role in synapsis and neuronal development and function; many are related to syndromes that can be in comorbidity with ASD and the remaining are involved in epigenetics, cell cycle, cell adhesion and cancer.
Highlights
“Autism spectrum disorder” (ASD) includes clinically and etiologically wide range of neurodevelopmental disorders such as the less severe disorders Asperger’s syndrome and pervasive developmental disorder, not otherwise specified, as well as the most severe childhood disintegrative disorder
Regarding the integration of networks and ASD genetic data, Cristino et al (2014) studied the interacting partners of genes known to be associated with ASDs and other related disorders; Noh et al (2013) identified a significantly interconnected network of genes affected by copy number variations (CNVs); Li et al (2014) studied the association between ASDs and genes forming topological communities; Gilman et al (2011) found functionally connected clusters of genes affected by CNVs
With the aim of characterizing the functional relations among SFARI genes and predict relevant risk genes for ASDs, we considered direct and indirect protein-protein interactions (PPI) and quantified, via the permutation-adjusted network smoothing index (NSI) (Sp) (Bersanelli et al, 2016), the network proximity of each human gene in relation to the network location of 154 genes reported as strongly associated with ASD (SFARIhn0 list, Table 1)
Summary
“Autism spectrum disorder” (ASD) includes clinically and etiologically wide range of neurodevelopmental disorders such as the less severe disorders Asperger’s syndrome and pervasive developmental disorder, not otherwise specified, as well as the most severe childhood disintegrative disorder. The approaches currently used to disentangle the genetic complexity of ASDs include large genome-wide association studies (GWAS), CNV testing and genome sequencing. The analysis of molecular interactions and pathways is crucial for the interpretation of the results emerging from genome-scale studies on a pathology marked by a significant genetic heterogeneity. Molecular interaction networks have been used in the analysis of ASD genetic data to define gene networks associated with ASD. Regarding the integration of networks and ASD genetic data, Cristino et al (2014) studied the interacting partners of genes known to be associated with ASDs and other related disorders; Noh et al (2013) identified a significantly interconnected network of genes affected by CNVs; Li et al (2014) studied the association between ASDs and genes forming topological communities (clusters of genes with a high density of connection between genes of the community and less connections with genes outside the community); Gilman et al (2011) found functionally connected clusters of genes affected by CNVs
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