Distilling Direct Effects via Conditional Differential Gene Expression Analysis

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ID: 333075
2026
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Abstract
Abstract Motivation Differential gene expression (DGE) analysis is foundational for interpreting RNA sequencing data, but it conflates direct biological effects with correlations propagated through gene co-expression. Across three RNA sequencing datasets (including a genome-scale perturb-seq experiment), we find that only a small fraction of differentially expressed genes have direct effects on the trait of interest, while the majority are undirected or passengers whose associations are mediated through other genes. Results To distinguish direct effect genes, we introduce conditional differential gene expression (CDGE) analysis, a framework that tests for conditional rather than marginal association between each gene and the trait of interest. Implemented via the GhostKnockoff procedure with lasso regression, CDGE delivers false discovery rate control, operates on summary statistics from existing DGE pipelines, and accommodates batch effects. The genes identified by CDGE mediate the effects of most other differentially expressed genes and show stronger enrichment for known protein-protein interactions and biological pathways than DGE-identified genes. These results suggest that the field has been systematically over-interpreting DGE outputs, and that distinguishing direct from mediated effects is essential for prioritizing genes for functional follow-up and therapeutic development. Availability To facilitate public access to knockoff-based CDGE analysis, we have developed the R package “KnockoffCDGE” as an integrated implementation, which is freely available at https://github.com/GuJQ5/KnockoffCDGE (DOI: 10.5281/zenodo.23241517). Supplementary information Supplementary data are available at Bioinformatics online.
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Authors Jiaqi Gu, Andrew J. Skelton, James Staley, Pierce Oran Popson, Lei Peng, Xiaoyu Song, Juliet K. Knowles, Zihuai He
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Journal BMC Bioinformatics
Year 2026
DOI
10.1093/bioinformatics/btag784
URL
https://doi.org/10.1093/bioinformatics/btag784
Keywords Keywords not found

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