Demonstrating stratification in a European American population (original) (raw)

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

Subscribe to this journal

Receive 12 print issues and online access

$259.00 per year

only $21.58 per issue

Buy this article

USD 39.95

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

Additional access options:

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
  2. Elizabeth L Ogburn
  3. Kathryn L Lunetta
  4. Helen N Lyon
  5. Matthew L Freedman
  6. Leif C Groop
  7. David Altshuler
  8. Kristin G Ardlie
  9. Joel N Hirschhorn

Corresponding author

Correspondence toJoel N Hirschhorn.

Ethics declarations

Competing interests

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

Rights 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