Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

Bias due to selection of rare variants using frequency in controls

Nature Genetics volume 43, pages 394–395 (2011)Cite this article

Subjects

Johansen et al. reply:

High-throughput sequencing technologies have enabled identification of rare genomic variants in large study samples, although standards for appropriate design, quality control, statistical analysis and interpretation are not yet established. An important issue that directly influences design of resequencing studies is how best to define rare variants. In our recent study in Nature Genetics1, we defined rare variants using a frequency threshold of <1% in healthy controls to eliminate variants with low probability of deleterious effects; this identified a significant excess of rare non-synonymous variants in triglyceride-associated genes gleaned from a genome-wide association study of patients with hypertriglyceridemia (HTG). Two separate correspondences reported in this issue, from Mathieu Lemire2 and Richard Pearson3, use simulated data to show that defining rare variants this way might overestimate their accumulation in cases. However, our own post hoc analysis of our data now shows that alternate definitions of rare variants do not effect either our results or our interpretation (Table 1). We believe these differences are probably caused by certain properties of simulated and real biological datasets in addition to essential hypotheses underlying our study design.

Table 1 Rare variant accumulation in genes identified by a genome-wide association study of hypertriglyceridemia is robust to rare variant definition or analysis strategy
Full size table

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Johansen, C.T. et al. Nat. Genet. 42, 684–687 (2010).

    Article  CAS  Google Scholar 

  2. Lemire, M. Nat. Genet. 43, 391–392 (2011).

    Article  CAS  Google Scholar 

  3. Pearson, R.D. Nat. Genet. 43, 392–393 (2011).

    Article  CAS  Google Scholar 

  4. Manolio, T.A. et al. Nature 461, 747–753 (2009).

    Article  CAS  Google Scholar 

  5. Plomin, R. et al. Nat. Rev. Genet. 10, 872–878 (2009).

    Article  CAS  Google Scholar 

  6. Reymer, P.W. et al. Nat. Genet. 10, 28–34 (1995).

    Article  CAS  Google Scholar 

  7. Bansal, V. et al. Nat. Rev. Genet. 11, 773–785 (2010).

    Article  CAS  Google Scholar 

  8. Durbin, R.M. et al. Nature 467, 1061–1073 (2010).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

C.T.J. is supported by a Canadian Institutes of Health Research (CIHR) Banting and Best Canada Graduate Scholarship, a Heart and Stroke Foundation Program Grant and a CIHR Vascular Research Fellowship. R.A.H. is supported by the Jacob J. Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Canada Research Chair in Human Genetics (Tier I), the Martha G. Blackburn Chair in Cardiovascular Research and operating grants from the Canadian Institutes for Health Research (MOP-13430, MOP-79523, CTP-79853), the Heart and Stroke Foundation of Ontario (NA-6059, T-6018, PRG-4854) and Genome Canada through the Ontario Genomics Institute.

Author information

Authors and Affiliations

  1. Department of Medicine, Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada

    Christopher T Johansen, Jian Wang & Robert A Hegele

  2. Department of Biochemistry, Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada

    Christopher T Johansen, Jian Wang & Robert A Hegele

Authors
  1. Christopher T Johansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jian Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert A Hegele
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert A Hegele.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Johansen, C., Wang, J. & Hegele, R. Bias due to selection of rare variants using frequency in controls. Nat Genet 43, 394–395 (2011). https://doi.org/10.1038/ng.817

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.817

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing