Functional dyadicity and heterophilicity of gene-gene interactions in statistical epistasis networks.

BACKGROUND

The interaction effect among multiple genetic factors, i.e. epistasis, plays an important role in explaining susceptibility on common human diseases and phenotypic traits. The uncertainty over the number of genetic attributes involved in interactions poses great challenges in genetic association studies and calls for advanced bioinformatics methodologies. Network science has gained popularity in modeling genetic interactions thanks to its structural characterization of large numbers of entities and their complex relationships. However, little has been done on functionally interpreting statistically inferred epistatic interactions using networks.

RESULTS

In this study, we propose to characterize gene functional properties in the context of interaction network structure. We used Gene Ontology (GO) to functionally annotate genes as vertices in a statistical epistasis network, and quantitatively characterize the correlation between the distribution of gene functional properties and the network structure by measuring dyadicity and heterophilicity of each functional category in the network. These two parameters quantify whether genetic interactions tend to occur more frequently for genes from the same functional category, i.e. dyadic effect, or more frequently for genes from across different functional categories, i.e. heterophilic effect.

CONCLUSIONS

By applying this framework to a population-based bladder cancer dataset, we were able to identify several GO categories that have significant dyadicity or heterophilicity associated with bladder cancer susceptibility. Thus, our informatics framework suggests a new methodology for embedding functional analysis in network modeling of statistical epistasis in genetic association studies.