Recent studies of the heritability of complex traits describe an omnigenic model, where a small proportion of trait inheritance is controlled by a few core genes with strong effects and the majority of trait inheritance is controlled by many small, distal (trans-acting) genetic effects. Often, trans-eQTL act through cis-mediators like nearby transcription factor genes, thus many trans-eQTL are also cis-eQTL. In this study, we performed a TWAS, testing the cis-genetically regulated component of gene expression for association with the measured abundance of proteins, to discover regulatory relationships between genes that are driven by cis-mediation. While traditional eQTL mapping studies are limited in their ability to detect trans-acting genetic variants due to the high multiple testing burden and the low effect sizes of trans-eQTL, our SNP prioritization method improved detection of trans-eQTL by reducing the multiple testing burden.
This repository houses code for the manuscript, "Transcriptome-wide association study of the plasma proteome reveals cis and trans regulatory mechanisms underlying complex traits." Summary statistics for all of the association analyses performed in the study can be found in the DropBox here. Significant results from our discovery and replication TWAS can be found in the following Zenodo repository: doi.org/10.5281/zenodo.10257676