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Phantom epistasis between unlinked loci

Nature volume 596, pages E1–E3 (2021)Cite this article

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The Original Article was published on 26 February 2014

arising from G. Hemani et al. Nature https://doi.org/10.1038/nature13005 (2014)

Statistical evidence for genetic interactions1 (epistasis) involving loci that are unlinked can be attenuated by fine-mapping additive effects at one of the interacting loci2, but the reason for this has remained unclear3. Here we show, using theory, simulation and data on the 501 genetic interactions we previously reported1 to influence gene expression, a previously unrecognized property of the gold-standard statistical test to detect interactions, namely that the presence of imperfectly tagged additive causal variants can lead to phantom epistasis between unlinked markers. Therefore, the false positive rate in studies that use the test may not be sufficiently controlled and, to our knowledge, no current statistical fix exists for this problem.

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Data availability

The gene expression data used to generate the original H2014 paper is available at the Gene Expression Omnibus (GEO) under accession code GSE53195. The ALSPAC genotype data can be accessed via http://www.bristol.ac.uk/alspac/. This study makes use of data from dbGaP (accessions phs000428.v1.p1) and EGA (accessions EGAS00001000108 and EGAS00001000090) (see Supplementary Information for a full list of acknowledgements to these datasets).

Code availability

Code is available at: https://github.com/explodecomputer/eqtl-2d.

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Acknowledgements

G.H. was funded by the Wellcome Trust and Royal Society (208806/Z/17/Z). J.E.P. is supported by National Health and Medical Research Council Fellowship (APP1175781). J.Y. and P.M.V. are supported by the Australian Research Council (DP160101343, DP160101056, FT180100186 and FL180100072) and the Australian National Health and Medical Research Council (1078037, 1078901, 1113400 and 1107258). J.Y. is supported by the Westlake Education Foundation. We are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses.

Author information

Author notes

  1. Unaffiliated

  2. These authors contributed equally: Gibran Hemani, Joseph E. Powell, Jian Yang, Peter M. Visscher

Authors and Affiliations

  1. MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol, UK

    Gibran Hemani

  2. Population Health Sciences, University of Bristol, Bristol, UK

    Gibran Hemani

  3. UNSW Cellular Genomics Futures Institute, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia

    Joseph E. Powell

  4. Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

    Joseph E. Powell

  5. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia

    Huanwei Wang, Anjali K. Henders, Allan F. McRae, Grant W. Montgomery, Jian Yang & Peter M. Visscher

  6. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Harm-Jan Westra & Lude Franke

  7. Estonian Genome Center, University of Tartu, Tartu, Estonia

    Tonu Esko & Andres Metspalu

  8. Medical and Population Genetics, Broad Institute, Cambridge, MA, USA

    Tonu Esko

  9. Divisions of Endocrinology, Children’s Hospital, Boston, MA, USA

    Tonu Esko

  10. Queensland Institute of Medical Research, Brisbane, Queensland, Australia

    Nicholas G. Martin

  11. Faculty of Veterinary and Agricultural Science, University of Melbourne, Melbourne, Victoria, Australia

    Michael E. Goddard

  12. School of Biology and Centre for Integrative Genomics, Georgia Institute of Technology, Atlanta, GA, USA

    Greg Gibson

  13. School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China

    Jian Yang

  14. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China

    Jian Yang

Authors
  1. Gibran Hemani
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  2. Joseph E. Powell
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  3. Huanwei Wang
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  4. Konstantin Shakhbazov
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  5. Harm-Jan Westra
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  6. Tonu Esko
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  7. Anjali K. Henders
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  8. Allan F. McRae
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  9. Nicholas G. Martin
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  10. Andres Metspalu
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  11. Lude Franke
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  12. Grant W. Montgomery
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  13. Michael E. Goddard
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  14. Greg Gibson
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  15. Jian Yang
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  16. Peter M. Visscher
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Contributions

G.H., J.E.P., J.Y. and P.M.V. conceived the analyses. M.E.G. and P.M.V. developed the theory. G.H., J.E.P. and H.W. conducted the analyses. G.H., J.E.P., P.M.V., J.Y. and G.G. wrote the paper. All authors provided critical feedback on the interpretation of the results

Corresponding author

Correspondence to Gibran Hemani.

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The authors declare no competing interests.

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Supplementary information

Supplementary Information

This file contains Supplementary Methods, Supplementary Notes 1-6, Supplementary Figures 1-9, and Supplementary References.

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Cite this article

Hemani, G., Powell, J.E., Wang, H. et al. Phantom epistasis between unlinked loci. Nature 596, E1–E3 (2021). https://doi.org/10.1038/s41586-021-03765-z

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