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The nature of confounding in genome-wide association studies

Abstract

The authors argue that population structure per se is not a problem in genome-wide association studies — the true sources are the environment and the genetic background, and the latter is greatly underappreciated. They conclude that mixed models effectively address this issue.

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References

  1. Lander, E. S. & Schork, N. J. Science 265, 2037–2048 (1994).

    CAS  PubMed  Google Scholar 

  2. Devlin, B. & Roeder, K. Biometrics 55, 997–1004 (1999).

    CAS  Article  PubMed  Google Scholar 

  3. Pritchard, J. K. et al. Am. J. Hum. Genet. 67, 170–181 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Price, A. L. et al. Nature Genet. 38, 904–909 (2006).

    CAS  Article  PubMed  Google Scholar 

  5. Lynch, M. & Walsh, B. Genetics and Analysis of Quantitative Traits (Sinauer Associates, 1998).

    Google Scholar 

  6. Fisher, R. A. Trans. R. Soc. Edinb. 52, 399–433 (1918).

    Article  Google Scholar 

  7. Haseman, J. K. & Elston, R. C. Behav. Genet. 2, 3–19 (1972).

    CAS  Article  PubMed  Google Scholar 

  8. Henderson, C. R. Applications of Linear Models in Animal Breeding (Univ. Guelph Press, 1984).

    Google Scholar 

  9. Yu, J. et al. Nature Genet. 38, 203–208 (2006).

    CAS  Article  PubMed  Google Scholar 

  10. Zhao, K. et al. PLoS Genet. 3, e4 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kang, H. M. et al. Nature Genet. 42, 348–354 (2010).

    CAS  Article  PubMed  Google Scholar 

  12. Price, A. L. et al. Nature Rev. Genet. 11, 459–463 (2010).

    CAS  Article  PubMed  Google Scholar 

  13. Yang, J. et al. Nature Genet. 42, 565–569 (2010).

    CAS  Article  PubMed  Google Scholar 

  14. Segura, V. et al. Nature Genet. 44, 825–830 (2012).

    CAS  Article  PubMed  Google Scholar 

  15. Zaitlen, N. & Kraft, P. Hum. Genet. 131, 1655–1664 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Zuk, O. et al. Proc. Natl Acad. Sci. USA 109, 1193–1198 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Atwell, S. et al. Nature 465, 627–631 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Platt, A., Vilhjálmsson, B. J. & Nordborg, M. Genetics 186, 1045–1052 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Dickson, S. P. et al. PLoS Biol. 8, e1000294 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Huang, X. et al. Nature Genet. 42, 961–967 (2010).

    CAS  Article  PubMed  Google Scholar 

  21. Listgarten, J. et al. Nature Methods 9, 525–526 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Zhou, X., Carbonetto, P. & Stephens, M. Preprint at arXiv [online], (2012).

  23. Deary, I. J. et al. Nature 482, 212–215 (2012).

    CAS  Article  PubMed  Google Scholar 

  24. Korte, A. et al. Nature Genet. 44, 1066–1071 (2012).Article

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank E. Buckler, D. Balding, P. Donnelly, A. Hancock, I. Hellmann, M. Horton, A. Korte, Q. Long, D. Meng, N. Patterson, A. Platt, A. Price, V. Segura, O. Stegle and Q. Zhang for discussions and/or comments on the manuscript. We are especially grateful to A. Price for sharing the observation that mixed models can explain a substantial fraction of the phenotypic covariance in randomly generated individuals. Remaining errors or omissions are our responsibility. This work was supported by US National Institutes of Health grant HG002790, European Research Council grant AdG-268962 and the Gregor Mendel Institute. We apologize to authors whose work could not be cited owing to space constraints.

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Correspondence to Bjarni J. Vilhjálmsson or Magnus Nordborg.

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Vilhjálmsson, B., Nordborg, M. The nature of confounding in genome-wide association studies. Nat Rev Genet 14, 1–2 (2013). https://doi.org/10.1038/nrg3382

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