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.

  • Letter
  • Published:

Demonstrating stratification in a European American population

Nature Genetics volume 37, pages 868–872 (2005)Cite this article

Abstract

Population stratification occurs in case-control association studies when allele frequencies differ between cases and controls because of ancestry. Stratification may lead to false positive associations, although this issue remains controversial1,2,3,4. Empirical studies have found little evidence of stratification in European-derived populations, but potentially significant levels of stratification could not be ruled out5,6,7. We studied a European American panel discordant for height, a heritable trait that varies widely across Europe8. Genotyping 178 SNPs and applying standard analytical methods6,9,10,11 yielded no evidence of stratification. But a SNP in the gene LCT that varies widely in frequency across Europe12 was strongly associated with height (P < 10−6). This apparent association was largely or completely due to stratification; rematching individuals on the basis of European ancestry greatly reduced the apparent association, and no association was observed in Polish or Scandinavian individuals. The failure of standard methods to detect this stratification indicates that new methods may be required.

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

Figure 1: The relationship between European ancestry, height and LCT −13910C → T allele frequency in the European American panel.
Figure 2: A complementary approach for assessing the likelihood of an association being explained by stratification.

Similar content being viewed by others

References

  1. Wacholder, S., Rothman, N. & Caporaso, N. Population stratification in epidemiologic studies of common genetic variants and cancer: quantification of bias. J. Natl. Cancer Inst. 92, 1151–1158 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Thomas, D.C. & Witte, J.S. Point: population stratification: a problem for case-control studies of candidate-gene associations? Cancer Epidemiol. Biomarkers Prev. 11, 505–512 (2002).

    PubMed  Google Scholar 

  3. Wacholder, S., Rothman, N. & Caporaso, N. Counterpoint: bias from population stratification is not a major threat to the validity of conclusions from epidemiological studies of common polymorphisms and cancer. Cancer Epidemiol. Biomarkers Prev. 11, 513–520 (2002).

    PubMed  Google Scholar 

  4. Marchini, J., Cardon, L.R., Phillips, M.S. & Donnelly, P. The effects of human population structure on large genetic association studies. Nat. Genet. 36, 512–517 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Ardlie, K.G., Lunetta, K.L. & Seielstad, M. Testing for population subdivision and association in four case-control studies. Am. J. Hum. Genet. 71, 304–311 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Freedman, M.L. et al. Assessing the impact of population stratification on genetic association studies. Nat. Genet. 36, 388–393 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Tang, H. et al. Genetic structure, self-identified race/ethnicity, and confounding in case-control association studies. Am. J. Hum. Genet. 76, 268–275 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Silventoinen, K. et al. Heritability of adult body height: a comparative study of twin cohorts in eight countries. Twin Res. 6, 399–408 (2003).

    Article  PubMed  Google Scholar 

  9. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. Devlin, B., Roeder, K. & Wasserman, L. Genomic control, a new approach to genetic-based association studies. Theor. Popul. Biol. 60, 155–166 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Reich, D.E. & Goldstein, D.B. Detecting association in a case-control study while correcting for population stratification. Genet. Epidemiol. 20, 4–16 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Bersaglieri, T. et al. Genetic signatures of strong recent positive selection at the lactase gene. Am. J. Hum. Genet. 74, 1111–1120 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hinds, D.A. et al. Matching strategies for genetic association studies in structured populations. Am. J. Hum. Genet. 74, 317–325 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rosenberg, N.A., Li, L.M., Ward, R. & Pritchard, J.K. Informativeness of genetic markers for inference of ancestry. Am. J. Hum. Genet. 73, 1402–1422 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Smith, M.W. et al. A high-density admixture map for disease gene discovery in african americans. Am. J. Hum. Genet. 74, 1001–1013 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Parra, E.J. et al. Estimating African American admixture proportions by use of population-specific alleles. Am. J. Hum. Genet. 63, 1839–1851 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pfaff, C.L., Kittles, R.A. & Shriver, M.D. Adjusting for population structure in admixed populations. Genet. Epidemiol. 22, 196–201 (2002).

