To garner additional information regarding the biology of ASD, we explored enrichment of association signals across a range of gene-sets and genomic annotations. Of the top canonical results, we observed enrichment in gene-sets related to synaptic structure and function. PDZ domain-binding, beta-catenin nuclear pathways, glutamate receptor activity, and adherens junctions all fit this categorization. PDZ domains (PSD95-disc large-zonula occludens-1) are found in scaffolding proteins, and those at neuronal excitatory synapses are thought to play a key role in synapse organisation and structure. These proteins organise glutamate receptors and associated protein composition at the synapse, subsequently determining the size and strength of the synapse (reviewed in [59]). Moreover, the beta-catenin and adherens gene-sets describe proteins that are involved in establishing synaptic contacts. Genetic insult which disrupts the synapse as a model of ASD is not novel [60], with genes encoding members of the SHANK, neurexin and neuroligin families, all well established as risk factors for ASD. Our data implicating gene-sets that interact with these genes confer additional support for the synaptic hypothesis of ASD.
