Sequence-based variation in gene expression is a key driver of disease risk. Common variants regulating expression in cis have been mapped in many expression quantitative trait locus (eQTL) studies, typically in single tissues from unrelated individuals. Here, we present a comprehensive analysis of gene expression across multiple tissues conducted in a large set of mono- and dizygotic twins that allows systematic dissection of genetic (cis and trans) and non-genetic effects on gene expression. Using identity-by-descent estimates, we show that at least 40% of the total heritable cis effect on expression cannot be accounted for by common cis variants, a finding that reveals the contribution of low-frequency and rare regulatory variants with respect to both transcriptional regulation and complex trait susceptibility. We show that a substantial proportion of gene expression heritability is trans to the structural gene, and we identify several replicating trans variants that act predominantly in a tissue-restricted manner and may regulate the transcription of many genes.

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The MuTHER Study was funded by a program grant from the Wellcome Trust (081917/Z/07/Z) and by core funding for the Wellcome Trust Centre for Human Genetics (090532). Additional funding came from the European Community's Seventh Framework Programme (FP7/2007-2013), ENGAGE project and grant agreement HEALTH-F4-2007-201413, the Swiss National Science Foundation and the NCCR Frontiers in Genetics, the Louis-Jeantet Foundation and a US National Institutes of Health–NIMH grant (GTEx project). Additional details on the funding for the participating studies and investigators are provided in the Supplementary Note.

Author information

Author notes

    • Stephen B Montgomery

    Present address: Department of Pathology, Stanford University School of Medicine, Stanford, California, USA, and Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.

    • Elin Grundberg
    • , Kerrin S Small
    • , Åsa K Hedman
    • , Alexandra C Nica
    •  & Alfonso Buil

    These authors contributed equally to this work.


  1. Wellcome Trust Sanger Institute, Hinxton, UK.

    • Elin Grundberg
    • , Kerrin S Small
    • , Tsun-Po Yang
    • , Eshwar Meduri
    • , James Nisbett
    • , Magdalena Sekowska
    • , Alicja Wilk
    • , So-Youn Shin
    • , Catherine Ingle
    • , Leopold Parts
    • , Simon Potter
    • , Loukia Tsaprouni
    • , Richard Durbin
    • , Nicole Soranzo
    •  & Panos Deloukas
  2. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

    • Elin Grundberg
    • , Kerrin S Small
    • , Jordana T Bell
    • , Eshwar Meduri
    • , Daniel Glass
    • , Gabriela Surdulescu
    • , Veronique Bataille
    • , Kourosh R Ahmadi
    •  & Tim D Spector
  3. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Åsa K Hedman
    • , Sarah Keildson
    • , Jordana T Bell
    • , Josine L Min
    • , Cecilia M Lindgren
    • , Krina T Zondervan
    •  & Mark I McCarthy
  4. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.

    • Alexandra C Nica
    • , Alfonso Buil
    • , Antigone S Dimas
    • , Stephen B Montgomery
    •  & Emmanouil T Dermitzakis
  5. Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland.

    • Alexandra C Nica
    • , Alfonso Buil
    • , Antigone S Dimas
    • , Stephen B Montgomery
    •  & Emmanouil T Dermitzakis
  6. Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.

    • Amy Barrett
    • , Mary Travers
    • , Neelam Hassanali
    •  & Mark I McCarthy
  7. Medical Research Council (MRC) Centre for Causal Analyses in Translational Epidemiology (CAiTE), School of Social and Community Medicine, University of Bristol, Bristol, UK.

    • Sue Ring
    • , Karen Ho
    •  & George Davey Smith
  8. deCODE genetics, Reykjavik, Iceland.

    • Gudmar Thorleifsson
    • , Augustine Kong
    • , Unnur Thorsteindottir
    •  & Kari Stefansson
  9. Faculty of Medicine, University of Iceland, Reykjavík, Iceland.

    • Unnur Thorsteindottir
    •  & Kari Stefansson
  10. Department of Informatics, School of Natural and Mathematical Sciences, King's College London, London, UK.

    • Chrysanthi Ainali
    •  & Sophia Tsoka
  11. Department of Engineering, University of Cambridge, Cambridge, UK.

    • David Knowles
  12. European Bioinformatics Institute, Hinxton, UK.

    • Maria Krestyaninova
  13. University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

    • Christopher E Lowe
    •  & Stephen O'Rahilly
  14. Cambridge National Institute for Health Research (NIHR) Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK.

    • Christopher E Lowe
    •  & Stephen O'Rahilly
  15. St. John's Institute of Dermatology, King's College London, London, UK.

    • Paola Di Meglio
    •  & Frank O Nestle
  16. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA.

    • Eric E Schadt
  17. Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK.

    • Mark I McCarthy


  1. The Multiple Tissue Human Expression Resource (MuTHER) Consortium

    A full list of members and affiliations is provided in the Supplementary Note.


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K.R.A., M.I.M., P.D., E.T.D. and T.D.S. conceived the study. E.G., K.S.S., Å.K.H., A.C.N., A. Buil and S.K. analyzed data. T.-P.Y., E.M., S.-Y.S., J.L.M., K.T.Z., S.R., K.H., G.T., A.K., U.T., S.P., N.S., E.E.S., K.S. and G.D.S. contributed reagents, materials, or analysis tools. A. Barrett, J.N., M.S., A.W., D.G., M.T., N.H., C.I., M.K. and G.S. performed wet lab experiments or collected samples. J.T.B., C.A., A.S.D., D.K., C.E.L., P.D.M., S.B.M., L.P., L.T., S.T., V.B., R.D., F.O.N., S.O. and C.M.L. contributed experimental and technical support as well as discussion. E.G. prepared the manuscript, with contributions from K.S.S., Å.K.H., A.C.N., A. Buil, M.I.M., P.D., E.T.D. and T.D.S. All authors read and approved the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Mark I McCarthy or Panos Deloukas or Emmanouil T Dermitzakis or Tim D Spector.

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