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A reference panel of 64,976 haplotypes for genotype imputation

Nature Genetics volume 48, pages 12791283 (2016) | Download Citation

Abstract

We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.

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Acknowledgements

We are grateful to all participants of all the studies that have contributed data to the HRC. J.M. acknowledges support from the ERC (grant 617306). W.K. acknowledges support from the Wellcome Trust (grant WT097307). S. McCarthy and R.D. acknowledge support from Wellcome Trust grant WT090851. A full list of acknowledgments for the cohorts is given in the Supplementary Note.

Author information

Author notes

    • Shane McCarthy
    • , Sayantan Das
    •  & Warren Kretzschmar

    These authors contributed equally to this work.

    • Richard Durbin
    • , Gonçalo Abecasis
    •  & Jonathan Marchini

    These authors jointly directed this work.

Affiliations

  1. Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.

    • Shane McCarthy
    • , Yang Luo
    • , Arthur Gilly
    • , Jeffrey C Barrett
    • , Eleftheria Zeggini
    • , Nicole Soranzo
    • , Klaudia Walter
    • , Carl A Anderson
    •  & Richard Durbin
  2. Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.

    • Sayantan Das
    • , Hyun Min Kang
    • , Christian Fuchsberger
    • , Alan Kwong
    • , Laura J Scott
    • , Sai Chen
    • , Michael Boehnke
    •  & Gonçalo Abecasis
  3. Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA.

    • Sayantan Das
    • , Hyun Min Kang
    • , Christian Fuchsberger
    • , Alan Kwong
    • , Laura J Scott
    • , Sai Chen
    • , Michael Boehnke
    •  & Gonçalo Abecasis
  4. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Warren Kretzschmar
    • , Anubha Mahajan
    • , Mark I McCarthy
    •  & Jonathan Marchini
  5. Genetics and Development, University of Geneva, Geneva, Switzerland.

    • Olivier Delaneau
  6. Genetics of Complex Traits, Institute of Biomedical Science, University of Exeter Medical School, Exeter, UK.

    • Andrew R Wood
    • , Marcus Tuke
    •  & Timothy Frayling
  7. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.

    • Alexander Teumer
  8. DZHK (German Centre for Cardiovascular Research), Greifswald, Germany.

    • Alexander Teumer
    •  & Matthias Nauck
  9. Vertebrate Resequencing Informatics, Wellcome Trust Sanger Institute, Hinxton, UK.

    • Petr Danecek
  10. Department of Statistics, University of Oxford, Oxford, UK.

    • Kevin Sharp
    •  & Jonathan Marchini
  11. IRGB, CNR, Sardinia, Italy.

    • Carlo Sidore
    • , Andrea Angius
    • , Fabio Busonero
    •  & Francesco Cucca
  12. MRC Integrative Epidemiology Unit, University of Bristol, Oakfield Grove, UK.

    • Nicholas Timpson
    • , Laura J Corbin
    • , George Davey Smith
    •  & Josine L Min
  13. THL, Helsinki, Finland.

    • Seppo Koskinen
    •  & Veikko Salomaa
  14. Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, USA.

    • Scott Vrieze
  15. Department of Psychology and Neurosurgery, University of Colorado, Boulder, Colorado, USA.

    • Scott Vrieze
  16. Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

    • He Zhang
    •  & Cristen Willer
  17. Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, Utrecht, the Netherlands.

    • Jan Veldink
    • , Leonard H Van den Berg
    • , Wouter Van Rheenen
    •  & Annelot Dekker
  18. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Ulrike Peters
    • , Tabitha Harrison
    •  & Charles Kooperberg
  19. Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA.

    • Ulrike Peters
  20. Department of Psychiatry, SUNY Downstate, Brooklyn, New York, USA.

    • Carlos Pato
    •  & Michele Pato
  21. Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands.

    • Cornelia M van Duijn
  22. Department of Pediatrics–Nephrology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.

    • Christopher E Gillies
    •  & Matthew G Sampson
  23. Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.

    • Ilaria Gandin
    • , Massimiliano Cocca
    • , Nicola Pirastu
    •  & Paolo Gasparini
  24. Genetica Medica, IRCCS Burlo Garofolo, Trieste, Italy.

    • Massimo Mezzavilla
  25. Department of Experimental Genetics, Sidra, Doha, Qatar.

    • Massimo Mezzavilla
    •  & Paolo Gasparini
  26. Genetics and Cell Biology, San Raffaele Research Institute, Milan, Italy.

    • Michela Traglia
    • , Cinzia Sala
    •  & Daniela Toniolo
  27. Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.

    • Dorrett Boomsma
  28. Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, USA.

    • Kari Branham
  29. MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

    • Gerome Breen
  30. NIHR Biomedical Research Centre for Mental Health, Institute of Psychiatry, Psychology and Neuroscience, King's College London and the South London Maudsley Hospital, London, UK.

    • Gerome Breen
  31. Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan, USA.

    • Chad M Brummett
    •  & Ross M Fraser
  32. Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.

    • Harry Campbell
    •  & James F Wilson
  33. Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.

    • Andrew Chan
  34. Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Andrew Chan
  35. Department of Computational Medicine, University of Michigan, Ann Arbor, Michigan, USA.

    • Sai Chen
    • , Matthias Kretzler
    •  & Cristen Willer
  36. Department of Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.

    • Sai Chen
    • , Matthias Kretzler
    •  & Cristen Willer
  37. Division of Epidemiology and Clinical Applications, National Eye Institute, Bethesda, Maryland, USA.

