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