Seminar by Prof. J. Douglas Armstrong

University of Edinburgh (UK)

Network topology analysis of the synaptic proteome reveals molecular substructures associated with complex human phenotypes and disease

The synaptic proteome is widely believed to be the molecular machine that underpins the core functions of neurons – the integration and transfer of information from one cell to another. Perhaps unsurprisingly it is enriched for proteins whose genes are linked to a wide range of human neurological conditions. However GWAS datasets from these conditions map less clearly onto the synaptic proteome often with weak or no significant enrichment. The synaptic proteome can be subdivided, on the basis of network topology into clusters that each have enriched functional associations. We hypothesised that these topological communities form natural groups for gene set analysis and contain information not only about protein encoding genes with a mechanistic association with the phenotype but also with interaction partners whose role is important but less direct. We combined 30 published synaptic proteomic studies from 2000 to date to obtain a list of 6500 molecules. We retrieved protein-protein interactions (PPIs) for combined list and built the most complete up-to-date PPI networks for presynaptic and postsynaptic compartments. We then divided this proteome up into sub-communities on the basis of network topology. We analysed three large Genome Wide Associations Studies of genetic associations with human cognitive ability, educational attainment or human diseases. We find closely interacting sub-communities within the synaptic proteome that are very highly enriched for genetic associations with a range of phenotypes and disorders. These sub-communities likely indicate molecular pathways that span complex traits and disease.