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.
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We thank the twins for their voluntary contribution to this project. This work has been funded by European Union Framework Programme 7 grant EuroBATS (259749), which also supports A.A.B., A.B., M.N.D., D.G., A.V. and T.D.S. A.A.B. is also supported by a grant from the South-Eastern Norway Health Authority (2011060). R.D. is supported by the Wellcome Trust (098051). The Louis-Jeantet Foundation, the Swiss National Science Foundation, the European Research Council (ERC) and the US National Institutes of Health/National Institute of Mental Health GTEx grant support E.T.D. T.D.S. is a National Institute of Health Research (NIHR) senior investigator and the holder of an ERC Advanced Principal Investigator award. J.B.R. and H.F.Z. are supported by the Canadian Institutes of Health Research, Fonds de Recherche Santé du Québec and the Quebec Consortium for Drug Discovery. Most computations were performed at the Vital-IT center for high-performance computing of the Swiss Institute of Bioinformatics (SIB; http://www.vital-it.ch/). The TwinsUK study was funded by the Wellcome Trust, European Community Framework Programme 7 (2007–2013), and the NIHR Clinical Research Facility at Guy's and St Thomas' National Health Service (NHS) Foundation Trust and the NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. SNP genotyping was performed by the Wellcome Trust Sanger Institute and National Eye Institute via US National Institutes of Health/Center for Inherited Disease Research (CIDR) funding.
Integrated supplementary information
Data for the comparison between the RNA-seq and mmPCR techniques.