EGAGenomicsN/Ahttps://ega-archive.org/datasets/EGAD00001001089685EGA dataset EGAD00001001089EGANon-additive interaction between genetic variants, or epistasis, is a possible explanation for the gap between heritability of complex traits and the variation explained by identified genetic loci. Interactions give rise to genotype dependent variance, and therefore the identification of variance quantitative trait loci can be an intermediate step to discover both epistasis and gene by environment effects (GxE). Using RNA-sequence data from lymphoblastoid cell lines (LCLs) from the TwinsUK cohort, we identify a candidate set of 508 variance associated SNPs. Exploiting the twin design we show that GxE plays a role in ∼70% of these associations. Further investigation of these loci reveals 57 epistatic interactions that replicated in a smaller dataset, explaining on average 4.3% of phenotypic variance. In 24 cases, more variance is explained by the interaction than their additive contributions. Using molecular phenotypes in this way may provide a route to uncovering genetic interactions underlying more complex traits.DOI: http://dx.doi.org/10.7554/eLife.01381.001.Understanding the genetic architecture of gene expression is an intermediate step in understanding the genetic architecture of complex diseases. RNA sequencing technologies have improved the quantification of gene expression and allow measurement of allele-specific expression (ASE). ASE is hypothesized to result from the direct effect of cis regulatory variants, but a proper estimation of the causes of ASE has not been performed thus far. In this study, we take advantage of a sample of twins to measure the relative contributions of genetic and environmental effects to ASE, and we find substantial effects from gene × gene (G×G) and gene × environment (G×E) interactions. We propose a model where ASE requires genetic variability in cis, a difference in the sequence of both alleles, but where the magnitude of the ASE effect depends on trans genetic and environmental factors that interact with the cis genetic variants.Genetic interactions affecting human gene expression identified by variance association mapping.Gene-gene and gene-environment interactions detected by transcriptome sequence analysis in twins.Buil Alfonso A, Brown Andrew Anand AA, Lappalainen Tuuli T, Viñuela Ana A, Davies Matthew N MN, Zheng Hou-Feng HF, Richards J Brent JB, Glass Daniel D, Small Kerrin S KS, Durbin Richard R, Spector Timothy D TD, Dermitzakis Emmanouil T ETBrown Andrew Anand AA, Buil Alfonso A, Viñuela Ana A, Lappalainen Tuuli T, Zheng Hou-Feng HF, Richards J Brent JB, Small Kerrin S KS, Spector Timothy D TD, Dermitzakis Emmanouil T ET, Durbin Richard Rfalseena-DATASET-GEN-GMD-02-12-2014-15:24:02:886-80 - samplesRNAseq BAM files for the Fat samples of the EUROBATS project2019-10-31 12:52:11EGAD0000100108996062543685724771767EGAC00001000274EGAS00001000805