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 language | English |
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Article number | e1010921 |
Pages (from-to) | 1-23 |
Number of pages | 23 |
Journal | PLoS Genetics |
Volume | 19 |
Issue number | 9 |
Early online date | 7 Sept 2023 |
DOIs | |
Publication status | Published - 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.
Funders | Funder number |
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NetherlandsOrganizationforScientificResearch | GrantNo.NWOVICI435–14–005, GWAS2FUNC834057 |
F. Hoffmann-La Roche | 916-19-152, :201G-064 |
F. Hoffmann-La Roche | |
European Research Council | ERC-2018-AdG GWAS2FUNC 834057 |
European Research Council | |
Nederlandse Organisatie voor Wetenschappelijk Onderzoek | NWO VICI 435–14–005, 024.004.012 |
Nederlandse Organisatie voor Wetenschappelijk Onderzoek |