Data from: Mediation analysis demonstrates that trans-eQTLs are often explained by cis-mediation: a genome-wide analysis among 1,800 South Asians

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.