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Integrating common and rare genetic variation in diverse human populations

Naturevolume 467, pages52–58 (2010)Cite this article

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Abstract

Despite great progress in identifying genetic variants that influence human disease, most inherited risk remains unexplained. A more complete understanding requires genome-wide studies that fully examine less common alleles in populations with a wide range of ancestry. To inform the design and interpretation of such studies, we genotyped 1.6 million common single nucleotide polymorphisms (SNPs) in 1,184 reference individuals from 11 global populations, and sequenced ten 100-kilobase regions in 692 of these individuals. This integrated data set of common and rare alleles, called ‘HapMap 3’, includes both SNPs and copy number polymorphisms (CNPs). We characterized population-specific differences among low-frequency variants, measured the improvement in imputation accuracy afforded by the larger reference panel, especially in imputing SNPs with a minor allele frequency of ≤5%, and demonstrated the feasibility of imputing newly discovered CNPs and SNPs. This expanded public resource of genome variants in global populations supports deeper interrogation of genomic variation and its role in human disease, and serves as a step towards a high-resolution map of the landscape of human genetic variation.

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Figure 1:Size and frequency spectra of common and rare CNPs.
Figure 2:SNP discovery informativeness across populations.
Figure 3:Effect of sample size on SNP ascertainment.
Figure 4:Haplotype sharing around SNPs and CNPs.
Figure 5:Imputation accuracy and reference panel size.
Figure 6:Imputation: new populations, new variants.

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Acknowledgements

We dedicate this work to Leena Peltonen for her vital leadership role in this study, and in memory of a valued friend and colleague. We thank E. Boerwinkle and R. Durbin for critical reading of the manuscript. We thank the USA National Institutes of Health, the National Human Genome Research Institute, the National Institute on Deafness and Other Communication Disorders and the Wellcome Trust for supporting the majority of this work. Funding was also provided by the Louis-Jeantet Foundation and the NCCR ‘Frontiers in Genetics’ (Swiss National Science Foundation). We thank the people from the following communities who were generous in donating their blood samples to be studied in this project: the Yoruba in Ibadan, Nigeria; the Maasai in Kinyawa, Kenya; the Luhya in Webuye, Kenya; the Han Chinese in Beijing, China; the Japanese in Tokyo, Japan; the Chinese in metropolitan Denver, Colorado; the Gujarati Indians in Houston, Texas; the Toscani in Italia; the community of African ancestry in the southwestern USA; and the community of Mexican ancestry in Los Angeles, California. We also thank the people in the Utah Centre d’Etude du Polymorphisme Humain community who allowed the samples they donated earlier to be used for the project. The authors acknowledge use of DNA from the 1958 British birth cohort collection, funded by the UK Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. The Illumina 550K genotype data for the 1958 British birth cohort samples were made available by the Sanger Institute. For the 1958 British birth cohort Affymetrix 500K genotype data, we thank the Wellcome Trust Case Control Consortium (http://www.wtccc.org.uk), which was funded by Wellcome Trust award 076113.

Author information

Author notes

  1. Leena Peltonen, Leena Peltonen and Leena Peltonen: ‡Deceased.

Authors and Affiliations

  1. Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02138, USA.,

    David M. Altshuler, David M. Altshuler, Stephen F. Schaffner, David M. Altshuler, Paul I. W. de Bakker (Co-leader), Stacey B. Gabriel, Xiaoming Jia, Melissa Parkin (Co-leader), Joshua M. Korn, Steven A. McCarroll (Co-leader), James Nemesh, Samuela Pollack, Wendy Brodeur, Huy Nguyen, Stephen F. Schaffner (Leader), Samuela Pollack, Stephen F. Schaffner (Co-leader) & Ilya Shlyakhter

  2. Department of Molecular and Human Genetics, Baylor College of Medicine, Human Genome Sequencing Center, One Baylor Plaza, Houston, Texas 77030, USA.,

    Richard A. Gibbs, Richard A. Gibbs, Fuli Yu, Penelope E. Bonnen, Richard A. Gibbs, Fuli Yu (Leader), Kyle Chang, Alicia Hawes, Lora R. Lewis, Yanru Ren, David Wheeler, Richard A. Gibbs, Donna Marie Muzny, Penelope E. Bonnen, Richard A. Gibbs, Claudia Gonzaga-Jauregui & Fuli Yu (Leader)

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

    Emmanouil Dermitzakis, Emmanouil Dermitzakis, Emmanouil Dermitzakis & Stephen B. Montgomery

  4. Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.,

    Paul I. W. de Bakker (Co-leader)

  5. Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1HH, UK.,

    Panos Deloukas (Co-leader), Rhian Gwilliam, Sarah Hunt, Michael Inouye (Co-leader), Aarno Palotie, Pamela Whittaker, Chris Barnes, Matthew Hurles (Co-leader), Kati Kristiansson, Nicole Soranzo, Verneri Anttila, Qingrun Zhang, Mohammed J. R. Ghori, Ralph McGinnis (Co-leader), William McLaren & Fumihiko Takeuchi

