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

http://www.cell.com/neuron/abstract/S0896-6273%2811%2900439-9

Authors
Sarah R. Gilman, Ivan Iossifovsend email, Dan Levy, Michael Ronemus, Michael Wigler, Dennis Vitkupsend email

* Highlights
* Rare de novo CNVs associated with autism contain functionally connected genes
* NETBAG method identifies a significant functional network affected by rare variants
* Identified network is related to synaptogenesis, axon guidance, and neuronal motility
* Genes perturbed in females carry more weight in the network than genes in males

Summary

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.