Analysis

Comparison of methods that use whole genome data to estimate the heritability and genetic architecture of complex traits

  • Nature Geneticsvolume 50pages737745 (2018)
  • doi:10.1038/s41588-018-0108-x
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Abstract

Multiple methods have been developed to estimate narrow-sense heritability, h2, using single nucleotide polymorphisms (SNPs) in unrelated individuals. However, a comprehensive evaluation of these methods has not yet been performed, leading to confusion and discrepancy in the literature. We present the most thorough and realistic comparison of these methods to date. We used thousands of real whole-genome sequences to simulate phenotypes under varying genetic architectures and confounding variables, and we used array, imputed, or whole genome sequence SNPs to obtain ‘SNP-heritability’ estimates. We show that SNP-heritability can be highly sensitive to assumptions about the frequencies, effect sizes, and levels of linkage disequilibrium of underlying causal variants, but that methods that bin SNPs according to minor allele frequency and linkage disequilibrium are less sensitive to these assumptions across a wide range of genetic architectures and possible confounding factors. These findings provide guidance for best practices and proper interpretation of published estimates.

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Acknowledgements

We thank D. Speed (University College London) for providing LDAK5. We thank the Keller and Vrieze lab groups, the Institute for Behavioral Genetics, N. Wray, A. Price, and S. Caron for helpful comments. This work was supported by NIH grant R01MH100141 (to M.C.K.), NHMRC grants 1078037 (to P.M.V.) and 1113400 (to P.M.V. and J.Y.), Sylvia & Charles Viertel Charitable Foundation Senior Medical Research Fellowship (to J.Y.), and NIH grants R01DA037904 and R01HG008983 (to S.V.). This work used the Janus supercomputer, which is supported by the National Science Foundation (award number CNS-0821794), the University of Colorado Boulder, the University of Colorado Denver, and the National Center for Atmospheric Research. The Janus supercomputer is operated by the University of Colorado Boulder. We thank the participants of the individual Haplotype Reference Consortium cohorts. This research has been conducted using the UK Biobank Resource.

Author information

Author notes

  1. A list of members and affiliations appears in the Supplementary Note.

Affiliations

  1. Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA

    • Luke M. Evans
    • , Rasool Tahmasbi
    • , Douglas W. Bjelland
    • , Teresa R. de Candia
    •  & Matthew C. Keller
  2. Department of Psychology, University of Minnesota, Minneapolis, MN, USA

    • Scott I. Vrieze
  3. Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA

    • Gonçalo R. Abecasis
    •  & Sayantan Das
  4. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    • Steven Gazal
  5. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    • Steven Gazal
    •  & Benjamin M. Neale
  6. Faculty of Veterinary and Agricultural Science, University of Melbourne, Parkville, VIC, Australia

    • Michael E. Goddard
  7. Agriculture Victoria, Bundoora, VIC, Australia

    • Michael E. Goddard
  8. Institute for Molecular Bioscience and the Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia

    • Jian Yang
    •  & Peter M. Visscher
  9. Department of Psychology and Neuroscience, University of Colorado, Boulder, CO, USA

    • Matthew C. Keller

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Consortia

  1. Haplotype Reference Consortium

    Contributions

    L.M.E. and M.C.K. conceived and designed the study. L.M.E. performed the statistical analyses and simulations. R.T., S.I.V., S.G., G.R.A., S.D., D.W.B., T.R.d.C., M.E.G., B.M.N., J.Y., and P.M.V. provided statistical support. The Haplotype Reference Consortium, G.R.A., and S.D. contributed to data collection and management. L.M.E. and M.C.K. wrote the manuscript with participation of all authors.

    Competing interests

    The authors declare no competing interests.

    Corresponding authors

    Correspondence to Luke M. Evans or Matthew C. Keller.

    Supplementary information

    1. Supplementary Text and Figures

      Supplementary Figures 1–34 and Supplementary Note

    2. Reporting Summary

    3. Supplementary Tables

      Supplementary Tables 1–10