Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Commentary
  • Published:

Population choice in mapping genes for complex diseases

Abstract

The difficulty of identifying susceptibility genes for common diseases has polarized geneticists' views on what disease models are appropriate and how best to proceed once high-density genome maps become available. Different disease models have different implications for using linkage or linkage-disequilibrium-based approaches for mapping complex disease genes. We argue that the choice of study population is a critical factor when designing a study, and that genetically simplified isolates are more useful than diverse continental populations under most assumptions.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Enrichment for disease alleles (D) in affected (A) individuals compared with the general population depending on the number of affected sibs (nS), the sib risk (λS), the disease allele frequency (δ) and the number of disease loci (k).
Figure 2: Demographic factors influencing LD mapping.
Figure 3: Detecting disease alleles by LD with a dense genome scan in the presence of allelic heterogeneity (for full description, see Box 4, http://genetics.nature.com/supplementary_info/.)
Figure 4: LD data from an isolated, inbred population.

References

  1. Collins, F.S. Positional cloning moves from perditional to traditional. Nature Genet. 9, 347–350 ( 1995).

    Article  CAS  PubMed  Google Scholar 

  2. Baird, P.A., Anderson, T.W., Newcombe, H.B. & Lowry, R.B. Genetic studies in children and young adults: a population study. Am. J. Hum. Genet. 42, 677–693 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Lander, E.S. & Schork, N.J. Genetic dissection of complex traits. Science 265, 2037–2047 (1994).

    Article  CAS  PubMed  Google Scholar 

  4. Risch, N. & Merikangas, K. The future of genetic studies of complex human diseases. Science 273, 1516–1517 (1996).

    Article  CAS  PubMed  Google Scholar 

  5. Jorde, L.B. Linkage disequilibrium as a gene-mapping tool. Am. J. Hum. Genet. 56, 11–14 ( 1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Kruglyak, L. What is significant in whole-genome linkage disequilibrium studies? Am. J. Hum. Genet. 61, 810–812 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Terwilliger, J.D., Zollner, S., Laan, M. & Pääbo, S. Mapping genes through the use of linkage disequilibrium generated by genetic drift: "drift mapping" in small populations with no demographic expansion. Hum. Hered. 48, 138–154 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Terwilliger, J.D. & Weiss, K.M. Linkage disequilibrium mapping of complex disease: fantasy or reality? Curr. Opin. Biotechnol. 9, 578–594 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  9. Weiss, K.M. Genetic Variation and Human Disease. Principles and Evolutionary Approaches (Cambridge University Press, Cambridge, 1993).

    Book  Google Scholar 

  10. Bickeboller, H. et al. Apolipoprotein E and Alzheimer disease: genotype-specific risks by age and sex. Am. J. Hum. Genet. 60, 439–446 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Todd, J.A., Bell, J.I. & McDevitt, H.O. HLA-DQ β gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329, 599–604 (1987).

    Article  CAS  PubMed  Google Scholar 

  12. Clark, A.G. et al. Haplotype structure and population genetic inferences from nucleotide-sequence variation in human lipoprotein lipase. Am. J. Hum. Genet. 63, 595–612 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lander, E.S. The new genomics: global views of biology. Science 274, 536–539 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Sing, C.F., Haviland, M.B. & Reilly, S.L. Genetic architecture of common multifactorial diseases. in Variation in the Human Genome (Ciba Foundation Symposium 197) 211–229 (John Wiley and Sons, Chichester, 1996).

    Google Scholar 

  15. Van Camp, G., Willems, P.J. & Smith, R.J. Nonsyndromic hearing impairment: unparalleled heterogeneity. Am. J. Hum. Genet. 60, 758– 764 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Sullivan, L.S. & Daiger, S.P. Inherited retinal degeneration: exceptional genetic and clinical heterogeneity. Mol. Med. Today 2, 380–386 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Motulsky, A.G. & Brunzell, J.D. The genetics of coronary atherosclerosis. in The Genetic Basis of Common Diseases (eds King, R.A., Rotter, J.I. & Motulsky, A.G.) 150– 169 (Oxford University Press, New York, 1992).

    Google Scholar 

  18. Falconer, D.S. & Mackay, T.F.C. Introduction to Quantitative Genetics (Longman, Harlow, 1996).

    Google Scholar 

  19. Tanksley, S.D. Mapping polygenes. Annu. Rev. Genet. 27, 205–233 (1993).

    Article  CAS  PubMed  Google Scholar 

  20. Mackay, T.F.C. The nature of quantitative genetic variation revisited: lessons from Drosophila bristles. Bioessays 18, 113– 121 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Risch, N., Ghosh, S. & Todd, J.A. Statistical evaluation of multiple-locus linkage data in experimental species and its relevance to human studies: application to nonobese diabetic (NOD) mouse and human insulin-dependent diabetes mellitus (IDDM). Am. J. Hum. Genet. 53, 702– 714 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Soubrier, F. & Lathrop, G.M. The genetic basis of hypertension. Curr. Opin. Nephrol. Hypertens. 4, 177– 181 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Kajiwara, K., Berson, E.L. & Dryja, T.P. Digenic inheritance due to mutations at the unlinked peripherin/RDS and ROM1 loci. Science 264, 1604–1608 (1994).

