Brasher, M. S. | bioRxiv Science

bioRxiv2022

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

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.

genetics↗

bioRxiv2022

Testing Human Anxiety Associations of Genes Previously Implicated by Mouse Anxiety Models

Anxiety disorders are common and can be debilitating, with effective treatments remaining hampered by an incomplete understanding of the underlying genetic etiology. Improvements have been made in understanding the genetic influences on mouse behavioral models of anxiety, yet it is unclear the extent to which genes identified in these experimental systems contribute to genetic variation in human anxiety phenotypes. Leveraging new and existing large-scale human genome-wide association studies, we tested whether sets of genes previously identified in mouse anxiety-like behavior studies contribute to a range of human anxiety disorders. When tested as individual genes, thirteen mouse-identified genes were associated with human anxiety phenotypes, suggesting an overlap of individual genes contributing to both mouse models of anxiety-like behaviors and human anxiety traits. When genes were tested as sets, we did identify fourteen significant associations between mouse gene sets and human anxiety, but the majority of gene sets showed no significant association with human anxiety phenotypes. These few significant associations indicate a need to identify and develop more translatable mouse models by identifying sets of genes that match between model systems and specific human phenotypes of interest. We suggest that continuing to develop improved behavioral paradigms and finer-scale experimental data, for instance from individual neuronal subtypes or cell-type-specific expression data, is likely to improve our understanding of the genetic etiology and underlying functional changes in anxiety disorders.

genetics↗