Finding the missing heritability of complex diseases

Teri A. Manolio (), Francis S. Collins, Nancy J. Cox, David B. Goldstein, Lucia A. Hindorff, David J. Hunter, Mark I. McCarthy, Erin M. Ramos, Lon R. Cardon, Aravinda Chakravarti, Judy H. Cho, Alan E. Guttmacher, Augustine Kong, Leonid Kruglyak, Elaine Mardis, Charles N. Rotimi, Montgomery Slatkin, David Valle, Alice S. Whittemore, Michael Boehnke, Andrew G. Clark, Evan E. Eichler, Greg Gibson, Jonathan L. Haines, Trudy F. C. Mackay, Steven A. McCarroll and Peter M. Visscher
Additional contact information
Teri A. Manolio: National Human Genome Research Institute, Building 31, Room 4B09, 31 Center Drive, MSC 2152, Bethesda, Maryland 20892-2152, USA
Francis S. Collins: National Institutes of Health, Building 1, Room 126, MSC 0148, Bethesda, Maryland 20892-0148, USA
Nancy J. Cox: University of Chicago, Room A612, MC 6091, 5841 South Maryland Avenue, Chicago, Illinois 60637, USA
David B. Goldstein: Duke University, The Institute for Genome Sciences and Policy (IGSP), Box 91009, Durham, North Carolina 27708, USA
Lucia A. Hindorff: National Human Genome Research Institute, Office of Population Genomics, Suite 4076, MSC 9305, 5635 Fishers Lane, Rockville, Maryland 20892-9305, USA
David J. Hunter: Harvard School of Public Health, 677 Huntington Avenue, Boston, Massachusetts 02115, USA
Mark I. McCarthy: 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
Erin M. Ramos: National Human Genome Research Institute, Office of Population Genomics, Suite 4076, MSC 9305, 5635 Fishers Lane, Rockville, Maryland 20892-9305, USA
Lon R. Cardon: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, USA
Aravinda Chakravarti: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 North Broadway BRB579, Baltimore, Maryland 21205, USA
Judy H. Cho: Yale University, 333 Cedar Street, New Haven, Connecticut 06520-8019, USA
Alan E. Guttmacher: National Human Genome Research Institute, Building 31, Room 4B09, 31 Center Drive, MSC 2152, Bethesda, Maryland 20892-2152, USA
Augustine Kong: deCODE Genetics, Sturlugata 8, Reykjavik IS-101, Iceland
Leonid Kruglyak: Lewis-Sigler Institute for Integrative Genomics, Howard Hughes Medical Institute, Princeton University, Princeton, New Jersey 08544, USA
Elaine Mardis: The Genome Center, Washington University School of Medicine, 4444 Forest Park Avenue, Campus Box 8501, Saint Louis, Missouri 63108, USA
Charles N. Rotimi: 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
Montgomery Slatkin: University of California, 3060 Valley Life Science Building, Berkeley, California 94720-3140, USA
David Valle: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 North Broadway BRB579, Baltimore, Maryland 21205, USA
Alice S. Whittemore: Stanford University, Health Research and Policy, Redwood Building, Room T204, 259 Campus Drive, Stanford, California 94305, USA
Michael Boehnke: University of Michigan, 1420 Washington Heights, Ann Arbor, Michigan 48109-2029, USA
Andrew G. Clark: 107 Biotechnology Building, Cornell University, Ithaca, New York 14853, USA
Evan E. Eichler: Howard Hughes Medical Institute and University of Washington, 1705 North-East Pacific Street, Foege Building, Box 355065, Seattle, Washington 98195-5065, USA
Greg Gibson: University of Queensland, School of Biological Sciences, Goddard Building, Saint Lucia Campus, Brisbane, Queensland 4072, Australia
Jonathan L. Haines: Vanderbilt University, Center for Human Genetics Research, 519 Light Hall, Nashville, Tennessee 37232-0700, USA
Trudy F. C. Mackay: North Carolina State University, Box 7614, Raleigh, North Carolina 27695, USA
Steven A. McCarroll: Harvard Medical School, 77 Avenue Louis Pasteur, NRB 0330, Boston, Massachusetts 02115, USA
Peter M. Visscher: Queensland Institute of Medical Research, 300 Herston Road, Brisbane, Queensland 4006, Australia

Nature, 2009, vol. 461, issue 7265, 747-753

Abstract: 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.

Date: 2009
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DOI: 10.1038/nature08494

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