The impact of inherited genetic variation on gene expression in humans is well-established. The majority of known expression quantitative trait loci (eQTLs) impact expression of local genes (cis-eQTLs). More research is needed to identify effects of genetic variation on distant genes (trans-eQTLs) and understand their biological mechanisms. One common trans-eQTLs mechanism is “mediation” by a local (cis) transcript. The multi-tissue expression data from the Genotype-Tissue Expression (GTEx) program provides a unique opportunity to study cis-mediation across human tissue types. We propose a method: Genomic Mediation analysis with Adaptive Confounding adjustment (GMAC). It adaptively selects potential confounding variables for each mediation test. Recently, we expand the analysis to jointly analyze multiple human tissues and the study of mediation would also help to identify trans-associations across tissue types.