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

摘要

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. Author Summary Expression quantitative trait locus (eQTL) studies have demonstrated that human genes can be regulated by genetic variation residing close to the gene ( cis- eQTLs) or in a distant region or on a different chromosome ( trans -eQTLs). While cis -eQTL variants are likely to affect transcription factor binding or chromatin structure, our understanding of the mechanisms underlying trans -eQTLs is incomplete. We hypothesize that a substantial fraction of trans -eQTLs influence expression of distant genes through mediation by expression levels of a cis -transcript. In this paper, we use genome-wide SNPs and expression data for 1,799 South Asians to identify cis- and trans-eQTLs and to test our hypothesis using Sobel tests of mediation. Among 189 observed trans-eQTL associations, we provide evidence of cis -mediation for 39, 6 of which show mediation in an independent European cohort. We used simulated data to demonstrate that complete mediation will be observed as partial mediation in the presence of mediator measurement error or imperfect LD between measured and causal variants. We also demonstrate how unobserved confounding variables and incorrect mediator selection can bias mediation estimates. In conclusion, we have identified cis -mediators for many trans -eQTLs and described a mediation analysis approach that can be used to validate, characterize, and enhance discovery of trans -eQTLs.