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Reply to: On powerful GWAS in admixed populations

Nature Genetics volume 53, pages 1634–1635 (2021)Cite this article

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The Original Article was published on 25 November 2021

replying to Hou, K., Bhattacharya, A., Mester, R., Burch, K. S. & Pasaniuc, B. Nature Genetics https://doi.org/10.1038/s41588-021-00953-5

Admixed populations are sorely underrepresented in genomics research1,2. To ensure that medical genetic breakthroughs equitably benefit individuals of all ancestries3, there is a need for the development of tools that facilitate the study of diverse and admixed populations. Our article4 proposes a methodology for the inclusion of admixed individuals in well-calibrated genome-wide association studies (GWAS) through the incorporation of local ancestry. In their comment, Hou et al. argue that alternative GWAS methods that do not include local ancestry can attain improved power in circumstances in which the effect sizes are equivalent across ancestries. We wish to clarify that while we indeed observe a power drop due to the increase in the number of parameters estimated in this edge case (addressed in ref. 4 in Fig. 2, Extended Data Figs. 3 and 4, and Discussion), in all other scenarios modeled we observe a power boost. Given that minor allele frequencies and patterns of linkage disequilibrium regularly differ between populations genome-wide5,6,7,8, and that differences in case ascertainment, epistasis and gene–environment interactions may differ across ancestries and induce marginal effect size differences, we expect the instance of perfectly identical marginal effect sizes to be the exception, not the rule, even assuming identical causal effects. Tractor is therefore expected to outperform other methods at most GWAS loci.

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Data availability

All data referred to in this reply is available as described in the original Tractor publication4.

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Author information

Authors and Affiliations

  1. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

    Elizabeth G. Atkinson, Alex Bloemendal, Mark J. Daly & Benjamin M. Neale

  2. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Elizabeth G. Atkinson, Alex Bloemendal, Mark J. Daly & Benjamin M. Neale

  3. Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA

    Adam X. Maihofer & Caroline M. Nievergelt

  4. Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland

    Mark J. Daly

Authors
  1. Elizabeth G. Atkinson
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  2. Alex Bloemendal
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  4. Caroline M. Nievergelt
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  5. Mark J. Daly
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  6. Benjamin M. Neale
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Contributions

E.G.A. drafted the primary text with input from A.B., A.M., B.M.N., C.M.N. and M.J.D. All authors reviewed and approved the final draft.

Corresponding author

Correspondence to Elizabeth G. Atkinson.

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Competing interests

M.J.D. is a founder of Maze Therapeutics. B.M.N. is a member of the Deep Genomics Scientific Advisory Board and serves as a consultant for the Camp4 Therapeutics Corporation, Takeda Pharmaceutical and Biogen. The remaining authors declare no competing interests.

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Peer review information Nature Genetics thanks Loïc Yengo and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Atkinson, E.G., Bloemendal, A., Maihofer, A.X. et al. Reply to: On powerful GWAS in admixed populations. Nat Genet 53, 1634–1635 (2021). https://doi.org/10.1038/s41588-021-00975-z

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