  6. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, Finland.,

    Aarno Palotie & Verneri Anttila

  7. Department of Medical Genetics, University of Helsinki and University Central Hospital, Haartmaninkatu 8, 00290 Helsinki, Finland.,

    Aarno Palotie & Verneri Anttila

  8. Department of Pathology, Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA.,

    Katayoon Darvishi & Charles Lee

  9. Department of Biological Statistics and Computational Biology, Cornell University, 102A Weill Hall, Ithaca, New York 14853, USA.,

    Alon Keinan (Leader) & Alon Keinan

  10. Departments of Epidemiology and Biostatistics, Harvard School of Public Health, 665 Huntington Avenue, Building 2 Room 211, Boston, Massachusetts 02115, USA.,

    Alkes L. Price, Alkes L. Price & Alkes L. Price (Co-leader)

  11. Massachusetts General Hospital, Center for Human Genetic Research, Simches Research Center, 185 Cambridge Street, Boston, Massachusetts 02114, USA.,

    Mark J. Daly

  12. Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK.,

    Stephen Leslie, Gil McVean & Loukas Moutsianas

  13. Department of Organismic and Evolutionary Biology, Harvard University, Center for Systems Biology, 52 Oxford Street, Room 469, Cambridge, Massachusetts 02215, USA.,

    Sharon R. Grossman, Elizabeth B. Hostetter & Pardis C. Sabeti (Leader)

  14. Department of Epidemiology and Preventative Medicine, University of Maryland School of Medicine, N406 Institute of Human Virology, 725 West Lombard Street, Baltimore, Maryland 21201, USA.,

    Clement A. Adebamowo

  15. Department of Anthropology, University of Oklahoma, 455 West Lindsey Room 505C, Norman, Oklahoma 73019, USA.,

    Morris W. Foster

  16. Department of Anthropology, University of California, San Francisco, History and Social Medicine, 3333 California Street Suite 485, San Francisco, 94143-0850, California, USA

    Deborah R. Gordon

  17. The Australian National University, John Curtin School of Medical Research, Garran Road, Building 131, Canberra, ACT2603, Australia.,

    Julio Licinio

  18. Institute for Oncological Study and Prevention, 50139, Florence, Italy

    Maria Cristina Manca

  19. Department of Bioethics, Case Western Reserve University, School of Medicine TA200, 10900 Euclid Avenue, Cleveland, Ohio 44106-4976, USA.,

    Patricia A. Marshall

  20. Health Sciences University of Hokkaido, 1757 Kanazawa, Tobetsu-cho, Ishikari-gun, Hokkaido 061-0293, Japan.,

    Ichiro Matsuda

  21. Department of Population and Family Health, Moi University, PO Box 4606, Eldoret 30100, Kenya.,

    Duncan Ngare

  22. National Human Genome Research Institute, National Institutes of Health, 5635 Fishers Lane Suite 3039, Bethesda, Maryland 20892, USA.,

    Vivian Ota Wang

  23. Department of Anthropology, University of Houston at Clear Lake, 2700 Bay Area Boulevard, PO Box 295, Houston, Texas 77058-1098, USA.,

    Deepa Reddy

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

    Charles N. Rotimi

  25. Duke University, Institute for Genome Sciences and Policy, 450 Research Drive, PO Box 91009, LSRC B-Wing, Room 320B, Durham, North Carolina 27708, USA.,

    Charmaine D. Royal

  26. Department of Bioethics, The Cleveland Clinic, 9500 Euclid Avenue JJ60, Cleveland, Ohio 44124, USA.,

    Richard R. Sharp

  27. Beijing Institute of Genomics, Chinese Academy of Science, Beijing Airport Industrial Zone B-6, Beijing 101300, China.,

    Changqing Zeng

  28. National Human Genome Research Institute, National Institutes of Health, 5635 Fishers Lane Suite 4076, Bethesda, Maryland 20892, USA ,

    Lisa D. Brooks & Jean E. McEwen

Consortia

The International HapMap 3 Consortium

  • Principal investigators

    • David M. Altshuler
    • , Richard A. Gibbs
    •  & Leena Peltonen

  • Project coordination leaders

    • David M. Altshuler
    • , Richard A. Gibbs
    • , Leena Peltonen
    •  & Emmanouil Dermitzakis

  • Manuscript writing group

    • Stephen F. Schaffner
    • , Fuli Yu
    • , Leena Peltonen
    • , Emmanouil Dermitzakis
    • , Penelope E. Bonnen
    • , David M. Altshuler
    • , Richard A. Gibbs

    • Genotyping and QC

      • Paul I. W. de Bakker (Co-leader)
      • , Panos Deloukas (Co-leader)
      • , Stacey B. Gabriel
      • , Rhian Gwilliam
      • , Sarah Hunt
      • , Michael Inouye (Co-leader)
      • , Xiaoming Jia
      • , Aarno Palotie
      • , Melissa Parkin (Co-leader)
      •  & Pamela Whittaker

