To better understand the cellular mechanisms of trans-eQTLs, we characterized several of their functional properties. Of the 673 trans-eQTLs from the genome-wide analysis, 161 also had a cis-association (at a cis P value threshold of P ≤ 1.0×10−5) with 113 unique variants, yielding the set of 296 unique trios of an eVariant, a cis-eGene and a trans-eGene. This suggests a common mechanism for trans regulation in which the eVariant directly regulates expression of a nearby gene whose protein product then affects other genes downstream. Considering this observation, we ran a restricted test for trans-associations, limiting variants to the set of significant cis-eVariants (Extended Data Fig. 12a). From this, we identified a total of 33 trans-eGenes (10% FDR) among this subset of tests, 14 of which were not discovered in the genome-wide analysis (Supplementary Information 10). There were substantially more trans-eQTLs at 50% FDR from this cis-eVariant restricted test than random variants matched for MAF and distance to TSS and stratified by tissue (Cochran–Mantel–Haenszel test, P ≤ 2.2×10−16).
