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Bioinformatics
Article . 2024 . Peer-reviewed
License: CC BY
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Bioinformatics
Article . 2024
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TWAS-GKF: a novel method for causal gene identification in transcriptome-wide association studies with knockoff inference

Authors: Anqi Wang; Peixin Tian; Yan Dora Zhang;

TWAS-GKF: a novel method for causal gene identification in transcriptome-wide association studies with knockoff inference

Abstract

Abstract Motivation Transcriptome-wide association study (TWAS) aims to identify trait-associated genes regulated by significant variants to explore the underlying biological mechanisms at a tissue-specific level. Despite the advancement of current TWAS methods to cover diverse traits, traditional approaches still face two main challenges: (i) the lack of methods that can guarantee finite-sample false discovery rate (FDR) control in identifying trait-associated genes; and (ii) the requirement for individual-level data, which is often inaccessible. Results To address this challenge, we propose a powerful knockoff inference method termed TWAS-GKF to identify candidate trait-associated genes with a guaranteed finite-sample FDR control. TWAS-GKF introduces the main idea of Ghostknockoff inference to generate knockoff variables using only summary statistics instead of individual-level data. In extensive studies, we demonstrate that TWAS-GKF successfully controls the finite-sample FDR under a pre-specified FDR level across all settings. We further apply TWAS-GKF to identify genes in brain cerebellum tissue from the Genotype-Tissue Expression (GTEx) v8 project associated with schizophrenia (SCZ) from the Psychiatric Genomics Consortium (PGC), and genes in liver tissue related to low-density lipoprotein cholesterol (LDL-C) from the UK Biobank, respectively. The results reveal that the majority of the identified genes are validated by Open Targets Validation Platform. Availability and implementation The R package TWAS.GKF is publicly available at https://github.com/AnqiWang2021/TWAS.GKF.

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Keywords

Original Paper, Gene Expression Profiling, Quantitative Trait Loci, Schizophrenia, Humans, Transcriptome, Polymorphism, Single Nucleotide, Algorithms, Genome-Wide Association Study

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selected citations
These citations are derived from selected sources.
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
4
Top 10%
Average
Average
Green
gold