VINTAGE: Variant-set test INtegrative TWAS for GEne-based analysis

An alternative framework for transcriptome-wide association studies to detect and decipher gene-trait associations

Integrative analysis of genome-wide association studies (GWAS) with gene expression mapping studies holds the promise to unravel the molecular mechanisms underlying disease etiology. Here, we present VINTAGE, an alternative statistical framework for such integrative analysis to identify and decipher gene-trait associations. VINTAGE explicitly quantifies and tests the proportion of genetic effects on a trait potentially mediated through gene expression using a local genetic correlation test, and further leverages such information to guide the integration of gene expression mapping study towards gene association mapping in GWAS through a genetic variance test. The explicit quantification of local genetic correlation in VINTAGE allows its gene association test to unify two seemingly unrelated methods, SKAT and TWAS, into the same analytic framework and include both as special cases, thus achieving robust performance across a range of scenarios. The framework of VINTAGE offers a clearer understanding of TWAS false signals when gene expression is not relevant to SNP-trait associations. VINTAGE also stands out as the only effective method in assessing potential gene mediation effects, revealing that most genes lack detectable mediation effects, which explains the power advantage of VINTAGE and SKAT over TWAS.

Installation

VINTAGE is implemented as an R package with underlying efficient C++ code interfaced through Rcpp and RcppArmadillo. VINTAGE depends on a few other R packages. Please refer to the package DESCRIPTION file for details. Dependent packages are supposed to be automatically installed while installing VINTAGE. The installation of VINTAGE has been tested on Ubuntu 20.04.6.

Install the VINTAGE R package maintained in github through the devtools package. It takes a few minutes to install the package depending on the number of dependencies that also need to be installed in the process.

if(!require(devtools))
  install.packages(devtools)
devtools::install_github("zhengli09/VINTAGE")
library(VINTAGE)
?VINTAGE
?run_vintage

How to use VINTAGE (v0.1.008)

Check our vignettes.

Citing the work

If you find the VINTAGE package or any of the source code in this repository useful for your work, please cite:

Li, Z., Gao, B, Zhou, X. VINTAGE: An alternative framework for transcriptome-wide association studies to detect and decipher gene-trait associations. Preprint

Visit our group website for more statistical tools on analyzing genetics and genomics data.