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Gene-gene and gene-environment interactions detected by transcriptome sequence analysis in twins

Nature Genetics volume 47, pages 8891 (2015) | Download Citation


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.

Author information


  1. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.

    • Alfonso Buil
    • , Tuuli Lappalainen
    •  & Emmanouil T Dermitzakis
  2. Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland.

    • Alfonso Buil
    • , Tuuli Lappalainen
    •  & Emmanouil T Dermitzakis
  3. Swiss Institute of Bioinformatics, Geneva, Switzerland.

    • Alfonso Buil
    • , Tuuli Lappalainen
    •  & Emmanouil T Dermitzakis
  4. Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.

    • Andrew Anand Brown
    •  & Richard Durbin
  5. NORMENT, KG Jebsen Center for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.

    • Andrew Anand Brown
  6. Department of Genetics, Stanford University, Stanford, California, USA.

    • Tuuli Lappalainen
  7. Department of Twin Research, King's College London, London, UK.

    • Ana Viñuela
    • , Matthew N Davies
    • , J Brent Richards
    • , Daniel Glass
    • , Kerrin S Small
    •  & Timothy D Spector
  8. Department of Medicine, McGill University, Montreal, Quebec, Canada.

    • Hou-Feng Zheng
    •  & J Brent Richards
  9. Department of Human Genetics, McGill University, Montreal, Quebec, Canada.

    • Hou-Feng Zheng
    •  & J Brent Richards
  10. Department of Epidemiology and Biostatistics, McGill University, Montreal, Quebec, Canada.

    • Hou-Feng Zheng
    •  & J Brent Richards


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A.B., R.D., T.D.S. and E.T.D. conceived the study. A.B., A.A.B., A.V. and M.N.D. analyzed the data. T.L. and K.S.S. contributed experimental and technical support as well as discussion. D.G. contributed to sample collection. H.F.Z. and J.B.R. contributed technical support and analyzed data. A.B. prepared the manuscript, with contributions from A.A.B. and E.T.D. All authors read and approved the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Alfonso Buil or Emmanouil T Dermitzakis.

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    Supplementary Figures 1–12 and Supplementary Tables 1–5.

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    Supplementary Data Set

    Data for the comparison between the RNA-seq and mmPCR techniques.

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