Letter | Published:

A reference panel of 64,976 haplotypes for genotype imputation

Nature Genetics 48, 1279–1283 (2016) | Download Citation

Subjects

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

Rent or Buy

All prices are NET prices.

References

  1. 1.

    International HapMap Consortium. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).

  2. 2.

    1000 Genomes Project Consortium. A global reference for human genetic variation. Nature 526, 68–74 (2015).

  3. 3.

    Genome of the Netherlands Consortium. Whole-genome sequence variation, population structure and demographic history of the Dutch population. Nat. Genet. 46, 818–825 (2014).

  4. 4.

    et al. Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel. Nat. Commun. 6, 8111 (2015).

  5. 5.

    et al. Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers. Nat. Genet. 47, 1272–1281 (2015).

  6. 6.

    , , , & A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).

  7. 7.

    , & A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).

  8. 8.

    , , , & MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet. Epidemiol. 34, 816–834 (2010).

  9. 9.

    , , , & Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat. Genet. 44, 955–959 (2012).

  10. 10.

    , & Improved whole-chromosome phasing for disease and population genetic studies. Nat. Methods 10, 5–6 (2013).

  11. 11.

    , & minimac2: faster genotype imputation. Bioinformatics 31, 782–784 (2015).

  12. 12.

    et al. Haplotype estimation for biobank-scale data sets. Nat. Genet. 48, 817–820 (2016).

  13. 13.

    et al. Subsystems contributing to the decline in ability to walk: bridging the gap between epidemiology and geriatric practice in the InCHIANTI study. J. Am. Geriatr. Soc. 48, 1618–1625 (2000).

  14. 14.

    et al. A genome-wide association study identifies protein quantitative trait loci (pQTLs). PLoS Genet. 4, e1000072 (2008).

  15. 15.

    et al. Imputation of variants from the 1000 Genomes Project modestly improves known associations and can identify low-frequency variant–phenotype associations undetected by HapMap based imputation. PLoS One 8, e64343 (2013).

  16. 16.

    , , & Structural and functional characterization of the abnormal Z α1-antitrypsin isolated from human liver. FEBS Lett. 177, 179–183 (1984).

  17. 17.

    et al. Serum levels and genotype distribution of α1-antitrypsin in the general population. Thorax (2012).

  18. 18.

    , , & Phasing for medical sequencing using rare variants and large haplotype reference panels. Bioinformatics 32, 1974–1980 (2016).

  19. 19.

    CONVERGE Consortium. Sparse whole-genome sequencing identifies two loci for major depressive disorder. Nature 523, 588–591 (2015).

  20. 20.

    et al. The African Genome Variation Project shapes medical genetics in Africa. Nature 517, 327–332 (2015).

  21. 21.

    et al. Genetic structure of human populations. Science 298, 2381–2385 (2002).

  22. 22.

    , , , & An integrative variant analysis pipeline for accurate genotype/haplotype inference in population NGS data. Genome Res. 23, 833–842 (2013).

  23. 23.

    et al. Cohort profile: the study of health in Pomerania. Int. J. Epidemiol. 40, 294–307 (2011).

  24. 24.

    & Genotype imputation for genome-wide association studies. Nat. Rev. Genet. 11, 499–511 (2010).

Download references

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

    • 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 figures

    1. 1.

      The effect of sites filtering on Ts/Tv ratio per sample

    2. 2.

      Data summaries before and after site filtering

    3. 3.

      Performance of imputation using different reference panels

    4. 4.

      Performance of imputation using different reference panel.

    5. 5.

      Site stratification by calling and filtering status across cohorts.

    6. 6.

      Comparison of methods for genotype calling as sample size increases

    Supplementary information

    PDF files

    1. 1.

      Supplementary Text and Figures

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

    To obtain permission to re-use content from this article visit RightsLink.

    About this article

    Publication history

    Received

    Accepted

    Published

    DOI

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

    Further reading

    Newsletter Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing