Subset-based method for cross-tissue transcriptome-wide association studies improves power and interpretability

Abstract

Integrating results from genome-wide association studies (GWAS) and studies of molecular phenotypes like gene expressions, can improve our understanding of the biological functions of trait-associated variants, and can help prioritize candidate genes for downstream analysis. Using reference expression quantitative trait loci (eQTL) studies, several methods have been proposed to identify significant gene-trait associations, primarily based on gene expression imputation. Further, to increase the statistical power by leveraging substantial eQTL sharing across tissues, meta-analysis methods aggregating such gene-based test results across multiple tissues or contexts have been developed as well. However, most existing meta-analysis methods have limited power to identify associations when the gene has weaker associations in only a few tissues and cannot identify the subset of tissues in which the gene is "activated" in. For this, we developed a novel cross-tissue subset-based meta-analysis (CSTWAS) method which improves power under such scenarios and can extract the set of potentially "active" tissues. To improve applicability, CSTWAS uses only GWAS summary statistics and pre-computed correlation matrices to identify a subset of tissues that have the maximal evidence of gene-trait association. We further developed an adaptive monte-carlo procedure with the generalized Pareto distribution (GPD) to accurately estimate highly significant p-values for the test statistics. Through numerical simulations, we found that CSTWAS can maintain a well-calibrated type-I error rate, improves power especially when there is a small number of "active" tissues for a gene-trait association and identifies an accurate "active" tissue-set. By analyzing several GWAS summary statistics of three complex traits and diseases, we demonstrated that CSTWAS could identify novel biological meaningful signals while providing an interpretation of disease etiology by extracting a set of potentially "active" tissues.