Genome-wide epistatic expression quantitative trait loci discovery in four human tissues reveals the importance of local chromosomal interactions governing gene expression

Background: Epistasis (synergistic interaction) among SNPs governing gene expression is likely to arise withintranscriptional networks. However, the power to detect it is limited by the large number of combinations to betested and the modest sample sizes of most datasets. By limiting the interaction search space firstly to cis-trans andthen cis-cis SNP pairs where both SNPs had an independent effect on the expression of the most variabletranscripts in the liver and brain, we greatly reduced the size of the search space.Results: Within the cis-trans search space we discovered three transcripts with significant epistasis. Surprisingly, allinteracting SNP pairs were located nearby each other on the chromosome (within 290 kb-2.16 Mb). Despite theirproximity, the interacting SNPs were outside the range of linkage disequilibrium (LD), which was absent betweenthe pairs (r2 < 0.01). Accordingly, we redefined the search space to detect cis-cis interactions, where a cis-SNP waslocated within 10 Mb of the target transcript. The results of this show evidence for the epistatic regulation of 50transcripts across the tissues studied. Three transcripts, namely, HLA-G, PSORS1C1 and HLA-DRB5 share commonregulatory SNPs in the pre-frontal cortex and their expression is significantly correlated. This pattern of epistasis isconsistent with mediation via long-range chromatin structures rather than the binding of transcription factors intrans. Accordingly, some of the interactions map to regions of the genome known to physically interact inlymphoblastoid cell lines while others map to known promoter and enhancer elements. SNPs involved in interactionsappear to be enriched for promoter markers.Conclusions: In the context of gene expression and its regulation, our analysis indicates that the study of cis-cisor local epistatic interactions may have a more important role than interchromosomal interactions.Irish Research CouncilScience Foundation IrelandICON-Newman Fellowshi