We apply integrative approaches to expression quantitative loci (eQTLs) from 44 tissues from the Genotype-Tissue Expression project and genome-wide association study data. About 60% of known trait-associated loci are in linkage disequilibrium with a cis-eQTL, over half of which were not found in previous large-scale whole blood studies. Applying polygenic analyses to metabolic, cardiovascular, anthropometric, autoimmune, and neurodegenerative traits, we find that eQTLs are significantly enriched for trait associations in relevant pathogenic tissues and explain a substantial proportion of the heritability (40–80%). For most traits, tissue-shared eQTLs underlie a greater proportion of trait associations, although tissue-specific eQTLs have a greater contribution to some traits, such as blood pressure. By integrating information from biological pathways with eQTL target genes and applying a gene-based approach, we validate previously implicated causal genes and pathways, and propose new variant and gene associations for several complex traits, which we replicate in the UK BioBank and BioVU.

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We thank the DIAGRAM, MAGIC, GIANT, GLGC, CARDIoGRAM, ICBP, IGAP, and IIBDGC consortia for making their GWAS meta-analysis summary statistics publicly available. This work was conducted using the UK Biobank Resource (application number 25331). E.R.G. acknowledges support from R01-MH101820, R01-MH090937, R01-MH113362, and R01-CA157823 and benefited immensely from a Fellowship at Clare Hall, University of Cambridge. A.V.S., F.A., M.K., G.G., and K.G.A. acknowledge support from the NIH contract HHSN268201000029C to The Broad Institute, Inc. M.v.d.B. acknowledges support by a Novo Nordisk postdoctoral fellowship run in partnership with the University of Oxford. F.H. and E.E. are supported by NIH grants R01-MH101782 and R01-ES022282. X.W. acknowledges support from NIH grants R01-HG007022 and R01-AR042742. M.I.McC. is a Wellcome Senior Investigator supported by Wellcome (098381, 090532, 106130, 203141) and the NIH (U01-DK105535, R01-MH101814). E.T.D. acknowledges support from the Swiss National Science Foundation, the European Research Council, the NIH-NIMH, and the Louis Jeantet Foundation. N.J.C. is supported by R01-MH113362, R01-MH101820, and R01-MH090937. The datasets used for part of the replication analysis were obtained from Vanderbilt University Medical Center’s BioVU, which is supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH funded Shared Instrumentation Grant S10-RR025141, and CTSA grants UL1-TR002243, UL1-TR000445, and UL1-RR024975. Genomic data are also supported by investigator-led projects that include U01-HG004798, R01-NS032830, RC2-GM092618, P50-GM115305, U01-HG006378, U19-HL065962, and R01-HD074711, and additional funding sources listed at https://victr.vanderbilt.edu/pub/biovu/.

Author information

Author notes

  1. These authors contributed equally to this work: Eric R. Gamazon, Ayellet V. Segrè, Martijn van de Bunt.

  2. A full list of members appears in the Supplementary Note.


  1. Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    • Eric R. Gamazon
    • , Anuar Konkashbaev
    •  & Nancy J. Cox
  2. Clare Hall, University of Cambridge, Cambridge, UK

    • Eric R. Gamazon
  3. The Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA

    • Ayellet V. Segrè
    • , François Aguet
    • , Manolis Kellis
    • , Gad Getz
    •  & Kristin G. Ardlie
  4. Department of Ophthalmology and Ocular Genomics Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA

    • Ayellet V. Segrè
  5. Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK

    • Martijn van de Bunt
    •  & Mark I. McCarthy
  6. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK

    • Martijn van de Bunt
    •  & Mark I. McCarthy
  7. Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA

    • Xiaoquan Wen
  8. Computational Sciences, Pfizer Inc, Cambridge, MA, USA

    • Hualin S. Xi
    •  & Jie Quan
  9. Department of Computer Science, University of California, Los Angeles, CA, USA

    • Farhad Hormozdiari
    •  & Eleazar Eskin
  10. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    • Farhad Hormozdiari
  11. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland

    • Halit Ongen
    •  & Emmanouil T. Dermitzakis
  12. Institute for Genetics and Genomics in Geneva (iG3), University of Geneva, Geneva, Switzerland

    • Halit Ongen
    •  & Emmanouil T. Dermitzakis
  13. Swiss Institute of Bioinformatics, Geneva, Switzerland

    • Halit Ongen
    •  & Emmanouil T. Dermitzakis
  14. Translational Neurogenomics Group, QIMR Berghofer, Brisbane, Queensland, Australia

    • Eske M. Derks
  15. Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, IL, USA

    • Dan L. Nicolae
  16. Department of Statistics, The University of Chicago, Chicago, IL, USA

    • Dan L. Nicolae
  17. Department of Human Genetics, The University of Chicago, Chicago, IL, USA

    • Dan L. Nicolae
  18. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA

    • Manolis Kellis
  19. Massachusetts General Hospital Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, MA, USA

    • Gad Getz


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  1. GTEx Consortium


    E.R.G. and A.V.S. jointly designed the study and led the analysis. E.R.G., A.V.S., M.v.d.B., and K.G.A. wrote the manuscript. E.R.G., A.V.S., M.v.d.B., X.W., H.S.X., F.H., H.O., A.K., E.M.D., F.A., and J.Q. performed the statistical analysis. E.R.G., A.V.S., M.v.d.B., X.W., H.S.X., F.H., E.M.D., D.L.N., E.E., M.K., G.G., M.I.McC, E.T.D., N.J.C., and K.G.A. interpreted the results of the analysis. All authors contributed to the critical review of the manuscript.

    Competing interests

    M.I.McC. serves on advisory panels for Pfizer and NovoNordisk. He has received honoraria from Pfizer, NovoNordisk, Sanofi-Aventis, and Eli-Lilly, and research funding from Pfizer, Eli-Lilly, Merck, Takeda, Sanofi Aventis, Astra Zeneca, NovoNordisk, Servier, Janssen, Boehringer Ingelheim, and Roche. M.v.d.B is an employee of Novo Nordisk. H.S.X. and J.Q. are employees of Pfizer.

    Corresponding authors

    Correspondence to Eric R. Gamazon or Ayellet V. Segrè.

    Supplementary information

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      Supplementary Note and Supplementary Figures 1–21

    2. Reporting Summary

    3. Supplementary Tables

      Supplementary Tables 1–23

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