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Trans -acting expression quantitative trait loci ( trans -eQTLs) account for ≥70 %  expression heritability and could therefore facilitate uncovering mechanisms underlying the origination of complex diseases. Identifying  trans -eQTLs is challenging because of small effect sizes, tissue specificity, and a severe multiple-testing burden. Tejaas predicts  trans -eQTLs by performing L2-regularized “reverse” multiple regression of each SNP on all genes, aggregating evidence from many small  trans -effects while being unaffected by the strong expression correlations. Combined with a novel unsupervised k-nearest neighbor method to remove confounders, Tejaas predicts 18851 unique  trans -eQTLs across 49 tissues from GTEx. They are enriched in open chromatin, enhancers, and other regulatory regions. Many overlap with disease-associated SNPs, pointing to tissue-specific transcriptional regulation mechanisms.   Supplementary Information  The online version contains supplementary material available at (10.1186/s13059-021-02361-8).

Tejaas: reverse regression increases power for detecting trans-eQTLs