Transcriptome-Wide Gene-Gene Interaction Association Study Elucidates Pathways and Functional Enrichment of Complex Traits

Abstract

It remains unknown to what extent gene-gene interactions contribute to complex traits. Here, we introduce a new approach using predicted gene expression to perform exhaustive transcriptome-wide interaction studies (TWISs) for multiple traits across all pairs of genes expressed in several tissue types. Using imputed transcriptomes, we simultaneously reduce the computational challenge and improve interpretability and statistical power. We discover and replicate several interaction associations, and find several hub genes with numerous interactions. We also demonstrate that TWIS can identify novel associated genes because genes with many or strong interactions have smaller single-locus model effect sizes. Finally, we develop a method to test gene set enrichment of TWIS associations (E-TWIS), finding numerous pathways and networks enriched in interaction associations. Epistasis is likely widespread, and our procedure represents a tractable framework for beginning to explore gene interactions and identify novel genomic targets.

Combinatorial transcriptomic and genetic dissection of insulin/IGF‐1 signaling‐regulated longevity in Caenorhabditis elegans

“…For example, transcriptomic analysis is adequate for the identification of many genes whose expression changes influence specific phenotypes (Garber et al., 2011; Wang et al., 2009; Wilhelm & Landry, 2009). Transcriptomic dissection analysis also provides quantitative measurements of genetic interactions in complex phenotypes (Angeles‐Albores et al., 2018; Evans et al., 2023). Thus, transcriptomic analysis of phenotypes represents an effective strategy for identifying multiple previously undetected genetic interactions.…”