Transcriptome-wide association studies (TWAS), 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, 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 correlation 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.