    Article  PubMed  Google Scholar 

  18. Pritchard, J.K., Stephens, M. & Donnelly, P. Inference of population structure using multilocus genotype data. Genetics 155, 945–959 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Pritchard, J.K. & Rosenberg, N.A. Use of unlinked genetic markers to detect population stratification in association studies. Am. J. Hum. Genet. 65, 220–228 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pritchard, J.K., Stephens, M., Rosenberg, N.A. & Donnelly, P. Association mapping in structured populations. Am. J. Hum. Genet. 67, 170–181 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Enattah, N.S. et al. Identification of a variant associated with adult-type hypolactasia. Nat. Genet. 30, 233–237 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Lohmueller, K.E., Pearce, C.L., Pike, M., Lander, E.S. & Hirschhorn, J.N. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat. Genet. 33, 177–182 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Spielman, R.S., McGinnis, R.E. & Ewens, W.J. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am. J. Hum. Genet. 52, 506–516 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Allison, D.B. Transmission-disequilibrium tests for quantitative traits. Am. J. Hum. Genet. 60, 676–690 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Abecasis, G.R., Cardon, L.R. & Cookson, W.O. A general test of association for quantitative traits in nuclear families. Am. J. Hum. Genet. 66, 279–292 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Helgason, A., Yngvadottir, B., Hrafnkelsson, B., Gulcher, J. & Stefansson, K. An Icelandic example of the impact of population structure on association studies. Nat. Genet. 37, 90–95 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Altshuler, D. et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat. Genet. 26, 76–80 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Gabriel, S.B. et al. The structure of haplotype blocks in the human genome. Science 296, 2225–2229 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Cavalli-Sforza, L.L. Genes, peoples, and languages. Proc. Natl. Acad. Sci. USA 94, 7719–7724 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank D. Reich for discussions and comments on the manuscript and members of the laboratory of J.N.H. for discussions. J.N.H. is a recipient of a Burroughs Wellcome Career Award in Biomedical Sciences, which supported this work. M.L.F. is supported by a Howard Hughes Medical Institute physician postdoctoral fellowship and Department of Defense Health Disparity Training-Prostate Scholar Award. L.C.G. is supported by the Sigrid Juselius Foundation. D.A. is a Clinical Scholar in Translational Research from the Burroughs Wellcome Fund and a Charles E. Culpeper Medical Scholar.

Author information

Author notes

  1. Kathryn L Lunetta

    Present address: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, 02118, USA

Authors and Affiliations

  1. Program in Genomics and Division of Endocrinology, Children's Hospital, 300 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Catarina D Campbell, Elizabeth L Ogburn, Helen N Lyon & Joel N Hirschhorn

  2. Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Catarina D Campbell, Helen N Lyon, David Altshuler & Joel N Hirschhorn

  3. Genomics Collaborative Inc., 99 Erie St., Cambridge, 02139, Massachusetts, USA

    Kathryn L Lunetta & Kristin G Ardlie

  4. Broad Institute of Harvard and MIT, One Kendall Square, Cambridge, 02139, Massachusetts, USA

    Matthew L Freedman, David Altshuler & Joel N Hirschhorn

  5. Departments of Medicine and Molecular Biology, Massachusetts General Hospital, 55 Fruit Street, Boston, 02114, Massachusetts, USA

    Matthew L Freedman & David Altshuler

  6. Department of Hematology-Oncology, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    Matthew L Freedman

  7. Department of Clinical Science/Diabetes and Endocrinology, University Hospital, Lund University, Malmö, Sweden

    Leif C Groop

Authors
  1. Catarina D Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elizabeth L Ogburn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kathryn L Lunetta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Helen N Lyon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Matthew L Freedman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Leif C Groop
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. David Altshuler
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kristin G Ardlie
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Joel N Hirschhorn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joel N Hirschhorn.

Ethics declarations

Competing interests

K.G.A. is an employee of Genomics Collaborative, Inc.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Campbell, C., Ogburn, E., Lunetta, K. et al. Demonstrating stratification in a European American population. Nat Genet 37, 868–872 (2005). https://doi.org/10.1038/ng1607

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1607

This article is cited by

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