    • ENCODE 3 sequencing and SNP discovery

      • Fuli Yu (Leader)
      • , Kyle Chang
      • , Alicia Hawes
      • , Lora R. Lewis
      • , Yanru Ren
      • , David Wheeler
      • , Richard A. Gibbs
      •  & Donna Marie Muzny

    • Copy number variation typing and analysis

      • Chris Barnes
      • , Katayoon Darvishi
      • , Matthew Hurles (Co-leader)
      • , Joshua M. Korn
      • , Kati Kristiansson
      • , Charles Lee
      • , Steven A. McCarroll (Co-leader)
      •  & James Nemesh

    • Population analysis

      • Emmanouil Dermitzakis
      • , Alon Keinan (Leader)
      • , Stephen B. Montgomery
      • , Samuela Pollack
      • , Alkes L. Price
      •  & Nicole Soranzo

    • Low frequency variation analysis

      • Penelope E. Bonnen
      • , Richard A. Gibbs
      • , Claudia Gonzaga-Jauregui
      • , Alon Keinan
      • , Alkes L. Price
      •  & Fuli Yu (Leader)

    • Linkage disequilibrium and haplotype sharing analysis

      • Verneri Anttila
      • , Wendy Brodeur
      • , Mark J. Daly
      • , Stephen Leslie
      • , Gil McVean
      • , Loukas Moutsianas
      • , Huy Nguyen
      • , Stephen F. Schaffner (Leader)
      •  & Qingrun Zhang

    • Imputation

      • Mohammed J. R. Ghori
      • , Ralph McGinnis (Co-leader)
      • , William McLaren
      • , Samuela Pollack
      • , Alkes L. Price (Co-leader)
      • , Stephen F. Schaffner (Co-leader)
      •  & Fumihiko Takeuchi

    • Natural selection

      • Sharon R. Grossman
      • , Ilya Shlyakhter
      • , Elizabeth B. Hostetter
      •  & Pardis C. Sabeti (Leader)

    • Community engagement and sample collection groups

      • Clement A. Adebamowo
      • , Morris W. Foster
      • , Deborah R. Gordon
      • , Julio Licinio
      • , Maria Cristina Manca
      • , Patricia A. Marshall
      • , Ichiro Matsuda
      • , Duncan Ngare
      • , Vivian Ota Wang
      • , Deepa Reddy
      • , Charles N. Rotimi
      • , Charmaine D. Royal
      • , Richard R. Sharp
      •  & Changqing Zeng

    • Scientific management

      • Lisa D. Brooks
      •  & Jean E. McEwen

Corresponding authors

Correspondence toDavid M. Altshuler,Richard A. Gibbs,David M. Altshuler,Richard A. Gibbs,David M. Altshuler,Richard A. Gibbs,Richard A. Gibbs orRichard A. Gibbs.

Ethics declarations

Competing interests

The author declare no competing financial interests.

Additional information

The HapMap 3/ENCODE 3 data set has been deposited athttp://www.hapmap.org. The sequence traces of ENCODE 3 can be accessed athttp://www.ncbi.nlm.nih.gov/Traces/trace.cgi by submitting the query:species_code5“HOMO SAPIENS” and CENTER_NAME 5 “BCM” and CENTER_PROJECT 5 “RHIAY”.

A list of participants and their affiliations appears at the end of the paper

Supplementary information

Supplementary Information

This file contains Supplementary Information comprising Introduction, Large Scale Genotyping, Rare Allele Calling Bias, Deep PCR Sequencing, Copy Number Polymorphism (CNP) Analysis, Population Analyses, Recurrent SNPs and Haplotype sharing (see Contents page for full details). It also includes Supplementary Tables 1-11, Supplementary Figures 1-9 with legends and additional references. (PDF 1111 kb)

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The International HapMap 3 Consortium. Integrating common and rare genetic variation in diverse human populations.Nature467, 52–58 (2010). https://doi.org/10.1038/nature09298

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Editorial Summary

Third-generation HapMap

The International HapMap Consortium, established to develop a haplotype map of the human genome describing the common patterns of DNA sequence variation, has now reached its third incarnation. HapMap1, published in 2005 (go.nature.com/gJisDm), contained more than a million SNP (single nucleotide polymorphism) genotypes generated in 269 individuals from four geographically diverse populations. Two years later, HapMap2 (go.nature.com/WttNWX) added more than 2.1 million SNPs to the original map in the same 269 individuals. With the aim of providing a resource for the latest wave of genome-wide studies focused on disease linkages, HapMap3 casts the net wider. About 1.6 million common SNPs were genotyped in 1,184 individuals from 11 global populations, and ten 100-kilobase regions were sequenced in 692 of these individuals.

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