RT Journal Article
SR Electronic
T1 Vulnerabilities of transcriptome-wide association studies
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 206961
DO 10.1101/206961
A1 Michael Wainberg
A1 Nasa Sinnott-Armstrong
A1 David A Knowles
A1 David Golan
A1 Raili David
A1 Arno Ruusalepp
A1 Thomas Quertermous
A1 Ke Hao
A1 Johan LM Björkegren
A1 Manuel A Rivas
A1 Anshul Kundaje
YR 2017
UL http://biorxiv.org/content/early/2017/10/27/206961.abstract
AB 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, 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.