Dataset Information

Transcriptome-wide association studies: a view from Mendelian randomization.

ABSTRACT:

Background

Genome-wide association studies (GWASs) have identified thousands of genetic variants that are associated with many complex traits. However, their biological mechanisms remain largely unknown. Transcriptome-wide association studies (TWAS) have been recently proposed as an invaluable tool for investigating the potential gene regulatory mechanisms underlying variant-trait associations. Specifically, TWAS integrate GWAS with expression mapping studies based on a common set of variants and aim to identify genes whose GReX is associated with the phenotype. Various methods have been developed for performing TWAS and/or similar integrative analysis. Each such method has a different modeling assumption and many were initially developed to answer different biological questions. Consequently, it is not straightforward to understand their modeling property from a theoretical perspective.

Results

We present a technical review on thirteen TWAS methods. Importantly, we show that these methods can all be viewed as two-sample Mendelian randomization (MR) analysis, which has been widely applied in GWASs for examining the causal effects of exposure on outcome. Viewing different TWAS methods from an MR perspective provides us a unique angle for understanding their benefits and pitfalls. We systematically introduce the MR analysis framework, explain how features of the GWAS and expression data influence the adaptation of MR for TWAS, and re-interpret the modeling assumptions made in different TWAS methods from an MR angle. We finally describe future directions for TWAS methodology development.

Conclusions

We hope that this review would serve as a useful reference for both methodologists who develop TWAS methods and practitioners who perform TWAS analysis.

SUBMITTER: Zhu H

PROVIDER: S-EPMC9009829 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Publications

Transcriptome-wide association studies: a view from Mendelian randomization.

Zhu Huanhuan H Zhou Xiang X

Quantitative biology (Beijing, China) 20210601 2

<h4>Background</h4>Genome-wide association studies (GWASs) have identified thousands of genetic variants that are associated with many complex traits. However, their biological mechanisms remain largely unknown. Transcriptome-wide association studies (TWAS) have been recently proposed as an invaluable tool for investigating the potential gene regulatory mechanisms underlying variant-trait associations. Specifically, TWAS integrate GWAS with expression mapping studies based on a common set of var ...[more]

PMID: 35433074

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Project description:It is of great interest and potential to discover causal relationships between pairs of exposures and outcomes using genetic variants as instrumental variables (IVs) to deal with hidden confounding in observational studies. Two most popular approaches are Mendelian randomization (MR), which usually use independent genetic variants/SNPs across the genome, and transcriptome-wide association studies (TWAS) (or their generalizations) using cis-SNPs local to a gene (or some genome-wide and likely dependent SNPs), as IVs. In spite of their many promising applications, both approaches face a major challenge: the validity of their causal conclusions depends on three critical assumptions on valid IVs, and more generally on other modeling assumptions, which however may not hold in practice. The most likely as well as challenging situation is due to the wide-spread horizontal pleiotropy, leading to two of the three IV assumptions being violated and thus to biased statistical inference. More generally, we'd like to conduct a goodness-of-fit (GOF) test to check the model being used. Although some methods have been proposed as being robust to various degrees to the violation of some modeling assumptions, they often give different and even conflicting results due to their own modeling assumptions and possibly lower statistical efficiency, imposing difficulties to the practitioner in choosing and interpreting varying results across different methods. Hence, it would help to directly test whether any assumption is violated or not. In particular, there is a lack of such tests for TWAS. We propose a new and general GOF test, called TEDE (TEsting Direct Effects), applicable to both correlated and independent SNPs/IVs (as commonly used in TWAS and MR respectively). Through simulation studies and real data examples, we demonstrate high statistical power and advantages of our new method, while confirming the frequent violation of modeling (including valid IV) assumptions in practice and thus the importance of model checking by applying such a test in MR/TWAS analysis.

Dataset Information

Transcriptome-wide association studies: a view from Mendelian randomization.

Background

Results

Conclusions

Publications

Transcriptome-wide association studies: a view from Mendelian randomization.

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