Abstract

Genome sequencing projects are discovering millions of genetic variants in humans, and interpretation of their functional effects is essential for understanding the genetic basis of variation in human traits. Here we report sequencing and deep analysis of messenger RNA and microRNA from lymphoblastoid cell lines of 462 individuals from the 1000 Genomes Project—the first uniformly processed high-throughput RNA-sequencing data from multiple human populations with high-quality genome sequences. We discover extremely widespread genetic variation affecting the regulation of most genes, with transcript structure and expression level variation being equally common but genetically largely independent. Our characterization of causal regulatory variation sheds light on the cellular mechanisms of regulatory and loss-of-function variation, and allows us to infer putative causal variants for dozens of disease-associated loci. Altogether, this study provides a deep understanding of the cellular mechanisms of transcriptome variation and of the landscape of functional variants in the human genome.

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Data deposits

The Geuvadis RNA-sequencing data, genotype data, variant annotations, splice scores, quantifications, and QTL results are freely and openly available with no restrictions. The main portal for accessing the data is EBI ArrayExpress, under accessions E-GEUV-1, E-GEUV-2 and E-GEUV-3 (see the data access schema in Supplementary Fig. 39). For visualization of the results we created the Geuvadis Data Browser (http://www.ebi.ac.uk/Tools/geuvadis-das) where quantifications and QTLs can be viewed, searched and downloaded (Supplementary Fig. 40). The project webpage (http://www.geuvadis.org) provides full documentation and links to all files, and the analysis group wiki is open to the public (http://geuvadiswiki.crg.es).

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Acknowledgements

We would like to thank E. Falconnet, L. Romano, A. Planchon, D. Bielsen, A. Yurovsky, A. Buil, J. Bryois, A. Nica, I. Topolsky, N. Fusi, S. Waszak, C. Bustamante, J. Rung, N. Kolesnikov, A. Roa, E. Bragin, S. Brent, J. Gonzalez, M. Morell, A. Puig, E. Palumbo, M. Ventayol Garcia, J. F. J. Laros, J. Blanc, R. Birkelund, G. Plaja, M. Ingham, J. Camps, M. Bayes, L. Agueda, A. Gouin, M.-L. Yaspo, E. Graf, A. Walther, C. Fischer, S. Loesecke, B. Schmick, D. Balzereit, S. Dökel, M. Linser, A. Kovacsovics, M. Friskovec, C. von der Lancken, M. Schlapkohl, A. Hellmann, M. Schilhabel, the SNP&SEQ Technology Platform in Uppsala, S. Sauer, the Vital-IT high-performance computing centre of the SIB Swiss Institute of Bioinformatics, B. Goldstein and others at the Coriell Institute, and J. Cooper, E. Burnett, K. Ball and others at the European Collection of Cell Cultures (ECACC) and the 1000 Genomes Consortium. This project was funded by the European Commission 7th Framework Program (FP7) (261123; GEUVADIS); the Swiss National Science Foundation (130326, 130342), the Louis Jeantet Foundation, and ERC (260927) (E.T.D.); NIH-NIMH (MH090941) (E.T.D., M.I.M., R.G.); Spanish Plan Nacional SAF2008-00357 (NOVADIS), the Generalitat de Catalunya AGAUR 2009 SGR-1502, and the Instituto de Salud Carlos III (FIS/FEDER PI11/00733) (X.E.); Spanish Plan Nacional (BIO2011-26205) and ERC (294653) (R.G.); ESGI, READNA (FP7 Health-F4-2008-201418), Spanish Ministry of Economy and Competitiveness (MINECO) and the Generalitat de Catalunya (I.G.G.); DFG Cluster of Excellence Inflammation at Interfaces, the INTERREG4A project HIT-ID, and the BMBF IHEC project DEEP SP 2.3 (P.Ro.); German Centre for Cardiovascular Research (DZHK) and the German Ministry of Education and Research (01GR0802, 01GM0867, 01GR0804, 16EX1020C) (T.M.); EurocanPlatform (FP7 260791), ENGAGE and CAGEKID (241669) (A.B.); FP7/2007-2013, ENGAGE project, HEALTH-F4-2007-201413, and the Centre for Medical Systems Biology within the framework of The Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific and Research (NWO) (P.AC.H and G.-J.v.O.); The Swedish Research Council (C0524801, A028001) and the Knut and Alice Wallenberg Foundation (2011.0073) (A.-C.S.); The Swiss National Science Foundation (127375, 144082) and ERC (249968) (S.E.A.); Instituto de Salud Carlos III (FIS/FEDER PS09/02368) (A.C.); German Federal Ministry of Education and Research (01GS08201) (R.S.); Max Planck Society (H.L.); Wellcome Trust (WT085532) and the European Molecular Biology Laboratory (P.F.); ENGAGE, Wellcome Trust (081917, 090367, 090532, 098381), and Medical Research Council UK (G0601261) (M.I.M.); Wellcome Trust Centre for Human Genetics (090532/Z/09/Z, 075491/Z/04/B), Wellcome Trust (098381, 090367, 076113, 083270), the WTCCC2 project (085475/B/08/Z, 085475/Z/08/Z), Royal Society Wolfson Merit Award, Wellcome Trust Senior Investigator Award (095552/Z/11/Z) (P.D.); EMBO long-term fellowship EMBO-ALTF 2010-337 (H.K.); NIH-NIGMS (R01 GM104371) (D.G.M.); Marie Curie FP7 fellowship (O.S.); Scholarship by the Clarendon Fund of the University of Oxford, and the Nuffield Department of Medicine (M.A.R.); EMBO long-term fellowship ALTF 225-2011 (M.R.F.); Emil Aaltonen Foundation and Academy of Finland fellowships (T.L.).

