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

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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.

Vyšlo v časopise: Mediation Analysis Demonstrates That -eQTLs Are Often Explained by -Mediation: A Genome-Wide Analysis among 1,800 South Asians. PLoS Genet 10(12): e32767. doi:10.1371/journal.pgen.1004818
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004818

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