Broker genes in human disease.

Genes that underlie human disease are important subjects of systems biology research. In the present study, we demonstrate that Mendelian and complex disease genes have distinct and consistent protein-protein interaction (PPI) properties. We show that five different network properties can be reduced to two independent metrics when applied to the human PPI network. These two metrics largely coincide with the degree (number of connections) and the clustering coefficient (the number of connections among the neighbors of a particular protein). We demonstrate that disease genes have simultaneously unusually high degree and unusually low clustering coefficient. Such genes can be described as brokers in that they connect many proteins that would not be connected otherwise. We show that these results are robust to the effect of gene age and inspection bias variation. Notably, genes identified in genome-wide association study (GWAS) have network patterns that are almost indistinguishable from the network patterns of nondisease genes and significantly different from the network patterns of complex disease genes identified through non-GWAS means. This suggests either that GWAS focused on a distinct set of diseases associated with an unusual set of genes or that mapping of GWAS-identified single nucleotide polymorphisms onto the causally affected neighboring genes is error prone.