Haplotype phasing is a fundamental problem in medical and population genetics. Phasing is generally performed via statistical phasing in a genotyped cohort, an approach that can yield high accuracy in very large cohorts but attains lower accuracy in smaller cohorts. Here we instead explore the paradigm of reference-based phasing. We introduce a new phasing algorithm, Eagle2, that attains high accuracy across a broad range of cohort sizes by efficiently leveraging information from large external reference panels (such as the Haplotype Reference Consortium; HRC) using a new data structure based on the positional Burrows-Wheeler transform. We demonstrate that Eagle2 attains a 20× speedup and 10% increase in accuracy compared to reference-based phasing using SHAPEIT2. On European-ancestry samples, Eagle2 with the HRC panel achieves >2× the accuracy of 1000 Genomes–based phasing. Eagle2 is open source and freely available for HRC-based phasing via the Sanger Imputation Service and the Michigan Imputation Server.

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We are grateful to S. Linderman, N. Patterson, L. O'Connor, A. Gusev, and B. van de Geijn for helpful discussions. This research was conducted using the UK Biobank Resource. P.L., P.P., and A.L.P. were supported by US National Institutes of Health grants R01 HG006399 and R01 MH101244 and fellowship F32 HG007805. P.D., S.M., R.D., and the Sanger Institute HRC server were supported by Wellcome Trust grant WT098051. C.F., G.R.A., and the Michigan Imputation Server were supported by the Austrian Science Fund (FWF) grant J-3401 and US National Institutes of Health grants HG007022 and HL117626. H.K.F. was supported by the Fannie and John Hertz Foundation. Computational analyses were performed on the Orchestra High Performance Compute Cluster at Harvard Medical School, which is partially supported by grant NCRR 1S10RR028832-01, and on the Lisa Genetic Cluster Computer hosted by SURFsara and financially supported by the Netherlands Scientific Organization (NWO 480-05-003, principal investigator D. Posthuma) along with a supplement from the Dutch Brain Foundation and the VU University Amsterdam.

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  1. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

    • Po-Ru Loh
    • , Pier Francesco Palamara
    • , Hilary K Finucane
    •  & Alkes L Price
  2. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

    • Po-Ru Loh
    • , Pier Francesco Palamara
    •  & Alkes L Price
  3. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Petr Danecek
    • , Shane McCarthy
    •  & Richard Durbin
  4. Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), affiliated with the University of Lübeck, Bolzano, Italy.

    • Christian Fuchsberger
  5. Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.

    • Christian Fuchsberger
    •  & Goncalo R Abecasis
  6. Department of Computer Science, Harvard University, Cambridge, Massachusetts, USA.

    • Yakir A Reshef
  7. Department of Mathematics, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Hilary K Finucane
  8. Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.

    • Sebastian Schoenherr
    •  & Lukas Forer
  9. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

    • Alkes L Price


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P.-R.L. and A.L.P. designed the study. P.-R.L., P.F.P., Y.A.R., and H.K.F. developed the algorithm. P.-R.L. wrote the software. P.-R.L. and P.D. performed experiments. P.D. and S.M. incorporated the software into the Sanger Imputation Service. C.F., S.S., and L.F. incorporated the software into the Michigan Imputation Server. All authors analyzed data and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Po-Ru Loh or Alkes L Price.

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