Predicting the genetic component of gene expression using gene regulatory networks.

Motivation: Gene expression prediction plays a vital role in transcriptome-wide association studies. Traditional models rely on genetic variants in close genomic proximity to the gene of interest to predict the genetic component of gene expression. Here, we propose a novel approach incorporating distal genetic variants acting through gene regulatory networks, in line with the omnigenic model of complex traits. Results: Using causal and coexpression Bayesian networks reconstructed from genomic and transcriptomic data, inference of gene expression from genotypic data is achieved through a two-step process. Initially, the expression level of each gene is predicted using its local genetic variants. The residual differences between the observed and predicted expression levels are then modeled using the genotype information of parent and/or grandparent nodes in the network. The final predicted expression level is obtained by summing the predictions from both models, effectively incorporating both local and distal genetic influences. Using regularized regression techniques for parameter estimation, we found that gene regulatory network-based gene expression prediction outperformed the traditional approach on simulated data and real data from yeast and humans. This study provides important insights into the challenge of gene expression prediction for transcriptome-wide association studies. Availability and implementation: The code is available on Github at github.com/guutama/GRN-TI.