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Demonstrating stratification in a European American population


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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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.

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Competing interests

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

Correspondence to Joel N Hirschhorn.

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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.