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

• Main Authors: Chen, L.S (Author), Duan, J. (Author), Gleason, K.J (Author), He, X. (Author), Pierce, B.L (Author), Wang, J. (Author), Yang, F. (Author)
• Format: Article
• Language: English
• Published: Oxford University Press 2021
• Online Access: View Fulltext in Publisher

 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, CCmedmostand CCmedspecfor 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. © 2021 Oxford University Press. All rights reserved.