    Article  CAS  PubMed  Google Scholar 

  24. Cox, N.J. et al. Loci on chromosomes 2 (NIDDM1) and 15 interact to increase susceptibility to diabetes in Mexican Americans. Nature Genet. 21, 213–215 ( 1999).

    Article  CAS  PubMed  Google Scholar 

  25. Balciuniene, J. et al. Evidence for digenic inheritance of non-syndromic hereditary hearing loss in a Swedish family. Am. J. Hum. Genet. 63, 786–793 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hartl, D.L. & Clark, A.G. Principles of Population Genetics (Sinauer, Sunderland, 1997).

    Google Scholar 

  27. Kruglyak, L. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nature Genet. 22, 139– 144 (1999).

    Article  CAS  PubMed  Google Scholar 

  28. Hacia, J.G. et al. Determination of ancestral alleles for human single-nucleotide polymorphisms using high-density oligonucleotide arrays. Nature Genet. 22, 164–167 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Kimura, M. The number of heterozygous nucleotide sites maintained in a finite population due to steady flux of mutations. Genetics 61, 893–903 (1969).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Nickerson, D.A. et al. DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene. Nature Genet. 19, 233– 240 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Harding, R.M. et al. Archaic African and Asian lineages in the genetic ancestry of modern humans. Am. J. Hum. Genet. 60, 772–789 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Rieder, M.J., Taylor, S.L., Clark, A.G. & Nickerson, D.A. Sequence variation in the human angiotensin converting enzyme. Nature Genet. 22, 59–62 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Neel, J.V. Diabetes mellitus: a "thrifty" genotype rendered detrimental by progress? Am. J. Hum. Genet. 14, 353– 362 (1962).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Bell, J.I., Boitard, C. & McDevitt, H.O. Biological basis of autoimmune disease. in The Genetic Basis of Common Diseases (eds. King, R.A., Rotter, J.I. & Motulsky, A.G.) 115–129 (Oxford University Press, New York, 1992).

    Google Scholar 

  35. Risch, N. Linkage strategies for genetically complex traits. I. Multilocus models. Am. J. Hum. Genet. 46, 222–228 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Martin, E.R., Kaplan, N.L. & Weir, B.S. Tests for linkage and association in nuclear families. Am. J. Hum. Genet. 61, 439– 448 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Teng, J. & Siegmund, D. Combining within and between pedigrees for mapping complex traits. Am. J. Hum. Genet. 60, 979–992 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Vogelstein, B. & Kinzler, K.W. The Genetic Basis of Human Cancer (McGraw-Hill, New York, 1998).

    Google Scholar 

  39. Schaid, D.J. Transmission disequilibrium, family controls, and great expectations. Am. J. Hum. Genet. 63, 935–941 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang, D.G. et al. Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science 280, 1077–1082 (1998).

    Article  CAS  PubMed  Google Scholar 

  41. Camp, N.J. Genomewide transmission/disequilibrium testing—consideration of the genotypic relative risks at disease loci. Am. J. Hum. Genet. 61, 1424–1430 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tu, I.-P. & Whittemore, A.S. Power of association and linkage tests when the disease alleles are unobserved. Am. J. Hum. Genet. 64, 641–649 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Scott, W.K., Pericak-Vance, M.A. & Haines, J.L. Genetic analysis of complex diseases. Science 275, 1327 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Jarvik, G.P. Genetic predictors of common disease: apolipoprotein E genotype as a paradigm. Ann. Epidemiol. 7, 357– 362 (1997).

    Article  CAS  PubMed  Google Scholar 

  45. Risch, N. & Merikangas, K. Genetic analysis of complex diseases. Science 275, 1329–1330 (1997).

    CAS  Google Scholar 

  46. Trembath, R.C. et al. Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis. Hum. Mol. Genet. 6, 813–820 (1997).

    Article  CAS  PubMed  Google Scholar 

  47. Kainulainen, K. et al. Evidence for involvement of the type 1 angiotensin II receptor locus in essential hypertension. Hypertension 33, 844–849 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. von Haeseler, A., Sajantila, A. & Pääbo, S. The genetical archaeology of the human genome. Nature Genet. 14, 135–140 (1995).

    Article  Google Scholar 

  49. Thompson, E.A. & Neel, J.V. Allelic disequilibrium and allele frequency distribution as a function of social and demographic history. Am. J. Hum. Genet. 60, 197– 204 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Harpending, H.C. et al. Genetic traces of ancient demography. Proc. Natl Acad. Sci. USA 95, 1961–1967 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Rogers, A.R. Genetic evidence for a Pleistocene population explosion. Evolution 49, 608–615 (1995).

