Vulnerabilities of transcriptome-wide association studies [article]

Michael Wainberg, Nasa Sinnott-Armstrong, David Knowles, David Golan, Raili Ermel, Arno Ruusalepp, Thomas Quertermous, Ke Hao, Johan L. M. Bjorkegren, Manuel A. Rivas, Anshul Kundaje
2017 bioRxiv   pre-print
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
more » ... hanged: 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, while non-causal genes at the same loci remain. While TWAS is statistically valid when used as a weighted burden test to identify trait-associated loci, it is invalid to interpret TWAS associations as causal genes because the false discovery rate for TWAS causal gene discovery is not only high, but unquantifiable. More broadly, our results showcase limitations of using expression variation across individuals to determine causal genes at GWAS loci.
doi:10.1101/206961 fatcat:vevcpi5g7zh4jh47s64gs5yrpu