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Reconsidering the validity of transcriptome-wide association studies

Christiaan de Leeuw, Josefin Werme, Jeanne Savage, Wouter Peyrot, Danielle Posthuma
doi: https://doi.org/10.1101/2021.08.15.456414
Christiaan de Leeuw
1Department of Complex Trait Genetics, Centre for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands
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  • For correspondence: c.a.de.leeuw@vu.nl
Josefin Werme
1Department of Complex Trait Genetics, Centre for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands
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Jeanne Savage
1Department of Complex Trait Genetics, Centre for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands
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Wouter Peyrot
1Department of Complex Trait Genetics, Centre for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands
2Department of Psychiatry, Amsterdam UMC, Vrije Universiteit, Amsterdam, the Netherlands
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Danielle Posthuma
1Department of Complex Trait Genetics, Centre for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands
3Department of Child and Adolescent Psychology and Psychiatry, section Complex Trait Genetics, Amsterdam Neuroscience, VU University Medical Centre, Amsterdam, The Netherlands
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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 estimates6,7, 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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted August 15, 2021.
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Reconsidering the validity of transcriptome-wide association studies
Christiaan de Leeuw, Josefin Werme, Jeanne Savage, Wouter Peyrot, Danielle Posthuma
bioRxiv 2021.08.15.456414; doi: https://doi.org/10.1101/2021.08.15.456414
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Reconsidering the validity of transcriptome-wide association studies
Christiaan de Leeuw, Josefin Werme, Jeanne Savage, Wouter Peyrot, Danielle Posthuma
bioRxiv 2021.08.15.456414; doi: https://doi.org/10.1101/2021.08.15.456414

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