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.