    Article  PubMed  Google Scholar 

  52. Barbujani, G., Magagni, A., Minch, E. & Cavalli-Sforza, L.L. An apportionment of human DNA diversity. Proc. Natl Acad. Sci. USA, 94, 4516–4519 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Google Scholar 

  54. Graham, J. & Thompson, E.A. (1998) Disequilibrium likelihoods for fine-scale mapping of a rare allele. Am. J. Hum. Genet. 63, 1517–1530 (1998).

  55. Hastbacka, J. et al. Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland. Nature Genet. 2, 204–211 (1992).

    Article  CAS  PubMed  Google Scholar 

  56. Puffenberger, E.G. et al. A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung's disease. Cell 79, 1257– 1266 (1994).

    Article  CAS  PubMed  Google Scholar 

  57. Kruglyak, L. & Lander, E.S. High-resolution genetic mapping of complex traits. Am. J. Hum. Genet. 56, 1212–1223 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Kaplan, N.L., Hill, W.G. & Weir, B.S. Likelihood methods for locating disease genes in non-equilibrium populations. Am. J. Hum. Genet. 56, 18– 32 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Jorde, L.B. et al. Linkage disequilibrium predicts physical distance in the adenomatous polyposis coli region. Am. J. Hum. Genet. 54, 884–898 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Kruglyak, S., Durrett, R.T., Schug, M.D. & Aquadro, C.F. Equilibrium distributions of microsatellite repeat length resulting from a balance between slippage events and point mutations. Proc. Natl Acad. Sci. USA 95, 10774–10778 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Peterson, A.C. et al. The distribution of linkage disequilibrium over anonymous genome regions. Hum. Mol. Genet. 4, 887– 894 (1995).

    Article  CAS  PubMed  Google Scholar 

  62. Laan, M. & Paabo, S. Demographic history and linkage disequilibrium in human populations. Nature Genet. 17, 435–438 (1997).

    Article  CAS  PubMed  Google Scholar 

  63. Laan, M. & Pääbo, S. Mapping genes by drift-generated linkage disequilibrium. Am. J. Hum. Genet. 63, 654–656 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Service, S.K., Lang, D.W.T., Freimer, N.B. & Sandkuijl, L.A. Linkage-disequilibrium mapping of disease genes by reconstruction of ancestral haplotypes in founder populations. Am. J. Hum. Genet. 64, 1728–1738.

  65. Genin, E. & Clerget-Darpoux, F. Association studies in consanguineous populations. Am J. Hum. Genet. 58, 861– 866 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Workman, P.L. et al. Genetic differentiation among Sardinian villages. Am. J. Phys. Anthropol. 43, 165–176 (1975).

    Article  CAS  PubMed  Google Scholar 

  67. Ellis, W.S. & Starmer, W.T. Inbreeding as measured by isonymy, pedigrees, and population size in Torbel, Switzerland. Am. J. Hum. Genet. 30, 366–376 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. McKusick, V.A. Genetic studies in American inbred populations with particular reference to the Old Order Amish. in Genetic Polymorphisms and Diseases in Man (eds Ramot, B., Adam, A., Bonne, B., Goodman, R.M. & Szeinberg, A.) 150–158 (Academic, New York, 1974).

    Google Scholar 

  69. Bear, J.C. et al. Inbreeding in outport Newfoundland. Am. J. Hum. Genet. 29, 649–660 (1988).

    Article  CAS  Google Scholar 

  70. Chakraborty, R. & Weiss, K.M. Admixture as a tool for finding linked genes and detecting that difference from allelic association between loci. Proc. Natl. Acad. Sci. USA 85, 9119–9123 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. McKeigue, P.M. Mapping genes that underlie ethnic differences in disease risk: methods for detecting linkage in admixed populations, by conditioning on parental admixture. Am. J. Hum. Genet. 63, 241– 251 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Zerba, K.E., Ferrell, R.E. & Sing, C.F. Genetic structure of five susceptibility gene regions for coronary artery disease: disequilibria within and among regions. Hum. Genet. 103, 346–354 (1998).

    Article  CAS  PubMed  Google Scholar 

  73. Bertranpetit, J. et al. Human mitochondrial DNA variation and the origin of Basques. Ann. Hum. Genet. 59, 63– 81 (1995).

    Article  CAS  PubMed  Google Scholar 

  74. Suarez, B.K., Hampe, C.L. & Van Eerdewegh, P. Problems of replicating linkage claims in psychiatry. in Genetic Approaches to Mental Disorders (eds Gershon, E.S. & Cloninger, C.R.) 23–46 (American Psychiatric Press, Washington DC, 1994).

    Google Scholar 

  75. Terwilliger, J.D. et al. True and false positive peaks in genomewide scans: applications of length-biased sampling to linkage mapping. Am. J. Hum. Genet. 61, 430–438 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank R. Harding, S. Pääbo, T. Meitinger and N. Hastie for critical comments; P. Melis, L. Morelli and A. Angius for sharing unpublished data; and N. Davidson and colleagues for illustrations.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Alan F Wright.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wright, A., Carothers, A. & Pirastu, M. Population choice in mapping genes for complex diseases. Nat Genet 23, 397–404 (1999). https://doi.org/10.1038/70501

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/70501

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing