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Rapid genotype imputation from sequence without reference panels

Nature Genetics volume 48, pages 965–969 (2016)Cite this article

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Abstract

Inexpensive genotyping methods are essential for genetic studies requiring large sample sizes. In human studies, array-based microarrays and high-density haplotype reference panels allow efficient genotype imputation for this purpose. However, these resources are typically unavailable in non-human settings. Here we describe a method (STITCH) for imputation based only on sequencing read data, without requiring additional reference panels or array data. We demonstrate its applicability even in settings of extremely low sequencing coverage, by accurately imputing 5.7 million SNPs at a mean r2 value of 0.98 in 2,073 outbred laboratory mice (0.15× sequencing coverage). In a sample of 11,670 Han Chinese (1.7× coverage), we achieve accuracy similar to that of alternative approaches that require a reference panel, demonstrating that our approach can work for genetically diverse populations. Our method enables straightforward progression from low-coverage sequence to imputed genotypes, overcoming barriers that at present restrict the application of genome-wide association study technology outside humans.

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Figure 1: Overview of STITCH.
Figure 2: Performance of STITCH on CFW mice in comparison to external validation.
Figure 3: Performance of STITCH on CONVERGE humans in comparison to external validation.
Figure 4: Effects of reduced sequence coverage.

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Acknowledgements

R.W.D. is supported by a grant from the Wellcome Trust (097308/Z/11/Z). S.M. is supported by Investigator Award 098387/Z/12/Z. This work was funded by the Wellcome Trust (WT090532/Z/09/Z, WT083573/Z/07/Z, WT089269/Z/09/Z and WT098387/Z/12/Z).

Author information

Author notes

  1. Simon Myers and Richard Mott: These authors contributed equally to this work.

Authors and Affiliations

  1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    Robert W Davies, Simon Myers & Richard Mott

  2. Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA

    Jonathan Flint

  3. Department of Statistics, University of Oxford, Oxford, UK

    Simon Myers

  4. UCL Genetics Institute, University College London, London, UK

    Richard Mott

Authors
  1. Robert W Davies
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  2. Jonathan Flint
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Contributions

R.W.D., S.M., and R.M. developed the method. R.W.D. wrote the algorithm and performed analyses. J.F. and R.M. conceived and managed the CFW and CONVERGE projects. All authors contributed to study design, drafted the paper, and reviewed and contributed to the final manuscript.

Corresponding author

Correspondence to Robert W Davies.

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The authors declare no competing financial interests.

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Supplementary Tables 1–8 and Supplementary Note. (PDF 1385 kb)

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Davies, R., Flint, J., Myers, S. et al. Rapid genotype imputation from sequence without reference panels. Nat Genet 48, 965–969 (2016). https://doi.org/10.1038/ng.3594

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