    • Emily Chew
  38. Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Francis S Collins
  39. Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.

    • George Dedoussis
    •  & Aliki-Eleni Farmaki
  40. Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.

    • Marcus Dorr
  41. Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.

    • Marcus Dorr
    • , Matthias Nauck
    •  & Uwe Volker
  42. Longitudinal Studies Section, Clinical Research Branch, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland, USA.

    • Luigi Ferrucci
  43. Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.

    • Lukas Forer
    •  & Sebastian Schoenherr
  44. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Stacey Gabriel
    • , Aarno Palotie
    •  & David Altshuler
  45. HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.

    • Shawn Levy
    •  & Richard M Myers
  46. Department of Clinical Sciences, Diabetes and Endocrinology, University of Lund, Malmö, Sweden.

    • Leif Groop
  47. Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.

    • Leif Groop
  48. Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.

    • Leif Groop
  49. Institute of Biomedical and Clinical Research, University of Exeter Medical School, Exeter, UK.

    • Andrew Hattersley
  50. Hunt Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway.

    • Oddgeir L Holmen
    •  & Kristian Hveem
  51. Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.

    • Matthias Kretzler
  52. Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.

    • James C Lee
  53. Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK.

    • James C Lee
  54. Department of Psychology, University of Minnesota, Minneapolis, Minnesota, USA.

    • Matt McGue
    •  & William Iacono
  55. Institute of Human Genetics, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Thomas Meitinger
  56. Institute of Human Genetics, Technische Universität München, Munich, Germany.

    • Thomas Meitinger
  57. DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.

    • Thomas Meitinger
  58. Epidemiology and Public Health, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.

    • David Melzer
  59. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Karen L Mohlke
  60. Molecular Neuropsychiatry and Development Laboratory, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

    • John B Vincent
  61. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.

    • John B Vincent
  62. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.

    • John B Vincent
  63. Department of Genome Sciences, University of Washington, Seattle, Washington, USA.

    • Deborah Nickerson
  64. Institute for Molecular Medicine, FIMM, Helsinki, Finland.

    • Aarno Palotie
  65. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Aarno Palotie
  66. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Aarno Palotie
    •  & David Altshuler
  67. Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Aarno Palotie
  68. Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Aarno Palotie
  69. Department of Psychiatry, University of Michigan, Ann Arbor, Michigan, USA.

    • Melvin McInnis
  70. Department of Medicine, McGill University, Montreal, Quebec, Canada.

    • J Brent Richards
  71. Department of Human Genetics, McGill University, Montreal, Quebec, Canada.

    • J Brent Richards
  72. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

    • J Brent Richards
    • , Kerrin Small
    •  & Timothy Spector
  73. National Institute on Aging, US National Institutes of Health, Baltimore, Maryland, USA.

    • David Schlessinger
  74. Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.

    • P Eline Slagboom
  75. Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Dwight Stambolian
  76. Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.

    • Jaakko Tuomilehto
  77. Dasman Diabetes Institute, Dasman, Kuwait.

    • Jaakko Tuomilehto
  78. Center for Vascular Prevention, Danube University Krems, Krems, Austria.

    • Jaakko Tuomilehto
  79. Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.

    • Jaakko Tuomilehto
  80. Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.

    • Uwe Volker
  81. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

    • Cisca Wijmenga
    •  & Morris A Swertz
  82. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK.

    • James F Wilson
  83. Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Paul I W de Bakker
  84. Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Paul I W de Bakker
  85. University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands.

    • Morris A Swertz
  86. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Steven McCarroll
  87. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Steven McCarroll
  88. Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • David Altshuler
  89. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • David Altshuler
  90. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • David Altshuler
  91. Vertex Pharmaceuticals, Boston, Massachusetts, USA.

    • David Altshuler
  92. Department of Public Health, University of Helsinki, Helsinki, Finland.

    • Samuli Ripatti
  93. Department of Haematology, University of Cambridge, Cambridge, UK.

    • Nicole Soranzo
  94. NIHR Blood and Transplant Unit (BTRU) in Donor Health and Genomics, University of Cambridge, Cambridge, UK.

    • Nicole Soranzo
  95. Neurobiology–Neurodegeneration and Repair Laboratory, National Eye Institute, US National Institutes of Health, Bethesda, Maryland, USA.

    • Anand Swaroop
  96. Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

    • Mark I McCarthy
  97. Oxford NIHR Biomedical Research Centre, Churchill Hospital, Headington, Oxford, UK.

    • Mark I McCarthy

Consortia

  1. the Haplotype Reference Consortium

Authors

    Contributions

    The HRC was initially conceived by discussions between J.M., G.A., R.D., M.I.M. and M.B. Analysis and methods development were carried out by S. McCarthy, S.D., W.K., O.D., A.R.W., P.D. and H.M.K. Supervision of the research was provided by J.M., G.A. and R.D. The Michigan Imputation Server was developed by C.F., L. Forer S.S. and G.A. The Sanger Imputation Service was developed by P.D., S. McCarthy and R.D. The Oxford Statistics Phasing Server was developed by W.K., K. Sharp and J.M. All other authors contributed data sets to the project or provided advice.

    Competing interests

    The author declare no competing financial interests.

    Corresponding authors

    Correspondence to Richard Durbin or Gonçalo Abecasis or Jonathan Marchini.

    Integrated supplementary information

    Supplementary information

    PDF files

    1. 1.

      Supplementary Text and Figures

      Supplementary Figures 1–6, Supplementary Tables 1–8 and Supplementary Note.

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    DOI

    https://doi.org/10.1038/ng.3643

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