Article

Rare De Novo Variants Associated with Autism Implicate a Large Functional Network of Genes Involved in Formation and Function of Synapses

Center for Computational Biology and Bioinformatics and Department of Biomedical Informatics, Columbia University, 1130 St. Nicolas Ave, New York, NY 10032, USA.
Neuron (Impact Factor: 15.05). 06/2011; 70(5):898-907. DOI: 10.1016/j.neuron.2011.05.021
Source: PubMed

ABSTRACT

Identification of complex molecular networks underlying common human phenotypes is a major challenge of modern genetics. In this study, we develop a method for network-based analysis of genetic associations (NETBAG). We use NETBAG to identify a large biological network of genes affected by rare de novo CNVs in autism. The genes forming the network are primarily related to synapse development, axon targeting, and neuron motility. The identified network is strongly related to genes previously implicated in autism and intellectual disability phenotypes. Our results are also consistent with the hypothesis that significantly stronger functional perturbations are required to trigger the autistic phenotype in females compared to males. Overall, the presented analysis of de novo variants supports the hypothesis that perturbed synaptogenesis is at the heart of autism. More generally, our study provides proof of the principle that networks underlying complex human phenotypes can be identified by a network-based functional analysis of rare genetic variants.

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    • "More recently, exome sequencing of parent– offspring trios has shown that de novo point mutations contribute to ASD in 10–30 % of sporadic patients (Murdoch and State 2013; Krumm et al. 2014; O'Roak et al. 2011, 2012; Sanders et al. 2012; Neale et al. 2012; Iossifov et al. 2012, 2014). These studies predicted that ASD could result from genetic abnormalities in several hundreds of different genes, many of which are, nonetheless, interconnected or part of common functional pathways (Neale et al. 2012; O'Roak et al. 2012; Sanders et al. 2012; Iossifov et al. 2012; Gilman et al. 2011). Examples of pathways repeatedly involved in ASD include: synaptic function, illustrated by mutations in SHANK1-3 scaffolding proteins, neuroligins , neurexins, contactins and contactin-associated proteins encoding genes; the mTOR pathway, illustrated by mutations in TSC1/TSC2 or PTEN that cause syndromic forms of ASD; chromatin remodeling; and Wnt signaling (Krumm et al. 2014; Jeste and Geschwind 2014; Huguet et al. 2013). "
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