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BackgroundGenome‐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. ResultsWe 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. ConclusionsWe hope that this review would serve as a useful reference for both methodologists who develop TWAS methods and practitioners who perform TWAS analysis.
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MR.RGM: an R package for fitting Bayesian multivariate bidirectional Mendelian randomization networks
Abstract MotivationMendelian randomization (MR) infers causal relationships between exposures and outcomes using genetic variants as instrumental variables. Typically, MR considers only a pair of exposure and outcome at a time, limiting its capability of capturing the entire causal network. We overcome this limitation by developing MR.RGM (Mendelian randomization via reciprocal graphical model), a fast R-package that implements the Bayesian reciprocal graphical model and enables practitioners to construct holistic causal networks with possibly cyclic/reciprocal causation and proper uncertainty quantifications, offering a comprehensive understanding of complex biological systems and their interconnections. ResultsWe developed MR.RGM, an open-source R package that applies bidirectional MR using a network-based strategy, enabling the exploration of causal relationships among multiple variables in complex biological systems. MR.RGM holds the promise of unveiling intricate interactions and advancing our understanding of genetic networks, disease risks, and phenotypic complexities. Availability and implementationMR.RGM is available at CRAN (https://CRAN.R-project.org/package=MR.RGM, DOI: 10.32614/CRAN.package.MR.RGM) and https://github.com/bitansa/MR.RGM.
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- Award ID(s):
- 2112943
- PAR ID:
- 10582374
- Publisher / Repository:
- Oxford University Press
- Date Published:
- Journal Name:
- Bioinformatics
- Volume:
- 41
- Issue:
- 4
- ISSN:
- 1367-4811
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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