Learning gene networks underlying clinical phenotypes using SNP perturbation

Availability of genome sequence, molecular, and clinical phenotype data for large patient cohorts generated by recent technological advances provides an opportunity to dissect the genetic architecture of complex diseases at system level. However, previous analyses of such data have largely focused on the co-localization of SNPs associated with clinical and expression traits, each identified from genome-wide association studies and expression quantitative trait locus mapping. Thus, their description of the molecular mechanisms behind the SNPs influencing clinical phenotypes was limited to the single gene linked to the co-localized SNP. Here we introduce PerturbNet, a statistical framework for learning gene networks that modulate the influence of genetic variants on phenotypes, using genetic variants as naturally occurring perturbation of a biological system. PerturbNet uses a probabilistic graphical model to directly model the cascade of perturbation from genetic variants to the gene network to the phenotype network along with the networks at each layer of the biological system. PerturbNet learns the entire model by solving a single optimization problem with an efficient algorithm that can analyze human genome-wide data within a few hours. PerturbNet inference procedures extract a detailed description of how the gene network modulates the genetic effects on phenotypes. Using simulated and asthma data, we demonstrate that PerturbNet improves statistical power for detecting disease-linked SNPs and identifies gene networks and network modules mediating the SNP effects on traits, providing deeper insights into the underlying molecular mechanisms.Author summary: We describe PerturbNet, a statistical framework for learning a gene network that modulates the influence of genetic variants on phenotypes, using genetic variants as naturally occurring perturbation of a biological system. PerturbNet directly models the cascade of perturbation from genetic variants to the gene network to the phenotype network, thus integrating the existing computational tools for eQTL mapping, GWAS, co-localization analysis of eQTL and GWAS variants, and gene network discovery under SNP perturbation within a single statistical framework. We demonstrate that PerturbNet improves statistical power for detecting disease-linked SNPs and uncovers gene networks mediating the SNP effects on traits, with computational efficiency that allows for human data analysis within several hours.