CCmed: cross-condition mediation analysis for identifying replicable trans-associations mediated by cis-gene expression

Motivation: Trans-acting expression quantitative trait loci (eQTLs) collectively explain a substantial proportion of expression variation, yet are challenging to detect and replicate since their effects are often individually weak. A large proportion of genetic effects on distal genes are mediated through cis-gene expression. Cis-association (between SNP and cis-gene) and gene-gene correlation conditional on SNP genotype could establish trans-association (between SNP and trans-gene). Both cis-association and gene-gene conditional correlation have effects shared across relevant tissues and conditions, and trans-associations mediated by cis-gene expression also have effects shared across relevant conditions. Results: We proposed a Cross-Condition Mediation analysis method (CCmed) for detecting cis-mediated trans-associations with replicable effects in relevant conditions/studies. CCmed integrates cis-association and gene-gene conditional correlation statistics from multiple tissues/studies. Motivated by the bimodal effect-sharing patterns of eQTLs, we proposed two variations of CCmed, CCmed(most) and CCmed(spec) for detecting cross-tissue and tissuespecific trans-associations, respectively. We analyzed data of 13 brain tissues from the Genotype-Tissue Expression (GTEx) project, and identified trios with cis-mediated trans-associations across brain tissues, many of which showed evidence of trans-association in two replication studies. We also identified trans-genes associated with schizophrenia loci in at least two brain tissues.

Automated summary

The study introduces a new analysis method CCmed to detect replicable cis-mediated trans-associations in relevant conditions/studies by integrating statistics from multiple tissues/studies. Analyses of data from 13 brain tissues in the GTEx project revealed multiple cross-tissue trans-associations mediated by cis-gene expression, with evidence of replication in two studies. Additionally, trans-genes associated with schizophrenia loci in at least two brain tissues were identified.