Mapping genes that underlie ethnic differences in disease risk: methods for detecting linkage in admixed populations, by conditioning on parental admixture (original) (raw)

Abstract

Genes that underlie ethnic differences in disease risk can be mapped in affected individuals of mixed descent if the ancestry of the alleles at each marker locus can be assigned to one of the two founding populations. Linkage can be detected by testing for association of the disease with the ancestry of alleles at the marker locus, by conditioning on the admixture (defined as the proportion of genes that have ancestry from the high-risk population) of both parents. With regard to exploiting the effects of admixture, this test is more flexible and powerful than the transmission-disequilibrium test. Under the assumption of a multiplicative model, the statistical power for a given sample size depends only on parental admixture and the risk ratio r between populations that is generated by the locus. The most informative families are those in which mean parental admixture is .2-.7 and in which admixture is similar in both parents. The number of markers required for a genome search depends on the number of generations since admixture and on the information content for ancestry (f) of the markers, defined as a function of allele frequencies in the two founding populations. Simulations using a hidden Markov model suggest that, when admixture has occurred 2-10 generations earlier, a multipoint analysis using 2,000 biallelic markers, with f values of 30%, can extract 70%-90% of the ancestry information for each locus. Sets of such markers could be selected from libraries of single-nucleotide polymorphisms, when these become available.

Full Text

The Full Text of this article is available as a PDF (478.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bowcock A. M., Kidd J. R., Mountain J. L., Hebert J. M., Carotenuto L., Kidd K. K., Cavalli-Sforza L. L. Drift, admixture, and selection in human evolution: a study with DNA polymorphisms. Proc Natl Acad Sci U S A. 1991 Feb 1;88(3):839–843. doi: 10.1073/pnas.88.3.839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ewens W. J., Spielman R. S. The transmission/disequilibrium test: history, subdivision, and admixture. Am J Hum Genet. 1995 Aug;57(2):455–464. [PMC free article] [PubMed] [Google Scholar]
  3. Gelman A., Rubin D. B. Markov chain Monte Carlo methods in biostatistics. Stat Methods Med Res. 1996 Dec;5(4):339–355. doi: 10.1177/096228029600500402. [DOI] [PubMed] [Google Scholar]
  4. Jorde L. B., Bamshad M. J., Watkins W. S., Zenger R., Fraley A. E., Krakowiak P. A., Carpenter K. D., Soodyall H., Jenkins T., Rogers A. R. Origins and affinities of modern humans: a comparison of mitochondrial and nuclear genetic data. Am J Hum Genet. 1995 Sep;57(3):523–538. doi: 10.1002/ajmg.1320570340. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Kaplan N. L., Martin E. R., Morris R. W., Weir B. S. Marker selection for the transmission/disequilibrium test, in recently admixed populations. Am J Hum Genet. 1998 Mar;62(3):703–712. doi: 10.1086/301760. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Knowler W. C., Williams R. C., Pettitt D. J., Steinberg A. G. Gm3;5,13,14 and type 2 diabetes mellitus: an association in American Indians with genetic admixture. Am J Hum Genet. 1988 Oct;43(4):520–526. [PMC free article] [PubMed] [Google Scholar]
  7. Kruglyak L., Lander E. S. Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am J Hum Genet. 1995 Aug;57(2):439–454. [PMC free article] [PubMed] [Google Scholar]
  8. Lander E. S., Green P. Construction of multilocus genetic linkage maps in humans. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2363–2367. doi: 10.1073/pnas.84.8.2363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Lin S., Thompson E., Wijsman E. An algorithm for Monte Carlo estimation of genotype probabilities on complex pedigrees. Ann Hum Genet. 1994 Oct;58(Pt 4):343–357. doi: 10.1111/j.1469-1809.1994.tb00731.x. [DOI] [PubMed] [Google Scholar]
  10. McKeigue P. M. Mapping genes underlying ethnic differences in disease risk by linkage disequilibrium in recently admixed populations. Am J Hum Genet. 1997 Jan;60(1):188–196. [PMC free article] [PubMed] [Google Scholar]
  11. Poloni E. S., Excoffier L., Mountain J. L., Langaney A., Cavalli-Sforza L. L. Nuclear DNA polymorphism in a Mandenka population from Senegal: comparison with eight other human populations. Ann Hum Genet. 1995 Jan;59(Pt 1):43–61. doi: 10.1111/j.1469-1809.1995.tb01605.x. [DOI] [PubMed] [Google Scholar]
  12. Reynolds J., Weir B. S., Cockerham C. C. Estimation of the coancestry coefficient: basis for a short-term genetic distance. Genetics. 1983 Nov;105(3):767–779. doi: 10.1093/genetics/105.3.767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Risch N., Merikangas K. The future of genetic studies of complex human diseases. Science. 1996 Sep 13;273(5281):1516–1517. doi: 10.1126/science.273.5281.1516. [DOI] [PubMed] [Google Scholar]
  14. Sobel E., Lange K. Metropolis sampling in pedigree analysis. Stat Methods Med Res. 1993;2(3):263–282. doi: 10.1177/096228029300200305. [DOI] [PubMed] [Google Scholar]
  15. Thompson E. A. Monte Carlo likelihood in the genetic mapping of complex traits. Philos Trans R Soc Lond B Biol Sci. 1994 Jun 29;344(1310):345–351. doi: 10.1098/rstb.1994.0073. [DOI] [PubMed] [Google Scholar]