PhenoGeneRanker: Gene and Phenotype Prioritization Using Multiplex Heterogeneous Networks.

Uncovering genotype-phenotype relationships is a fundamental challenge in genomics. Gene prioritization is an important step for this endeavor to make a short manageable list from a list of thousands of genes coming from high-throughput studies. Network propagation methods are promising and state of the art methods for gene prioritization based on the premise that functionally related genes tend to be close to each other in the biological networks. Recently, we introduced PhenoGeneRanker, a network-propagation algorithm for multiplex heterogeneous networks. PhenoGeneRanker allows multi-layer gene and phenotype networks. It also calculates empirical p values of gene and phenotype ranks using random stratified sampling of seeds of genes and phenotypes based on their connectivity degree in the network. In this study, we introduce the PhenoGeneRanker Bioconductor package and its application to multi-omics rat genome datasets to rank hypertension disease-related genes and strains. We showed that PhenoGeneRanker performed better to rank hypertension disease-related genes using multiplex gene networks than aggregated gene networks. We also showed that PhenoGeneRanker performed better to rank hypertension disease-related strains using multiplex phenotype network than single or aggregated phenotype networks. We performed a rigorous hyperparameter analysis and, finally showed that Gene Ontology (GO) enrichment of statistically significant top-ranked genes resulted in hypertension disease-related GO terms.