On the interpretation of transcriptome-wide association studies.
Journal
PLoS genetics
ISSN: 1553-7404
Titre abrégé: PLoS Genet
Pays: United States
ID NLM: 101239074
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
received:
04
05
2023
accepted:
15
08
2023
revised:
19
09
2023
medline:
20
9
2023
pubmed:
7
9
2023
entrez:
7
9
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37676898
doi: 10.1371/journal.pgen.1010921
pii: PGENETICS-D-23-00513
pmc: PMC10508613
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1010921Informations de copyright
Copyright: © 2023 de Leeuw et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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