Pierce Brandon L, Tong Lin, Chen Lin S, Rahaman Ronald, Argos Maria, Jasmine Farzana, Roy Shantanu, Paul-Brutus Rachelle, Westra Harm-Jan, Franke Lude, Esko Tonu, Zaman Rakibuz, Islam Tariqul, Rahman Mahfuzar, Baron John A, Kibriya Muhammad G, Ahsan Habibul
Department of Public Health Sciences, The University of Chicago, Chicago, Illinois, United States of America; Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois, United States of America.
Department of Public Health Sciences, The University of Chicago, Chicago, Illinois, United States of America.
PLoS Genet. 2014 Dec 4;10(12):e1004818. doi: 10.1371/journal.pgen.1004818. eCollection 2014 Dec.
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.
很大一部分人类基因受到转录序列附近遗传变异（顺式表达数量性状基因座，cis - eQTL）的调控，许多顺式eQTL与人类疾病相关。关于遗传变异对远距离基因表达（反式表达数量性状基因座，trans - eQTL）的影响及其生物学机制，我们了解得较少。在这项研究中，我们使用了来自一个基于人群的1799名孟加拉个体队列的单核细胞中SNP的全基因组数据和基于芯片的表达测量数据，以表征顺式和反式eQTL，并使用中介效应的Sobel检验来确定观察到的反式eQTL关联是否由与显示反式关联的SNP呈顺式的转录本表达介导。我们在错误发现率为0.05时观察到434个独立的反式eQTL关联，其中189个反式eQTL也是顺式eQTL（富集P < 0.0001）。在这189个反式eQTL关联中，基于Sobel P < 10⁻⁵对顺式中介因子进行调整后，39个关联显著减弱。我们试图在两个欧洲队列中重复其中21个中介信号，虽然只有7个反式eQTL关联在一个或两个队列中出现，但6个显示出顺式中介的证据。对模拟数据的分析表明，在存在中介因子测量误差或测量变异与因果变异之间不完全连锁不平衡的情况下，完全中介将被观察为部分中介。我们的数据表明，在对潜在中介因子进行调整后，反式关联可能会显著增强或改变方向。使用模拟数据，我们证明在存在强烈的顺式 - 反式混杂以及测量的顺式转录本与真实（未测量）中介因子相关时，这种现象是预期的。总之，通过将中介分析应用于eQTL数据，我们表明很大一部分观察到的反式eQTL关联可以由顺式中介来解释。未来的研究应专注于理解广泛存在的顺式中介的潜在机制及其与疾病生物学的相关性，以及使用中介分析来改进eQTL的发现。
