Reconsidering the validity of transcriptome-wide association studies

Abstract

Transcriptome-wide association studies (TWAS)^1–5, which aim to detect relationships between gene expression and a phenotype, are commonly used for secondary analysis of genome-wide association study (GWAS) results. Results of TWAS analyses are often interpreted as indicating a genetically mediated relationship between gene expression and the phenotype, but because the traditional TWAS framework does not model the uncertainty in the expression quantitative trait loci (eQTL) effect estimates^6,7, this interpretation is not justified. In this study we outline the implications of this issue. Using simulations, we show severely inflated type 1 error rates for TWAS when evaluating a null hypothesis of no genetic relationship between gene expression and the phenotype. Moreover, in our application to real data only 51% of the TWAS associations were confirmed with local genetic correlation⁸ analysis, an approach which correctly evaluates the same null. Our results thus demonstrate that TWAS is unsuitable for investigating genetic relationships between gene expression and a phenotype.