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Nature
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Finding the missing heritability of complex diseases

Naturevolume 461, pages747–753 (2009)Cite this article

Abstract

Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, ‘missing’ heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.

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Figure 1:Feasibility of identifying genetic variants by risk allele frequency and strength of genetic effect (odds ratio).

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Article26 August 2021

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Acknowledgements

This paper is inspired by the deliberations of an expert working group convened by the National Human Genome Research Institute (NHGRI) on 2–3 February 2009, to address the heritability unexplained in GWAS. The authors acknowledge the participation of J. C. Cohen, M. Daly and A. P. Feinberg in the workshop.

Author Contributions T.A.M., F.S.C., N.J.C., D.B.G., L.A.H., D.J.H., M.I.M. and E.M.R. planned and participated in the workshop; L.R.C., A.C., J.H.C., A.E.G., A.K., L.K., E.M., C.N.R., M.S., D.V., A.S.W., M.B., A.G.C., E.E.E., G.G., J.L.H., T.F.C.M., S.A.M. and P.M.V. participated in the workshop; T.A.M., P.M.V., G.G., M.I.M., E.E.E., T.F.C.M. and S.A.M. drafted the manuscript; F.S.C., N.J.C., D.B.G., L.A.H., D.J.H., E.M.R., L.R.C., A.C., J.H.C., A.P.R., A.E.G., A.K., L.K., E.M., C.N.R., M.S., D.V., A.S.W., M.B., A.G.C. and J.L.H. critically reviewed and revised the manuscript for content.

Author information

Authors and Affiliations

  1. National Human Genome Research Institute, Building 31, Room 4B09, 31 Center Drive, MSC 2152, Bethesda, Maryland 20892-2152, USA ,

    Teri A. Manolio & Alan E. Guttmacher

  2. National Institutes of Health, Building 1, Room 126, MSC 0148, Bethesda, Maryland 20892-0148, USA ,

    Francis S. Collins

  3. Departments of Medicine and Human Genetics, University of Chicago, Room A612, MC 6091, 5841 South Maryland Avenue, Chicago, Illinois 60637, USA,

    Nancy J. Cox

  4. Duke University, The Institute for Genome Sciences and Policy (IGSP), Box 91009, Durham, North Carolina 27708, USA ,

    David B. Goldstein

  5. National Human Genome Research Institute, Office of Population Genomics, Suite 4076, MSC 9305, 5635 Fishers Lane, Rockville, Maryland 20892-9305, USA ,

    Lucia A. Hindorff & Erin M. Ramos

  6. Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, Massachusetts 02115, USA,

    David J. Hunter

  7. University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Old Road, Oxford OX3 7LJ, UK, and Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK ,

    Mark I. McCarthy

  8. GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, USA ,

    Lon R. Cardon

  9. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 North Broadway BRB579, Baltimore, Maryland 21205, USA ,

    Aravinda Chakravarti & David Valle

  10. Department of Medicine, Division of Digestive Diseases, Yale University, 333 Cedar Street, New Haven, Connecticut 06520-8019, USA,

    Judy H. Cho

  11. deCODE Genetics, Sturlugata 8, Reykjavik IS-101, Iceland ,

    Augustine Kong

  12. and Department of Ecology and Evolutionary Biology, Lewis-Sigler Institute for Integrative Genomics, Howard Hughes Medical Institute, Princeton University, Princeton, New Jersey 08544, USA,

    Leonid Kruglyak

  13. The Genome Center, Washington University School of Medicine, 4444 Forest Park Avenue, Campus Box 8501, Saint Louis, Missouri 63108, USA ,

    Elaine Mardis

  14. National Human Genome Research Institute, Center for Research on Genomics and Global Health, Building 12A, Room 4047, 12 South Drive, MSC 5635, Bethesda, Maryland 20892-5635, USA ,

    Charles N. Rotimi

  15. Department of Integrative Biology, University of California, 3060 Valley Life Science Building, Berkeley, California 94720-3140, USA,

    Montgomery Slatkin

  16. Stanford University, Health Research and Policy, Redwood Building, Room T204, 259 Campus Drive, Stanford, California 94305, USA ,

    Alice S. Whittemore

  17. Department of Biostatistics, University of Michigan, 1420 Washington Heights, Ann Arbor, Michigan 48109-2029, USA,

    Michael Boehnke

  18. Department of Molecular Biology and Genetics, 107 Biotechnology Building, Cornell University, Ithaca, New York 14853, USA,

    Andrew G. Clark

  19. Department of Genome Sciences, Howard Hughes Medical Institute and University of Washington, 1705 North-East Pacific Street, Foege Building, Box 355065, Seattle, Washington 98195-5065, USA,

    Evan E. Eichler

  20. University of Queensland, School of Biological Sciences, Goddard Building, Saint Lucia Campus, Brisbane, Queensland 4072, Australia ,

    Greg Gibson

  21. Vanderbilt University, Center for Human Genetics Research, 519 Light Hall, Nashville, Tennessee 37232-0700, USA ,

    Jonathan L. Haines

  22. Department of Genetics, North Carolina State University, Box 7614, Raleigh, North Carolina 27695, USA,

    Trudy F. C. Mackay

  23. Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, NRB 0330, Boston, Massachusetts 02115, USA,

    Steven A. McCarroll

  24. Queensland Institute of Medical Research, 300 Herston Road, Brisbane, Queensland 4006, Australia ,

    Peter M. Visscher

Authors
  1. Teri A. Manolio

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  2. Francis S. Collins

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  3. Nancy J. Cox

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  4. David B. Goldstein

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  5. Lucia A. Hindorff

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  6. David J. Hunter

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  7. Mark I. McCarthy

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  8. Erin M. Ramos

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  9. Lon R. Cardon

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  10. Aravinda Chakravarti

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  11. Judy H. Cho

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  12. Alan E. Guttmacher

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  13. Augustine Kong

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  14. Leonid Kruglyak

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  15. Elaine Mardis

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  16. Charles N. Rotimi

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  17. Montgomery Slatkin

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  18. David Valle

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  19. Alice S. Whittemore

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  20. Michael Boehnke

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  21. Andrew G. Clark

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  22. Evan E. Eichler

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  23. Greg Gibson

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  24. Jonathan L. Haines

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  25. Trudy F. C. Mackay

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  26. Steven A. McCarroll

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  27. Peter M. Visscher

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Corresponding author

Correspondence toTeri A. Manolio.

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Competing interests

[COMPETING INTERESTS: L.R.C. is employed by a pharmaceutical company; A.K. is an employee of decode Genetics, a commercial company that participates in gene discoveries and the development of diagnostic tests. He also owns stocks of the company. E.E.E. is a Pacific Biosciences SAB member. A.C. is a member of the Affymetrix SAB, a potential conflict of interest overseen by Johns Hopkins University policies.]

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Manolio, T., Collins, F., Cox, N.et al. Finding the missing heritability of complex diseases.Nature461, 747–753 (2009). https://doi.org/10.1038/nature08494

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Editorial Summary

Genetics of complex diseases

Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases, but most confer quite small increments of risk. There seems to be a large component of heritability somehow evading detection. Possible explanations for this 'missing heritability' include great numbers of small-effect variants yet to be found, rare structural or epigenetic variation not detected by current genotyping technology and hard-to-detect gene–gene and gene–environment interactions. Teri Manolio and colleagues examine the research strategies most likely to distinguish between these and other possible explanations.

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