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An Icelandic example of the impact of population structure on association studies

Abstract

The impact of population structure on association studies undertaken to identify genetic variants underlying common human diseases is an issue of growing interest1,2,3,4. Spurious associations of alleles with disease phenotypes may be obtained or true associations overlooked when allele frequencies differ notably among subpopulations that are not represented equally among cases and controls. Population structure influences even carefully designed studies and can affect the validity of association results1,2. Most study designs address this problem by sampling cases and controls from groups that share the same nationality or self-reported ethnic background, with the implicit assumption that no substructure exists within such groups. We examined population structure in the Icelandic gene pool using extensive genealogical and genetic data. Our results indicate that sampling strategies need to take account of substructure even in a relatively homogenous5 genetic isolate6. This will probably be even more important in larger populations.

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Figure 1: The distribution of geographic ancestry in three cohorts of Icelanders.
Figure 2: Partitioning the total variance in geographic ancestry.
Figure 3: The effect of stratification on association studies as measured by the genomic control λ statistic in the three cohorts of genotyped individuals: (a) 1895–1935, (b) 1940–1955 and (c) 1960–2000.

References

  1. Freedman, M.L. et al. Assessing the impact of population stratification on genetic association studies. Nat. Genet. 36, 388–393 (2004).

    Article  CAS  Google Scholar 

  2. 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  Google Scholar 

  3. Ziv, E. & Burchard, E.G. Human population structure and genetic association studies. Pharmacogenomics 4, 431–441 (2003).

    Article  Google Scholar 

  4. 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  Google Scholar 

  5. Helgason, A., Nicholson, G., Stefansson, K. & Donnelly, P. A reassessment of genetic diversity in Icelanders: strong evidence from multiple loci for relative homogeneity caused by genetic drift. Ann. Hum. Genet. 67, 281–297 (2003).

    Article  CAS  Google Scholar 

  6. Cavalli-Sforza, L.L., Menozzi, P. & Piazza, A. The History and Geography of Human Genes (Princeton University Press, Princeton, 1994).

    Google Scholar 

  7. Clayton, D. Population association. in Handbook of Statistical Genetics (eds. Balding, D.J., Bishop, M. & Cannings, C.) 519–540 (John Wiley and Sons, Chichester, 2001).

    Google Scholar 

  8. Steffensen, J. Menning og meinsemdir: Ritgerðarsafn um mótunarsögu íslenskrar þjóðar og baráttu hennar við hungur og sóttir (Ísafoldarprentsmiðja, Reykjavík, 1975).

    Google Scholar 

  9. Excoffier, L. Analysis of population subdivision. in Handbook of Statistical Genetics (eds. Balding, D.J., Bishop, M. & Cannings, C.) 271–308 (John Wiley & Sons, Chichester, 2001).

    Google Scholar 

  10. Tills, D., Warlow, A., Kopec, A.C., Fridriksson, S. & Mourant, A.E. The blood groups and other hereditary blood factors of the Icelanders. Ann. Hum. Biol. 9, 507–520 (1982).

    Article  CAS  Google Scholar 

  11. Jorde, L.B., Eriksson, A.W., Morgan, K. & Workman, P.L. The genetic-structure of Iceland. Hum. Hered. 32, 1–7 (1982).

    Article  CAS  Google Scholar 

  12. Williams, J.T. Origin and population-structure of the Icelanders. Hum. Biol. 65, 167–191 (1993).

    CAS  PubMed  Google Scholar 

  13. Falsetti, A.B. & Sokal, R.R. Genetic structure of human populations in the British Isles. Ann. Hum. Biol. 20, 215–229 (1993).

    Article  CAS  Google Scholar 

  14. Jorde, L.B. The genetic structure of subdivided human populations. in Current Developments in Anthropological Genetics Vol. 1: Theory (eds. Mielke, J.H. & Crawford, M.H.) 133–206 (Plenum, New York, 1980).

    Google Scholar 

  15. Tills, D. The use of the FST statistic of Wright for estimating the effects of genetic drift, selection and migration populations, with special reference to Ireland. Hum. Hered. 27, 153–159 (1977).

    Article  CAS  Google Scholar 

  16. Workman, P.L., Mielke, J.H. & Nevanlinna, H.R. The genetic structure of Finland. Am. J. Phys. Anthropol. 44, 341–367 (1976).

    Article  CAS  Google Scholar 

  17. Helgadottir, A. et al. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nat. Genet. 36, 233–239 (2004).

    Article  CAS  Google Scholar 

  18. Gretarsdottir, S. et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat. Genet. 35, 131–138 (2003).

    Article  CAS  Google Scholar 

  19. Raymond, M. & Rousset, F. An exact test for population differentiation. Evolution 49, 1280–1283 (1995).

    Article  Google Scholar 

  20. Nicholson, G. et al. Assessing population differentiation and isolation from single-nucleotide polymorphism data. J. R. Stat. Soc. (B) 64, 695–715 (2002).

    Article  Google Scholar 

  21. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).

    Article  CAS  Google Scholar 

  22. 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  Google Scholar 

  23. Helgason, A. et al. Estimating Scandinavian and Gaelic ancestry in the male settlers of Iceland. Am. J. Hum. Genet. 67, 697–717 (2000).

    Article  CAS  Google Scholar 

  24. Helgason, A. et al. mtDNA and the Islands of the North Atlantic: Estimating the Proportions of Norse and Gaelic Ancestry. Am. J. Hum. Genet. 68, 723–737 (2001).

    Article  CAS  Google Scholar 

  25. Barbujani, G. & Sokal, R.R. Genetic population-structure of Italy. 2. Physical and cultural barriers to gene flow. Am. J. Hum. Genet. 48, 398–411 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Helgason, A., Hrafnkelsson, B., Gulcher, J.R., Ward, R. & Stefansson, K. A populationwide coalescent analysis of Icelandic matrilineal and patrilineal genealogies: evidence for a faster evolutionary rate of mtDNA lineages than Y chromosomes. Am. J. Hum. Genet. 72, 1370–1388 (2003).

    Article  CAS  Google Scholar 

  27. Excoffier, L., Smouse, P.E. & Quattro, J.M. Analysis of molecular variance inferred from metric distances among DNA haplotypes - Application to human mitochondrial-DNA restriction data. Genetics 131, 479–491 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Kong, A. et al. A high-resolution recombination map of the human genome. Nat. Genet. 31, 241–247 (2002).

    Article  CAS  Google Scholar 

  29. Kong, A. et al. Recombination rate and reproductive success in humans. Nat. Genet. 36, 1203–1206 (2004).

    Article  CAS  Google Scholar 

  30. Cavalli-Sforza, L.L. & Edwards, A.W.F. Phylogenetic analysis: models and estimation procedures. Am. J. Hum. Genet. 19, 233–257 (1967).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank P. Donnelly and D. Altshuler for comments on a previous version of this paper.

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Correspondence to Agnar Helgason.

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Competing interests

A.H., J.G. and K.S. have stocks or equity interests in deCODE Genetics.

Supplementary information

Supplementary Fig. 1

Genetic divergence measured by the c parameter among 11 subpopulations for three cohorts of genotypes. (PDF 268 kb)

Supplementary Table 1

Descriptive statistics for the 40 microsatellite loci used in the genetic analyses of population structure. (PDF 46 kb)

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Helgason, A., Yngvadóttir, B., Hrafnkelsson, B. et al. An Icelandic example of the impact of population structure on association studies. Nat Genet 37, 90–95 (2005). https://doi.org/10.1038/ng1492

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