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.
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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).
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).
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).
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).
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).
Freedman, M.L. et al. Assessing the impact of population stratification on genetic association studies. Nat. Genet. 36, 388–393 (2004).
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).
Silventoinen, K. et al. Heritability of adult body height: a comparative study of twin cohorts in eight countries. Twin Res. 6, 399–408 (2003).
Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).
Devlin, B., Roeder, K. & Wasserman, L. Genomic control, a new approach to genetic-based association studies. Theor. Popul. Biol. 60, 155–166 (2001).
Reich, D.E. & Goldstein, D.B. Detecting association in a case-control study while correcting for population stratification. Genet. Epidemiol. 20, 4–16 (2001).
Bersaglieri, T. et al. Genetic signatures of strong recent positive selection at the lactase gene. Am. J. Hum. Genet. 74, 1111–1120 (2004).
Hinds, D.A. et al. Matching strategies for genetic association studies in structured populations. Am. J. Hum. Genet. 74, 317–325 (2004).
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).
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).
Parra, E.J. et al. Estimating African American admixture proportions by use of population-specific alleles. Am. J. Hum. Genet. 63, 1839–1851 (1998).
Pfaff, C.L., Kittles, R.A. & Shriver, M.D. Adjusting for population structure in admixed populations. Genet. Epidemiol. 22, 196–201 (2002).
Pritchard, J.K., Stephens, M. & Donnelly, P. Inference of population structure using multilocus genotype data. Genetics 155, 945–959 (2000).
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).
Pritchard, J.K., Stephens, M., Rosenberg, N.A. & Donnelly, P. Association mapping in structured populations. Am. J. Hum. Genet. 67, 170–181 (2000).
Enattah, N.S. et al. Identification of a variant associated with adult-type hypolactasia. Nat. Genet. 30, 233–237 (2002).
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).
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).
Allison, D.B. Transmission-disequilibrium tests for quantitative traits. Am. J. Hum. Genet. 60, 676–690 (1997).
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).
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).
Altshuler, D. et al. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat. Genet. 26, 76–80 (2000).
Gabriel, S.B. et al. The structure of haplotype blocks in the human genome. Science 296, 2225–2229 (2002).
Cavalli-Sforza, L.L. Genes, peoples, and languages. Proc. Natl. Acad. Sci. USA 94, 7719–7724 (1997).
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.