CCmed: cross-condition mediation analysis for identifying robust trans-eQTLs and assessing their effects on human traits

Abstract

Trans-eQTLs collectively explain a substantial proportion of expression variation, yet are challenging to detect and replicate since their effects are individually weak. Many trans-effects are mediated by cis-gene expression and some of those effects are shared across tissue types/conditions. To detect robust cis-mediated trans-associations at the gene-level and for specific single nucleotide polymorphisms (SNPs), we proposed two Cross-Condition Mediation methods - CCmedgene and CCmedGWAS, respectively. We analyzed data from 13 brain tissue types from the Genotype-Tissue Expression (GTEx) project, and identified trios with cis-eQTLs of a cis-gene having associations with a trans-gene, many of which show evidence of replication in other datasets. By applying CCmedGWAS, we identified trans-genes associated with known schizophrenia susceptibility loci. We further conducted validation analyses assessing the schizophrenia-risk-associations of the identified trans-genes, by harnessing GWAS summary statistics from the Psychiatric Genomics Consortium and multitissue eQTL statistics from GTEx.