Abstract
Transcriptome-wide association studies (TWAS) integrate GWAS and expression quantitative trait locus (eQTL) datasets to discover candidate causal gene-trait associations. We integrate multi-tissue expression panels and summary GWAS for LDL cholesterol and Crohn's disease to show that TWAS are highly vulnerable to discovering non-causal genes, because variants at a single GWAS hit locus are often eQTLs for multiple genes. TWAS exhibit acute instability when the tissue of the expression panel is changed: candidate causal genes that are TWAS hits in one tissue are usually no longer hits in another, due to lack of expression or strong eQTLs, even though non-causal genes at the same loci remain. Because of these vulnerabilities, it is invalid to use TWAS as a method for finding causal genes, though it can be used as a weighted burden test to identify trait-associated loci. More broadly, our results showcase limitations of using expression variation across individuals to determine causal genes at GWAS loci.
