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

Integrating results from genome-wide association studies (GWASs) and studies of molecular phenotypes such as 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 locus (eQTL) studies, several methods have been proposed to identify gene-trait associations, primarily based on gene expression imputation. 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.” For this, we developed a cross-tissue subset-based transcriptome-wide association study (CSTWAS) meta-analysis method that improves power under such scenarios and can extract the set of potentially associated 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. 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 associated tissues for a gene-trait association, and identifies an accurate associated tissue set. By analyzing GWAS summary statistics of three complex traits and diseases, we demonstrate that CSTWAS could identify biological meaningful signals while providing an interpretation of disease etiology by extracting a set of potentially associated tissues.