On the interpretation of transcriptome-wide association studies

Christiaan de Leeuw*, Josefin Werme, Jeanne E. Savage, Wouter J. Peyrot, Danielle Posthuma

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Transcriptome-wide association studies (TWAS) aim to detect relationships between gene expression and a phenotype, and are commonly used for secondary analysis of genome-wide association study (GWAS) results. Results from TWAS analyses are often interpreted as indicating a genetic relationship between gene expression and a phenotype, but this interpretation is not consistent with the null hypothesis that is evaluated in the traditional TWAS framework. In this study we provide a mathematical outline of this TWAS framework, and elucidate what interpretations are warranted given the null hypothesis it actually tests. We then use both simulations and real data analysis to assess the implications of misinterpreting TWAS results as indicative of a genetic relationship between gene expression and the phenotype. Our simulation results show considerably inflated type 1 error rates for TWAS when interpreted this way, with 41% of significant TWAS associations detected in the real data analysis found to have insufficient statistical evidence to infer such a relationship. This demonstrates that in current implementations, TWAS cannot reliably be used to investigate genetic relationships between gene expression and a phenotype, but that local genetic correlation analysis can serve as a potential alternative.

Original languageEnglish
Article numbere1010921
Pages (from-to)1-23
Number of pages23
JournalPLoS Genetics
Volume19
Issue number9
Early online date7 Sept 2023
DOIs
Publication statusPublished - Sept 2023

Bibliographical note

Funding Information:
Funding: This work was funded by The Netherlands Organization for Scientific Research (Grant No. NWO VICI 435–14–005 [to DP]) and NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012 [to DP]), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057 [to DP, and funding CdL]). CdL was funded by F. Hoffmann-La Roche AG. WJP was funded by an NWO Veni grant (NWO: 916-19-152). JES was supported by an NWO Veni grant (NWO: 201G-064). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Funding Information:
Funding:ThisworkwasfundedbyThe NetherlandsOrganizationforScientificResearch (GrantNo.NWOVICI435–14–005[toDP])and NWOGravitation:BRAINSCAPES:ARoadmap fromNeurogeneticstoNeurobiology(GrantNo. 024.004.012[toDP]),andaEuropeanResearch Counciladvancedgrant(GrantNo,ERC-2018-AdG GWAS2FUNC834057[toDP,andfundingCdL]). CdLwasfundedbyF.Hoffmann-LaRocheAG. WJPwasfundedbyanNWOVenigrant(NWO: 916-19-152).JESwassupportedbyanNWOVeni grant(NWO:201G-064).Thefundershadnorole instudydesign,datacollectionandanalysis, decisiontopublish,orpreparationofthe manuscript.

Publisher Copyright:
Copyright: © 2023 de Leeuw et al.

Funding

Funding: This work was funded by The Netherlands Organization for Scientific Research (Grant No. NWO VICI 435–14–005 [to DP]) and NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012 [to DP]), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057 [to DP, and funding CdL]). CdL was funded by F. Hoffmann-La Roche AG. WJP was funded by an NWO Veni grant (NWO: 916-19-152). JES was supported by an NWO Veni grant (NWO: 201G-064). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding:ThisworkwasfundedbyThe NetherlandsOrganizationforScientificResearch (GrantNo.NWOVICI435–14–005[toDP])and NWOGravitation:BRAINSCAPES:ARoadmap fromNeurogeneticstoNeurobiology(GrantNo. 024.004.012[toDP]),andaEuropeanResearch Counciladvancedgrant(GrantNo,ERC-2018-AdG GWAS2FUNC834057[toDP,andfundingCdL]). CdLwasfundedbyF.Hoffmann-LaRocheAG. WJPwasfundedbyanNWOVenigrant(NWO: 916-19-152).JESwassupportedbyanNWOVeni grant(NWO:201G-064).Thefundershadnorole instudydesign,datacollectionandanalysis, decisiontopublish,orpreparationofthe manuscript.

FundersFunder number
NetherlandsOrganizationforScientificResearchGrantNo.NWOVICI435–14–005, GWAS2FUNC834057
F. Hoffmann-La Roche916-19-152, :201G-064
F. Hoffmann-La Roche
European Research CouncilERC-2018-AdG GWAS2FUNC 834057
European Research Council
Nederlandse Organisatie voor Wetenschappelijk OnderzoekNWO VICI 435–14–005, 024.004.012
Nederlandse Organisatie voor Wetenschappelijk Onderzoek

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