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document
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 .
69028
Intervention_Other
genome-wide data on SNPs
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Intervention_Educational
array-based expression measures
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Outcome_Physical
trans-eQTLs
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Outcome_Physical
expression of distant genes ( trans-eQTLs )
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Outcome_Physical
cis- and trans-eQTLs
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Outcome_Physical
trans-eQTL associations
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Outcome_Mental
Sobel tests of mediation
69035
Outcome_Physical
trans-eQTL associations
69036
Outcome_Physical
trans-eQTLs
69037
Outcome_Physical
trans-eQTL associations
69038
Outcome_Physical
trans-eQTL associations
69039
Outcome_Physical
trans-eQTL associations
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Participant_Sample-size
1,800 South Asians
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Participant_Sample-size
1,799 Bangladeshi individuals
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Participant_Sample-size
39