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Finding the missing heritability of complex diseases

Author

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  • 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)

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.

Suggested Citation

  • 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 &, 2009. "Finding the missing heritability of complex diseases," Nature, Nature, vol. 461(7265), pages 747-753, October.
    • Handle: RePEc:nat:nature:v:461:y:2009:i:7265:d:10.1038_nature08494
    DOI: 10.1038/nature08494
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    Cited by:

    1. Zhuoran Xu & Quan Li & Luigi Marchionni & Kai Wang, 2023. "PhenoSV: interpretable phenotype-aware model for the prioritization of genes affected by structural variants," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
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    10. Bingxin Zhao & Fei Zou, 2022. "On polygenic risk scores for complex traits prediction," Biometrics, The International Biometric Society, vol. 78(2), pages 499-511, June.
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    12. von Stumm, Sophie & Kandaswamy, Radhika & Maxwell, Jessye, 2023. "Gene-environment interplay in early life cognitive development," Intelligence, Elsevier, vol. 98(C).
    13. Surina Singh & Ananyo Choudhury & Scott Hazelhurst & Nigel J. Crowther & Palwendé R. Boua & Hermann Sorgho & Godfred Agongo & Engelbert A. Nonterah & Lisa K. Micklesfield & Shane A. Norris & Isaac Kis, 2023. "Genome-wide association study meta-analysis of blood pressure traits and hypertension in sub-Saharan African populations: an AWI-Gen study," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    14. Ting Fu & Kofi Amoah & Tracey W. Chan & Jae Hoon Bahn & Jae-Hyung Lee & Sari Terrazas & Rockie Chong & Sriram Kosuri & Xinshu Xiao, 2024. "Massively parallel screen uncovers many rare 3′ UTR variants regulating mRNA abundance of cancer driver genes," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    15. Ilias Georgakopoulos-Soares & Chengyu Deng & Vikram Agarwal & Candace S. Y. Chan & Jingjing Zhao & Fumitaka Inoue & Nadav Ahituv, 2023. "Transcription factor binding site orientation and order are major drivers of gene regulatory activity," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    16. Andrea R. Waksmunski & Yeunjoo E. Song & Tyler G. Kinzy & Reneé A. Laux & Jane Sewell & Denise Fuzzell & Sarada Fuzzell & Sherri Miller & Janey L. Wiggs & Louis R. Pasquale & Jonathan M. Skarie & Jona, 2021. "The GGLEAM Study: Understanding Glaucoma in the Ohio Amish," IJERPH, MDPI, vol. 18(4), pages 1-13, February.
    17. Ian Barnett & Rajarshi Mukherjee & Xihong Lin, 2017. "The Generalized Higher Criticism for Testing SNP-Set Effects in Genetic Association Studies," Journal of the American Statistical Association, Taylor & Francis Journals, vol. 112(517), pages 64-76, January.
    18. Lucas Alvizi & Diogo Nani & Luciano Abreu Brito & Gerson Shigeru Kobayashi & Maria Rita Passos-Bueno & Roberto Mayor, 2023. "Neural crest E-cadherin loss drives cleft lip/palate by epigenetic modulation via pro-inflammatory gene–environment interaction," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    19. Zheng Xu & Song Yan & Shuai Yuan & Cong Wu & Sixia Chen & Zifang Guo & Yun Li, 2023. "Efficient Two-Stage Analysis for Complex Trait Association with Arbitrary Depth Sequencing Data," Stats, MDPI, vol. 6(1), pages 1-14, March.
    20. Margaret Sunitha Selvaraj & Xihao Li & Zilin Li & Akhil Pampana & David Y. Zhang & Joseph Park & Stella Aslibekyan & Joshua C. Bis & Jennifer A. Brody & Brian E. Cade & Lee-Ming Chuang & Ren-Hua Chung, 2022. "Whole genome sequence analysis of blood lipid levels in >66,000 individuals," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    21. Remo Monti & Pia Rautenstrauch & Mahsa Ghanbari & Alva Rani James & Matthias Kirchler & Uwe Ohler & Stefan Konigorski & Christoph Lippert, 2022. "Identifying interpretable gene-biomarker associations with functionally informed kernel-based tests in 190,000 exomes," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    22. Jayshree Advani & Puja A. Mehta & Andrew R. Hamel & Sudeep Mehrotra & Christina Kiel & Tobias Strunz & Ximena Corso-Díaz & Madeline Kwicklis & Freekje Asten & Rinki Ratnapriya & Emily Y. Chew & Dena G, 2024. "QTL mapping of human retina DNA methylation identifies 87 gene-epigenome interactions in age-related macular degeneration," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    23. Agnieszka Boroń & Małgorzata Śmiarowska & Anna Grzywacz & Krzysztof Chmielowiec & Jolanta Chmielowiec & Jolanta Masiak & Tomasz Pawłowski & Dariusz Larysz & Andrzej Ciechanowicz, 2022. "Association of Polymorphism within the Putative miRNA Target Site in the 3′UTR Region of the DRD2 Gene with Neuroticism in Patients with Substance Use Disorder," IJERPH, MDPI, vol. 19(16), pages 1-21, August.

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