High false sign rates in transcriptome-wide association studies
Open accessAbstract
Transcriptome-wide association studies (TWAS) are widely used to identify genes involved in complex traits and to infer the direction of gene effects on traits. However, despite their popularity, it remains unclear how accurately TWAS recover the true direction of a gene’s effect on a trait. Here we estimate the false sign rate of TWAS for plasma proteins, leveraging the expectation that increased gene expression should generally increase protein expression. We then extend this framework to complex traits, where loss-of-function burden tests provide the expected direction of effect. In both analyses, we observe high discordance with expectations, with TWAS showing a false sign rate of 23% for plasma proteins and 33% for complex traits. We propose that much of the sign discordance arises when expression quantitative trait loci in non-trait-relevant tissues tag haplotypes associated with traits in genome-wide association studies via distinct, tightly linked regulatory variants, yielding spurious TWAS associations with the correct genes but with unreliable direction of effect. These findings show that TWAS-based direction-of-effect estimates should be interpreted with caution and raise concerns about the reliability of TWAS more broadly.
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Co-regulation confounds direction of genetic effects in transcriptome-wide association studies
Amariuta, T. (2026) · Nature Genetics · doi:10.1038/s41588-026-02793-7
- Authors
- Gerlach, P. A., Milind, N., Spence, J. P., & Pritchard, J. K.
- Affiliations
- Stanford Medicine (US)
- University of California, San Francisco (US)
- Stanford University (US)
- Corresponding author
- Gerlach, Peter A.
- Milind, Nikhil
- Spence, Jeffrey P.
- Pritchard, Jonathan K.
- Venue
- Nature Genetics
- Published
- 2026-10-22
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W7223179007
- Cited by
- 1
- References
- 58
- Citations by year
- 2026: 1
- FWCI
- 4.05
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Genetics (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Foundation for the National Institutes of Health (R01HG014005, U01HG012069)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- transcriptome-wide association study, direction of effect, gene expression, plasma proteins, complex traits, expression quantitative trait loci, regulatory variants, haplotype tagging, spurious association, methodological reliability
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