A method for estimating coherence of molecular mechanisms in major human disease and traits.

Background: Phenotypes such as height and intelligence, are thought to be a product of the collective effects of multiple phenotype-associated genes and interactions among their protein products. High/low degree of interactions is suggestive of coherent/random molecular mechanisms, respectively. Comparing the degree of interactions may help to better understand the coherence of phenotype-specific molecular mechanisms and the potential for therapeutic intervention. However, direct comparison of the degree of interactions is difficult due to different sizes and configurations of phenotype-associated gene networks.

Methods: We introduce a metric for measuring coherence of molecular-interaction networks as a slope of internal versus external distributions of the degree of interactions. The internal degree distribution is defined by interaction counts within a phenotype-specific gene network, while the external degree distribution counts interactions with other genes in the whole protein-protein interaction (PPI) network. We present a novel method for normalizing the coherence estimates, making them directly comparable.

Results: Using STRING and BioGrid PPI databases, we compared the coherence of 116 phenotype-associated gene sets from GWAScatalog against size-matched KEGG pathways (the reference for high coherence) and random networks (the lower limit of coherence). We observed a range of coherence estimates for each category of phenotypes. Metabolic traits and diseases were the most coherent, while psychiatric disorders and intelligence-related traits were the least coherent. We demonstrate that coherence and modularity measures capture distinct network properties.

Conclusions: We present a general-purpose method for estimating and comparing the coherence of molecular-interaction gene networks that accounts for the network size and shape differences. Our results highlight gaps in our current knowledge of genetics and molecular mechanisms of complex phenotypes and suggest priorities for future GWASs.