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

<div><p>A large fraction of human genes are regulated by genetic variation near the transcribed sequence (<i>cis</i>-eQTL, expression quantitative trait locus), and many <i>cis</i>-eQTLs have implications for human disease. Less is known regarding the effects of genetic variation on expression of distant genes (<i>trans</i>-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 <i>cis</i>- and <i>trans</i>-eQTLs and determine if observed <i>trans</i>-eQTL associations are mediated by expression of transcripts in <i>cis</i> with the SNPs showing <i>trans</i>-association, using Sobel tests of mediation. We observed 434 independent <i>trans</i>-eQTL associations at a false-discovery rate of 0.05, and 189 of these <i>trans</i>-eQTLs were also <i>cis</i>-eQTLs (enrichment P<0.0001). Among these 189 <i>trans</i>-eQTL associations, 39 were significantly attenuated after adjusting for a <i>cis</i>-mediator based on Sobel P<10^-5. We attempted to replicate 21 of these mediation signals in two European cohorts, and while only 7 <i>trans</i>-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 <i>trans</i>-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 <i>cis</i>-<i>trans</i> confounding and when the measured <i>cis</i>-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 <i>trans</i>-eQTL associations can be explained by <i>cis</i>-mediation. Future studies should focus on understanding the mechanisms underlying widespread <i>cis</i>-mediation and their relevance to disease biology, as well as using mediation analysis to improve eQTL discovery.</p>