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A large fraction of human genes are regulated by genetic variation near the transcribed sequence ( cis -eQTL, expression quantitative trait locus), and many  cis -eQTLs have implications for human disease. Less is known regarding the effects of genetic variation on expression of distant genes ( trans -eQTLs) and their biological mechanisms. In this work, we use genome-wide data on SNPs and array-based expression measures from mononuclear cells obtained from a population-based cohort of 1,799 Bangladeshi individuals to characterize  cis - and  trans -eQTLs and determine if observed  trans -eQTL associations are mediated by expression of transcripts in  cis  with the SNPs showing  trans -association, using Sobel tests of mediation. We observed 434 independent  trans -eQTL associations at a false-discovery rate of 0.05, and 189 of these  trans -eQTLs were also  cis -eQTLs (enrichment P<0.0001). Among these 189  trans -eQTL associations, 39 were significantly attenuated after adjusting for a  cis -mediator based on Sobel P<10 -5 . We attempted to replicate 21 of these mediation signals in two European cohorts, and while only 7  trans -eQTL associations were present in one or both cohorts, 6 showed evidence of cis-mediation. Analyses of simulated data show that complete mediation will be observed as partial mediation in the presence of mediator measurement error or imperfect LD between measured and causal variants. Our data demonstrates that  trans -associations can become significantly stronger or switch directions after adjusting for a potential mediator. Using simulated data, we demonstrate that this phenomenon is expected in the presence of strong  cis - trans  confounding and when the measured  cis -transcript is correlated with the true (unmeasured) mediator. In conclusion, by applying mediation analysis to eQTL data, we show that a substantial fraction of observed  trans -eQTL associations can be explained by  cis -mediation. Future studies should focus on understanding the mechanisms underlying widespread  cis -mediation and their relevance to disease biology, as well as using mediation analysis to improve eQTL discovery.

Mediation Analysis Demonstrates That Trans-eQTLs Are Often Explained by Cis-Mediation: A Genome-Wide Analysis among 1,800 South Asians