Abstract

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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References

  1. 1.

    et al. Missing heritability and strategies for finding the underlying causes of complex disease. Nat. Rev. Genet. 11, 446–450 (2010).

  2. 2.

    et al. Mapping determinants of human gene expression by regional and genome-wide association. Nature 437, 1365–1369 (2005).

  3. 3.

    et al. Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes. Nat. Genet. 39, 1208–1216 (2007).

  4. 4.

    et al. Population genomics in a disease targeted primary cell model. Genome Res. 19, 1942–1952 (2009).

  5. 5.

    et al. Population genomics of human gene expression. Nat. Genet. 39, 1217–1224 (2007).

  6. 6.

    et al. A survey of genetic human cortical gene expression. Nat. Genet. 39, 1494–1499 (2007).

  7. 7.

    et al. Mapping the genetic architecture of gene expression in human liver. PLoS Biol. 6, e107 (2008).

  8. 8.

    et al. Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008).

  9. 9.

    et al. Common regulatory variation impacts gene expression in a cell type–dependent manner. Science 325, 1246–1250 (2009).

  10. 10.

    et al. A survey of the genetics of stomach, liver, and adipose gene expression from a morbidly obese cohort. Genome Res. 21, 1008–1016 (2011).

  11. 11.

    et al. The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. PLoS Genet. 7, e1002003 (2011).

  12. 12.

    et al. Genetics and beyond—the transcriptome of human monocytes and disease susceptibility. PLoS ONE 5, e10693 (2010).

  13. 13.

    et al. Gene expression in skin and lymphoblastoid cells: refined statistical method reveals extensive overlap in cis-eQTL signals. Am. J. Hum. Genet. 87, 779–789 (2010).

  14. 14.

    et al. Candidate causal regulatory effects by integration of expression QTLs with complex trait genetic associations. PLoS Genet. 6, e1000895 (2010).

  15. 15.

    et al. A genome-wide association study of global gene expression. Nat. Genet. 39, 1202–1207 (2007).

  16. 16.

    et al. Single-tissue and cross-tissue heritability of gene expression via identity-by-descent in related or unrelated individuals. PLoS Genet. 7, e1001317 (2011).

  17. 17.

    & The UK Adult Twin Registry (TwinsUK). Twin Res. Hum. Genet. 9, 899–906 (2006).

  18. 18.

    et al. Are twins and singletons comparable? A study of disease-related and lifestyle characteristics in adult women. Twin Res. 4, 464–477 (2001).

  19. 19.

    , & The use of linear mixed models to estimate variance components from data on twin pairs by maximum likelihood. Twin Res. 7, 670–674 (2004).

  20. 20.

    & Statistical significance for genomewide studies. Proc. Natl. Acad. Sci. USA 100, 9440–9445 (2003).

  21. 21.

    et al. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat. Genet. 41, 47–55 (2009).

  22. 22.

    et al. Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight. Nat. Genet. 42, 430–435 (2010).

  23. 23.

    et al. Common sequence variants on 20q11.22 confer melanoma susceptibility. Nat. Genet. 40, 838–840 (2008).

  24. 24.

    et al. Genetic determinants of hair, eye and skin pigmentation in Europeans. Nat. Genet. 39, 1443–1452 (2007).

  25. 25.

    , , & Synthetic associations are unlikely to account for many common disease genome-wide association signals. PLoS Biol. 9, e1000580 (2011).

  26. 26.

    et al. Rare variants create synthetic genome-wide associations. PLoS Biol. 8, e1000294 (2010).

  27. 27.

    et al. Genetic control of gene expression in whole blood and lymphoblastoid cell lines is largely independent. Genome Res. 22, 456–466 (2012).

  28. 28.

    et al. A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. Nature 467, 460–464 (2010).

  29. 29.

    et al. Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes. Nat. Genet. 43, 561–564 (2011).

  30. 30.

    et al. Regulation of ploidy and senescence by the AMPK-related kinase NUAK1. EMBO J. 29, 376–386 (2010).

  31. 31.

    , & Mapping short DNA sequencing reads and calling variants using mapping quality scores. Genome Res. 18, 1851–1858 (2008).

  32. 32.

    et al. A genotype calling algorithm for the Illumina BeadArray platform. Bioinformatics 23, 2741–2746 (2007).

  33. 33.

    , & Genomewide rapid association using mixed model and regression: a fast and simple method for genomewide pedigree-based quantitative trait loci association analysis. Genetics 177, 577–585 (2007).

  34. 34.

    & Family-based association tests for genomewide association scans. Am. J. Hum. Genet. 81, 913–926 (2007).

  35. 35.

    , , & GenABEL: an R library for genome-wide association analysis. Bioinformatics 23, 1294–1296 (2007).

  36. 36.

    , & ProbABEL package for genome-wide association analysis of imputed data. BMC Bioinformatics 11, 134 (2010).

  37. 37.

    R Development Core Team. R: A Language and Environment for Statistical Computing. (R Foundation for Statistical Computing, Vienna, 2010).

  38. 38.

    et al. The fine-scale structure of recombination rate variation in the human genome. Science 304, 581–584 (2004).

  39. 39.

    lme4: Linear Mixed-Effects Models Using S4 Classes. (R Foundation for Statistical Computing, Vienna, 2010).

  40. 40.

    , , & Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat. Genet. 30, 97–101 (2002).

  41. 41.

    et al. The use of genome-wide eQTL associations in lymphoblastoid cell lines to identify novel genetic pathways involved in complex traits. PLoS ONE 6, e22070 (2011).

  42. 42.

    , & ALSPAC—the Avon Longitudinal Study of Parents and Children. I. Study methodology. Paediatr. Perinat. Epidemiol. 15, 74–87 (2001).

  43. 43.

    et al. MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet. Epidemiol. 34, 816–834 (2010).

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Acknowledgements

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.

Affiliations

  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

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  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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Contributions

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.

Supplementary information

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DOI

https://doi.org/10.1038/ng.2394

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