title: Mediation analysis demonstrates that trans-eQTLs are often explained by cis-mediation: a genome-wide analysis among 1,800 South Asians.
abstract: 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.
authors.affiliation: 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.
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Pierce
authors.affiliation: Department of Public Health Sciences, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Lin
authors.initials: L
authors.lastname: Tong
authors.affiliation: Department of Public Health Sciences, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Lin S
authors.initials: LS
authors.lastname: Chen
authors.affiliation: Department of Public Health Sciences, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Ronald
authors.initials: R
authors.lastname: Rahaman
authors.affiliation: Department of Public Health Sciences, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Maria
authors.initials: M
authors.lastname: Argos
authors.affiliation: Department of Public Health Sciences, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Farzana
authors.initials: F
authors.lastname: Jasmine
authors.affiliation: Department of Public Health Sciences, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Shantanu
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Public Health Sciences, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Rachelle
authors.initials: R
authors.lastname: Paul-Brutus
authors.affiliation: University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Harm-Jan
authors.initials: HJ
authors.lastname: Westra
authors.affiliation: University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors.forename: Tonu
authors.initials: T
authors.lastname: Esko
authors.affiliation: UChicago Research Bangladesh, Mohakhali, Dhaka, Bangladesh.
authors.forename: Rakibuz
authors.initials: R
authors.lastname: Zaman
authors.affiliation: UChicago Research Bangladesh, Mohakhali, Dhaka, Bangladesh.
authors.forename: Tariqul
authors.initials: T
authors.lastname: Islam
authors.affiliation: UChicago Research Bangladesh, Mohakhali, Dhaka, Bangladesh; Research and Evaluation Division, BRAC, Dhaka, Bangladhesh.
authors.forename: Mahfuzar
authors.initials: M
authors.lastname: Rahman
authors.affiliation: University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, United States of America.
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.affiliation: Department of Public Health Sciences, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Muhammad G
authors.initials: MG
authors.lastname: Kibriya
authors.affiliation: 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 Medicine The University of Chicago, Chicago, Illinois, United States of America; Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Habibul
authors.initials: H
authors.lastname: Ahsan
mesh_terms: D001208:Asia / Q000453:epidemiology; D044466:Asian People / Q000235:genetics* / Q000706:statistics & numerical data; D001459:Bangladesh / Q000453:epidemiology; D018890:Chemoprevention; D003198:Computer Simulation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000235:genetics*; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D040641:Quantitative Trait Loci; D012643:Selenium / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000453:epidemiology / Q000235:genetics / Q000517:prevention & control; D014810:Vitamin E / Q000627:therapeutic use
chemical_list: D014810:Vitamin E; D012643:Selenium