Author information

Author notes

    • Michael Sammeth
    • , Stephen B. Montgomery
    •  & Ralf Sudbrak

    Present addresses: Bioinformatics Laboratory, National Laboratory of Scientific Computing (LNCC), Petropolis 25651-075, Rio de Janeiro, Brazil (M.S.); Departments of Pathology and Genetics, Stanford University, Stanford, California 94305-5324, USA (S.B.M.); Alacris Theranostics GmbH, 14195 Berlin, Germany (R.S.).

    • Michael Sammeth
    • , Marc R. Friedländer
    • , Peter A. C. ‘t Hoen
    • , Jean Monlong
    •  & Manuel A. Rivas

    These authors contributed equally to this work.

Affiliations

  1. Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland

    • Tuuli Lappalainen
    • , Thomas Giger
    • , Ismael Padioleau
    • , Halit Ongen
    • , Helena Kilpinen
    • , Stephen B. Montgomery
    • , Stylianos E. Antonarakis
    •  & Emmanouil T. Dermitzakis
  2. Institute for Genetics and Genomics in Geneva (iG3), University of Geneva, 1211 Geneva, Switzerland

    • Tuuli Lappalainen
    • , Ismael Padioleau
    • , Halit Ongen
    • , Helena Kilpinen
    • , Stylianos E. Antonarakis
    •  & Emmanouil T. Dermitzakis
  3. Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland

    • Tuuli Lappalainen
    • , Ismael Padioleau
    • , Halit Ongen
    • , Helena Kilpinen
    •  & Emmanouil T. Dermitzakis
  4. Centro Nacional de Análisis Genómico, 08028 Barcelona, Catalonia, Spain

    • Michael Sammeth
    • , Thasso Griebel
    • , Paolo Ribeca
    • , Sergi Beltran
    • , Marta Gut
    • , Katja Kahlem
    •  & Ivo G. Gut
  5. Centre for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain

    • Michael Sammeth
    • , Marc R. Friedländer
    • , Jean Monlong
    • , Pedro G. Ferreira
    • , Gabrielle Bertier
    • , Esther Lizano
    • , Roderic Guigó
    •  & Xavier Estivill
  6. Pompeu Fabra University (UPF), 08003 Barcelona, Catalonia, Spain

    • Michael Sammeth
    • , Marc R. Friedländer
    • , Jean Monlong
    • , Pedro G. Ferreira
    • , Gabrielle Bertier
    • , Esther Lizano
    • , Roderic Guigó
    •  & Xavier Estivill
  7. CRG Hospital del Mar Research Institute, 08003 Barcelona, Catalonia, Spain

    • Michael Sammeth
    • , Marc R. Friedländer
    • , Jean Monlong
    • , Pedro G. Ferreira
    • , Esther Lizano
    • , Roderic Guigó
    •  & Xavier Estivill
  8. CRG CIBERESP, 08003 Barcelona, Catalonia, Spain

    • Marc R. Friedländer
    • , Esther Lizano
    •  & Xavier Estivill
  9. Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands

    • Peter A. C. ‘t Hoen
    • , Maarten van Iterson
    • , Irina Pulyakhina
    • , Henk P. J. Buermans
    •  & Gert-Jan van Ommen
  10. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK

    • Manuel A. Rivas
    • , Matti Pirinen
    • , Peter Donnelly
    •  & Mark I. McCarthy
  11. European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, CB10 1SD, UK

    • Mar Gonzàlez-Porta
    • , Natalja Kurbatova
    • , Liliana Greger
    • , Andrew Tikhonov
    • , Oliver Stegle
    • , Paul Flicek
    •  & Alvis Brazma
  12. Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, D-24105 Kiel, Germany

    • Matthias Barann
    • , Daniela Esser
    • , Stefan Schreiber
    • , Robert Häsler
    •  & Philip Rosenstiel
  13. Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany

    • Thomas Wieland
    • , Thomas Schwarzmayr
    • , Tim M. Strom
    •  & Thomas Meitinger
  14. Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden

    • Jonas Almlöf
    • , Olof Karlberg
    •  & Ann-Christine Syvänen
  15. Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany

    • Marc Sultan
    • , Vyacheslav Amstislavskiy
    • , Hans Lehrach
    •  & Ralf Sudbrak
  16. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA

    • Daniel G. MacArthur
    •  & Monkol Lek
  17. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA

    • Daniel G. MacArthur
    •  & Monkol Lek
  18. Leiden Genome Technology Center, 2300 RC Leiden, the Netherlands

    • Henk P. J. Buermans
  19. Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford OX3 7BN, UK

    • Mark I. McCarthy
  20. Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany

    • Tim M. Strom
    •  & Thomas Meitinger
  21. Dahlem Centre for Genome Research and Medical Systems Biology, 14195 Berlin, Germany

    • Hans Lehrach
    •  & Ralf Sudbrak
  22. Fundacion Publica Galega de Medicina Xenomica (SERGAS), Genomic Medicine Group, CIBERER, Universidade de Santiago de Compostela, Santiago de Compostela, Spain

    • Ángel Carracedo
  23. Deutsches Forschungszentrum für Herz-Kreislauferkrankungen (DZHK), Partner Site Munich Heart Alliance, 81675 Munich, Germany

    • Thomas Meitinger

Consortia

  1. The Geuvadis Consortium

    A list of authors and their affiliations appears in the Supplementary Information.

Authors

  1. Search for Tuuli Lappalainen in:

  2. Search for Michael Sammeth in:

  3. Search for Marc R. Friedländer in:

  4. Search for Peter A. C. ‘t Hoen in:

  5. Search for Jean Monlong in:

  6. Search for Manuel A. Rivas in:

  7. Search for Mar Gonzàlez-Porta in:

  8. Search for Natalja Kurbatova in:

  9. Search for Thasso Griebel in:

  10. Search for Pedro G. Ferreira in:

  11. Search for Matthias Barann in:

  12. Search for Thomas Wieland in:

  13. Search for Liliana Greger in:

  14. Search for Maarten van Iterson in:

  15. Search for Jonas Almlöf in:

  16. Search for Paolo Ribeca in:

  17. Search for Irina Pulyakhina in:

  18. Search for Daniela Esser in:

  19. Search for Thomas Giger in:

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  21. Search for Marc Sultan in:

  22. Search for Gabrielle Bertier in:

  23. Search for Daniel G. MacArthur in:

  24. Search for Monkol Lek in:

  25. Search for Esther Lizano in:

  26. Search for Henk P. J. Buermans in:

  27. Search for Ismael Padioleau in:

  28. Search for Thomas Schwarzmayr in:

  29. Search for Olof Karlberg in:

  30. Search for Halit Ongen in:

  31. Search for Helena Kilpinen in:

  32. Search for Sergi Beltran in:

  33. Search for Marta Gut in:

  34. Search for Katja Kahlem in:

  35. Search for Vyacheslav Amstislavskiy in:

  36. Search for Oliver Stegle in:

  37. Search for Matti Pirinen in:

  38. Search for Stephen B. Montgomery in:

  39. Search for Peter Donnelly in:

  40. Search for Mark I. McCarthy in:

  41. Search for Paul Flicek in:

  42. Search for Tim M. Strom in:

  43. Search for Hans Lehrach in:

  44. Search for Stefan Schreiber in:

  45. Search for Ralf Sudbrak in:

  46. Search for Ángel Carracedo in:

  47. Search for Stylianos E. Antonarakis in:

  48. Search for Robert Häsler in:

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  51. Search for Alvis Brazma in:

  52. Search for Thomas Meitinger in:

  53. Search for Philip Rosenstiel in:

  54. Search for Roderic Guigó in:

  55. Search for Ivo G. Gut in:

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Contributions

Designed the study: T.L., T.Gi., S.B.M., P.AC.H., E.L., H.L., S.S., R.S., A.C., S.E.A., R.H., A.-C.S., G.-J.v.O., A.B., T.M., P.Ro., R.G., I.G.G., X.E. and E.T.D. Coordinated the project: T.L., T.Gi., G.B., X.E. and E.T.D. Participated in data production: T.L., T.Gi., I.Pa., M.Su., E.L., S.B., M.G., V.A., K.K., D.E., P.Ri. and O.K. Analysed the data: T.L., M.Sa., M.R.F., P.A.C.H., J.M., M.A.R., M.G.-P., N.K., T.Gr., P.G.F., M.B., T.W., L.G., M.v.I., J.A., P.Ri., I.Pu., D.E., A.T., M.Su., D.G.M., M.L., E.L., H.P.J.B., I.Pa., T.S., O.K., H.O., H.K., S.B., M.G., K.K., V.A., O.S., M.P., P.D., M.I.M., P.F. and T.M.S. Drafted the paper: T.L. and E.T.D. See Supplementary Note for Members of the Geuvadis Consortium.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Tuuli Lappalainen or Emmanouil T. Dermitzakis.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains a Supplementary Note, Supplementary Figures 1-40, Supplementary Methods, Supplementary Tables 1-3 and 6, and full legends for Supplementary Tables 4-5 – see contents page for details.

Excel files

  1. 1.

    Supplementary Data

    This file contains Supplementary Table 4 showing miRNA-mRNA correlations and Supplementary Table 5 showing Top eQTL variants for 91 GWAS SNPs.

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DOI

https://doi.org/10.1038/nature12531

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