© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 14, 1151-1158,
July 19, 2000
© 2000 Oxford University Press
Population Stratification in Epidemiologic Studies of Common Genetic Variants and Cancer: Quantification of Bias
Affiliation of authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.
Correspondence to: Sholom Wacholder, Ph.D., National Institutes of Health, EPS 8046, 6120 Executive Blvd., Bethesda, MD 20892-7244 (e-mail: Wacholder{at}nih.gov).
Background: Some critics argue that bias from population stratification (the mixture of individuals from heterogeneous genetic backgrounds) undermines the credibility of epidemiologic studies designed to estimate the association between a genotype and the risk of disease. We investigated the degree of bias likely from population stratification in U.S. studies of cancer among non-Hispanic Caucasians of European origin. Methods: An expression of the confounding risk ratio—the ratio of the effect of the genetic factor on risk of disease with and without adjustment for ethnicity—is used to measure the potential relative bias from population stratification. We first use empirical data on the frequency of the N-acetyltransferase (NAT2) slow acetylation genotype and incidence rates of male bladder cancer and female breast cancer in non-Hispanic U.S. Caucasians with ancestries from eight European countries to assess the bias in a hypothetical population-based U.S. study that does not take ethnicity into consideration. Then, we provide theoretical calculations of the bias over a large range of allele frequencies and disease rates. Results: Ignoring ethnicity leads to a bias of 1% or less in our empirical studies of NAT2. Furthermore, evaluation of a wide range of allele frequencies and representative ranges of cancer rates that exist across European populations shows that the risk ratio is biased by less than 10% in U.S. studies except under extreme conditions. We note that the bias decreases as the number of ethnic strata increases. Conclusions: There will be only a small bias from population stratification in a well-designed case–control study of genetic factors that ignores ethnicity among non-Hispanic U.S. Caucasians of European origin. Further work is needed to estimate the effect of population stratification within other populations.
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L.-L. Xu, G. Liu, D. P. Miller, W. Zhou, T. J. Lynch, J. C. Wain, L. Su, and D. C. Christiani Counterpoint: The Myeloperoxidase -463G->A Polymorphism Does Not Decrease Lung Cancer Susceptibility in Caucasians Cancer Epidemiol. Biomarkers Prev., December 1, 2002; 11(12): 1555 - 1559. [Abstract] [Full Text] [PDF]
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 M. Klerk, P. Verhoef, R. Clarke, H. J. Blom, F. J. Kok, E. G. Schouten, and and the MTHFR Studies Collaboration Group MTHFR 677C->T Polymorphism and Risk of Coronary Heart Disease: A Meta-analysis JAMA, October 23, 2002; 288(16): 2023 - 2031. [Abstract] [Full Text] [PDF]
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F. D. Gilliland, Y.-F. Li, L. Dubeau, K. Berhane, E. Avol, R. McConnell, W. J. Gauderman, and J. M. Peters Effects of Glutathione S-Transferase M1, Maternal Smoking during Pregnancy, and Environmental Tobacco Smoke on Asthma and Wheezing in Children Am. J. Respir. Crit. Care Med., August 15, 2002; 166(4): 457 - 463. [Abstract] [Full Text] [PDF]
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J. Little, L. Bradley, M. S. Bray, M. Clyne, J. Dorman, D. L. Ellsworth, J. Hanson, M. Khoury, J. Lau, T. R. O'Brien, et al. Reporting, Appraising, and Integrating Data on Genotype Prevalence and Gene-Disease Associations Am. J. Epidemiol., August 15, 2002; 156(4): 300 - 310. [Abstract] [Full Text] [PDF]
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E. J. Duell, E. A. Holly, P. M. Bracci, J. K. Wiencke, and K. T. Kelsey A Population-based Study of the Arg399Gln Polymorphism in X-Ray Repair Cross- Complementing Group 1 (XRCC1) and Risk of Pancreatic Adenocarcinoma Cancer Res., August 15, 2002; 62(16): 4630 - 4636. [Abstract] [Full Text] [PDF]
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D. Hasin, E. Aharonovich, X. Liu, Z. Mamman, K. Matseoane, L. Carr, and T.-K. Li Alcohol and ADH2 in Israel: Ashkenazis, Sephardics, and Recent Russian Immigrants Am J Psychiatry, August 1, 2002; 159(8): 1432 - 1434. [Abstract] [Full Text] [PDF]
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K. Hemminki and A. Forsti Proper controls for SNP studies? Carcinogenesis, August 1, 2002; 23(8): 1405 - 1406. [Full Text] [PDF]
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G. Malcolm Taylor, S. Dearden, P. Ravetto, M. Ayres, P. Watson, A. Hussain, M. Greaves, F. Alexander, O. B. Eden, and UKCCS Investigators Genetic susceptibility to childhood common acute lymphoblastic leukaemia is associated with polymorphic peptide-binding pocket profiles in HLA-DPB1*0201 Hum. Mol. Genet., July 1, 2002; 11(14): 1585 - 1597. [Abstract] [Full Text] [PDF]
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S. Wacholder, N. Rothman, and N. Caporaso 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., June 1, 2002; 11(6): 513 - 520. [Full Text] [PDF]
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P. Brennan Gene-environment interaction and aetiology of cancer: what does it mean and how can we measure it? Carcinogenesis, March 1, 2002; 23(3): 381 - 387. [Abstract] [Full Text] [PDF]
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S. Garte, L. Gaspari, A.-K. Alexandrie, C. Ambrosone, H. Autrup, J. L. Autrup, H. Baranova, L. Bathum, S. Benhamou, P. Boffetta, et al. Metabolic Gene Polymorphism Frequencies in Control Populations Cancer Epidemiol. Biomarkers Prev., December 1, 2001; 10(12): 1239 - 1248. [Abstract] [Full Text] [PDF]
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P. F. Sullivan, L. J. Eaves, K. S. Kendler, and M. C. Neale Genetic Case-Control Association Studies in Neuropsychiatry Arch Gen Psychiatry, November 1, 2001; 58(11): 1015 - 1024. [Abstract] [Full Text] [PDF]
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R. A. Kittles, R. K. Panguluri, W. Chen, A. Massac, C. Ahaghotu, A. Jackson, F. Ukoli, L. Adams-Campbell, W. Isaacs, and G. M. Dunston CYP17 Promoter Variant Associated with Prostate Cancer Aggressiveness in African Americans Cancer Epidemiol. Biomarkers Prev., September 1, 2001; 10(9): 943 - 947. [Abstract] [Full Text] [PDF]
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W. Zheng, N. Kataoka, D. Xie, and S. R. Young RESPONSE: Re: Population-Based, Case-Control Study of HER2 Genetic Polymorphism and Breast Cancer Risk J Natl Cancer Inst, April 4, 2001; 93(7): 558 - 559. [Full Text] [PDF]
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R. C. Millikan Re: Population Stratification in Epidemiologic Studies of Common Genetic Variants and Cancer: Quantification of Bias J Natl Cancer Inst, January 17, 2001; 93(2): 156 - 157. [Full Text] [PDF]
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S. Wacholder, N. Rothman, and N. Caporaso RESPONSE: Re: Population Stratification in Epidemiologic Studies of Common Genetic Variants and Cancer: Quantification of Bias J Natl Cancer Inst, January 17, 2001; 93(2): 157 - 158. [Full Text] [PDF]
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D. M. Umbach Invited Commentary: On Studying the Joint Effects of Candidate Genes and Exposures Am. J. Epidemiol., October 15, 2000; 152(8): 701 - 703. [Full Text] [PDF]
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