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'Racial' differences in genetic effects for complex diseases


'Racial' differences are frequently debated in clinical, epidemiological and molecular research and beyond1,2. In particular, there is considerable controversy regarding the existence and importance of 'racial' differences in genetic effects for complex diseases3,4,5,6 influenced by a large number of genes7. An important question is whether ancestry influences the impact of each gene variant on the disease risk. Here, we addressed this question by examining the genetic effects for 43 validated gene-disease associations across 697 study populations of various descents. The frequencies of the genetic marker of interest in the control populations often (58%) showed large heterogeneity (statistical variability) between 'races'. Conversely, we saw large heterogeneity in the genetic effects (odds ratios) between 'races' in only 14% of cases. Genetic markers for proposed gene-disease associations vary in frequency across populations, but their biological impact on the risk for common diseases may usually be consistent across traditional 'racial' boundaries.

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Figure 1: Frequencies of the allele(s) or genotype(s) of interest in control populations of various descents in each meta-analysis of gene-disease associations.
Figure 2: Odds ratios for the observed genetic association in studies of groups of various descents in each meta-analysis of gene-disease associations.
Figure 3: Correlation between the available total sample size and the I2 for the observed heterogeneity between the frequency estimates (a) and between the odds ratios (b) of the 'racial' groups in each meta-analysis.


  1. Cooper, R.S., Kaufman, J.S. & Ward, R. Race and genomics. N. Engl. J. Med. 348, 1166–1170 (2003).

    Article  PubMed  Google Scholar 

  2. Burchard, E.G. et al. The importance of race and ethnic background in biomedical research and clinical practice. N. Engl. J. Med. 348, 1170–1175 (2003).

    Article  PubMed  Google Scholar 

  3. The International HapMap Consortium. The International HapMap Project. Nature 426, 789–796 (2003).

  4. 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 

  5. Kaufman, J.S. & Cooper, R.S. Commentary: considerations for use of racial/ethnic classification in etiologic research. Am. J. Epidemiol. 154, 291–298 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. 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 

  7. Lander, E.S. & Schork, N.J. Genetic dissection of complex traits. Science 265, 2037–2048 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. Rosenberg, N.A. et al. Genetic structure of human populations. Science 298, 2381–2385 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. King, M.C. & Motulsky, A.G. Human genetics. Mapping human history. Science 298, 2342–2343 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Feldman, M.W., Lewontin, R.C. & King, M.C. Race: a genetic melting-pot. Nature 424, 374 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Risch, N., Burchard, E., Ziv, E. & Tang, H. Categorization of humans in biomedical research: genes, race and disease. Genome Biol. 3, 2007 (2002).

    Article  Google Scholar 

  12. Kressin, N.R., Chang, B.H., Hendricks, A. & Kazis, L.E. Agreement between administrative data and patients' self-reports of race/ethnicity. Am. J. Public Health 93, 1734–1739 (2003).

    Article  PubMed Central  PubMed  Google Scholar 

  13. Ioannidis, J.P., Ntzani, E.E., Trikalinos, T.A. & Contopoulos-Ioannidis, D.G. Replication validity of genetic association studies. Nat. Genet. 29, 306–309 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Ioannidis, J.P., Trikalinos, T.A., Ntzani, E.E. & Contopoulos-Ioannidis, D.G. Genetic associations in large versus small studies: an empirical assessment. Lancet 361, 567–571 (2003).

    Article  PubMed  Google Scholar 

  15. Pettiti, D. Meta-analysis, Decision Analysis and Cost-Effectiveness Analysis (Oxford University Press, New York, 1999).

    Book  Google Scholar 

  16. Higgins, J.P. & Thompson, S.G. Quantifying heterogeneity in a meta-analysis. Stat. Med. 21, 1539–1558 (2002).

    Article  PubMed  Google Scholar 

  17. Collins, F.S. The case for a US prospective cohort study of genes and environment. Nature 429, 475–477 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Lichtenstein, P. et al. Environmental and heritable factors in the causation of cancer–analyses of cohorts of twins from Sweden, Denmark, and Finland. N. Engl. J. Med. 343, 78–85 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Doll, R. & Peto, R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J. Natl. Cancer Inst. 66, 1191–1308 (1981).

    Article  CAS  PubMed  Google Scholar 

  20. Cardon, L.R. & Bell, J.I. Association study designs for complex diseases. Nat. Rev. Genet. 2, 91–99 (2001).

    Article  CAS  PubMed  Google Scholar 

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J.P.A.I. generated the idea for this project and wrote the protocol that was further elaborated by the other two authors. E.E.N. carried out additional data extraction with help from T.A.T. These two authors carried out the statistical analyses with contribution from J.P.A.I. All authors interpreted the data and the analyses. The final draft was written by J.P.A.I. and commented on critically by the other two authors. We thank D. Contopoulos-Ioannidis for her scientific contribution to important background work for this project and A. Wu, S. Glatt, M. Preisig, A. Lalovic, R. Inzelberg and L. Le Marchand for providing additional data on their published meta-analyses. The project was supported by a PENED grant from the General Secretariat for Research and Technology, Greece and the European Commission.

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Correspondence to John P A Ioannidis.

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Supplementary information

Supplementary Fig. 1

Control frequencies and effect sizes for overall-validated marker-disease associations. (PDF 46 kb)

Supplementary Table 1

Included and excluded meta-analyses of gene-diseases associations. (PDF 23 kb)

Supplementary Table 2

Within-race and between-race variance for control frequencies. (PDF 3 kb)

Supplementary Table 3

Pair-wise comparisons for control frequencies. (PDF 5 kb)

Supplementary Table 4

Within-race and between-race variance for odds ratios. (PDF 5 kb)

Supplementary Table 5

Pair-wise comparisons for odds ratios. (PDF 4 kb)

Supplementary Note (PDF 121 kb)

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Ioannidis, J., Ntzani, E. & Trikalinos, T. 'Racial' differences in genetic effects for complex diseases. Nat Genet 36, 1312–1318 (2004).

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