Dataset Information

OTTERS: a powerful TWAS framework leveraging summary-level reference data.

ABSTRACT: Most existing TWAS tools require individual-level eQTL reference data and thus are not applicable to summary-level reference eQTL datasets. The development of TWAS methods that can harness summary-level reference data is valuable to enable TWAS in broader settings and enhance power due to increased reference sample size. Thus, we develop a TWAS framework called OTTERS (Omnibus Transcriptome Test using Expression Reference Summary data) that adapts multiple polygenic risk score (PRS) methods to estimate eQTL weights from summary-level eQTL reference data and conducts an omnibus TWAS. We show that OTTERS is a practical and powerful TWAS tool by both simulations and application studies.

SUBMITTER: Dai Q

PROVIDER: S-EPMC9992663 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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OTTERS: a powerful TWAS framework leveraging summary-level reference data.

Dai Qile Q Zhou Geyu G Zhao Hongyu H Võsa Urmo U Franke Lude L Battle Alexis A Teumer Alexander A Lehtimäki Terho T Raitakari Olli T OT Esko Tõnu T Epstein Michael P MP Yang Jingjing J

Nature communications 20230307 1

Most existing TWAS tools require individual-level eQTL reference data and thus are not applicable to summary-level reference eQTL datasets. The development of TWAS methods that can harness summary-level reference data is valuable to enable TWAS in broader settings and enhance power due to increased reference sample size. Thus, we develop a TWAS framework called OTTERS (Omnibus Transcriptome Test using Expression Reference Summary data) that adapts multiple polygenic risk score (PRS) methods to e ...[more]

PMID: 36882394

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Project description:Transcriptome wide association studies (TWAS) can be used as a powerful method to identify and interpret the underlying biological mechanisms behind GWAS by mapping gene expression levels with phenotypes. In TWAS, gene expression is often imputed from individual-level genotypes of regulatory variants identified from external resources, such as Genotype-Tissue Expression (GTEx) Project. In this setting, a straightforward approach to impute expression levels of a specific tissue is to use the model trained from the same tissue type. When multiple tissues are available for the same subjects, it has been demonstrated that training imputation models from multiple tissue types improves the accuracy because of shared eQTLs between the tissues and increase in effective sample size. However, existing joint-tissue methods require access of genotype and expression data across all tissues. Moreover, they cannot leverage the abundance of various expression datasets across various tissues for non-overlapping individuals. Here, we explore the optimal way to combine imputed levels across training models from multiple tissues and datasets in a flexible manner using summary-level data. Our proposed method (SWAM) combines arbitrary number of transcriptome imputation models to linearly optimize the imputation accuracy given a target tissue. By integrating models across tissues and/or individuals, SWAM can improve the accuracy of transcriptome imputation or to improve power to TWAS while only requiring individual-level data from a single reference cohort. To evaluate the accuracy of SWAM, we combined 49 tissue-specific gene expression imputation models from the GTEx Project as well as from a large eQTL study of Depression Susceptibility Genes and Networks (DGN) Project and tested imputation accuracy in GEUVADIS lymphoblastoid cell lines samples. We also extend our meta-imputation method to meta-TWAS to leverage multiple tissues in TWAS analysis with summary-level statistics. Our results capitalize on the importance of integrating multiple tissues to unravel regulatory impacts of genetic variants on complex traits.

Project description:MotivationMany GWAS conducted in the past decade have identified tens of thousands of disease related variants, which in total explained only part of the heritability for most traits. There remain many more genetics variants with small effect sizes to be discovered. This has motivated the development of sequencing studies with larger sample sizes and increased resolution of genotyped variants, e.g., the ongoing NHLBI Trans-Omics for Precision Medicine (TOPMed) whole genome sequencing project. An alternative approach is the development of novel and more powerful statistical methods. The current dominating approach in the field of GWAS analysis is the "single trait single variant" association test, despite the fact that most GWAS are conducted in deeply-phenotyped cohorts with many correlated traits measured. In this paper, we aim to develop rigorous methods that integrate multiple correlated traits and multiple variants to improve the power to detect novel variants. In recognition of the difficulty of accessing raw genotype and phenotype data due to privacy and logistic concerns, we develop methods that are applicable to publicly available GWAS summary data.ResultsWe build rigorous statistical models for GWAS summary statistics to motivate novel multi-trait SNP-set association tests, including variance component test, burden test and their adaptive test, and develop efficient numerical algorithms to quickly compute their analytical P-values. We implement the proposed methods in an open source R package. We conduct thorough simulation studies to verify the proposed methods rigorously control type I errors at the genome-wide significance level, and further demonstrate their utility via comprehensive analysis of GWAS summary data for multiple lipids traits and glycemic traits. We identified many novel loci that were not detected by the individual trait based GWAS analysis.Availability and implementationWe have implemented the proposed methods in an R package freely available at http://www.github.com/baolinwu/MSKAT.Supplementary informationSupplementary data are available at Bioinformatics online.

Dataset Information

OTTERS: a powerful TWAS framework leveraging summary-level reference data.

Publications

OTTERS: a powerful TWAS framework leveraging summary-level reference data.

Similar Datasets

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