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.
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References
Collins, F.S. Positional cloning moves from perditional to traditional. Nature Genet. 9, 347–350 ( 1995).
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).
Lander, E.S. & Schork, N.J. Genetic dissection of complex traits. Science 265, 2037–2047 (1994).
Risch, N. & Merikangas, K. The future of genetic studies of complex human diseases. Science 273, 1516–1517 (1996).
Jorde, L.B. Linkage disequilibrium as a gene-mapping tool. Am. J. Hum. Genet. 56, 11–14 ( 1995).
Kruglyak, L. What is significant in whole-genome linkage disequilibrium studies? Am. J. Hum. Genet. 61, 810–812 (1997).
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).
Terwilliger, J.D. & Weiss, K.M. Linkage disequilibrium mapping of complex disease: fantasy or reality? Curr. Opin. Biotechnol. 9, 578–594 ( 1998).
Weiss, K.M. Genetic Variation and Human Disease. Principles and Evolutionary Approaches (Cambridge University Press, Cambridge, 1993).
Bickeboller, H. et al. Apolipoprotein E and Alzheimer disease: genotype-specific risks by age and sex. Am. J. Hum. Genet. 60, 439–446 (1997).
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).
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).
Lander, E.S. The new genomics: global views of biology. Science 274, 536–539 (1996).
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).
Van Camp, G., Willems, P.J. & Smith, R.J. Nonsyndromic hearing impairment: unparalleled heterogeneity. Am. J. Hum. Genet. 60, 758– 764 (1997).
Sullivan, L.S. & Daiger, S.P. Inherited retinal degeneration: exceptional genetic and clinical heterogeneity. Mol. Med. Today 2, 380–386 (1996).
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).
Falconer, D.S. & Mackay, T.F.C. Introduction to Quantitative Genetics (Longman, Harlow, 1996).
Tanksley, S.D. Mapping polygenes. Annu. Rev. Genet. 27, 205–233 (1993).
Mackay, T.F.C. The nature of quantitative genetic variation revisited: lessons from Drosophila bristles. Bioessays 18, 113– 121 (1996).
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).
Soubrier, F. & Lathrop, G.M. The genetic basis of hypertension. Curr. Opin. Nephrol. Hypertens. 4, 177– 181 (1995).
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).
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).
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).
Hartl, D.L. & Clark, A.G. Principles of Population Genetics (Sinauer, Sunderland, 1997).
Kruglyak, L. Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nature Genet. 22, 139– 144 (1999).
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).
Kimura, M. The number of heterozygous nucleotide sites maintained in a finite population due to steady flux of mutations. Genetics 61, 893–903 (1969).
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).
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).
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).
Neel, J.V. Diabetes mellitus: a "thrifty" genotype rendered detrimental by progress? Am. J. Hum. Genet. 14, 353– 362 (1962).
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).
Risch, N. Linkage strategies for genetically complex traits. I. Multilocus models. Am. J. Hum. Genet. 46, 222–228 (1990).
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).
Teng, J. & Siegmund, D. Combining within and between pedigrees for mapping complex traits. Am. J. Hum. Genet. 60, 979–992 (1997).
Vogelstein, B. & Kinzler, K.W. The Genetic Basis of Human Cancer (McGraw-Hill, New York, 1998).
Schaid, D.J. Transmission disequilibrium, family controls, and great expectations. Am. J. Hum. Genet. 63, 935–941 (1998).
Wang, D.G. et al. Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science 280, 1077–1082 (1998).
Camp, N.J. Genomewide transmission/disequilibrium testing—consideration of the genotypic relative risks at disease loci. Am. J. Hum. Genet. 61, 1424–1430 (1997).
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).
Scott, W.K., Pericak-Vance, M.A. & Haines, J.L. Genetic analysis of complex diseases. Science 275, 1327 (1997).
Jarvik, G.P. Genetic predictors of common disease: apolipoprotein E genotype as a paradigm. Ann. Epidemiol. 7, 357– 362 (1997).
Risch, N. & Merikangas, K. Genetic analysis of complex diseases. Science 275, 1329–1330 (1997).
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).
Kainulainen, K. et al. Evidence for involvement of the type 1 angiotensin II receptor locus in essential hypertension. Hypertension 33, 844–849 (1999).
von Haeseler, A., Sajantila, A. & Pääbo, S. The genetical archaeology of the human genome. Nature Genet. 14, 135–140 (1995).
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).
Harpending, H.C. et al. Genetic traces of ancient demography. Proc. Natl Acad. Sci. USA 95, 1961–1967 (1998).
Rogers, A.R. Genetic evidence for a Pleistocene population explosion. Evolution 49, 608–615 (1995).
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).
Cavalli-Sforza, L.L., Menozzi, P. & Piazza, A. The History and Geography of Human Genes (Princeton University Press, Princeton, 1994).
Graham, J. & Thompson, E.A. (1998) Disequilibrium likelihoods for fine-scale mapping of a rare allele. Am. J. Hum. Genet. 63, 1517–1530 (1998).
Hastbacka, J. et al. Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland. Nature Genet. 2, 204–211 (1992).
Puffenberger, E.G. et al. A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung's disease. Cell 79, 1257– 1266 (1994).
Kruglyak, L. & Lander, E.S. High-resolution genetic mapping of complex traits. Am. J. Hum. Genet. 56, 1212–1223 (1995).
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).
Jorde, L.B. et al. Linkage disequilibrium predicts physical distance in the adenomatous polyposis coli region. Am. J. Hum. Genet. 54, 884–898 (1994).
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).
Peterson, A.C. et al. The distribution of linkage disequilibrium over anonymous genome regions. Hum. Mol. Genet. 4, 887– 894 (1995).
Laan, M. & Paabo, S. Demographic history and linkage disequilibrium in human populations. Nature Genet. 17, 435–438 (1997).
Laan, M. & Pääbo, S. Mapping genes by drift-generated linkage disequilibrium. Am. J. Hum. Genet. 63, 654–656 (1998).
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.
Genin, E. & Clerget-Darpoux, F. Association studies in consanguineous populations. Am J. Hum. Genet. 58, 861– 866 (1996).
Workman, P.L. et al. Genetic differentiation among Sardinian villages. Am. J. Phys. Anthropol. 43, 165–176 (1975).
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).
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).
Bear, J.C. et al. Inbreeding in outport Newfoundland. Am. J. Hum. Genet. 29, 649–660 (1988).
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).
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).
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).
Bertranpetit, J. et al. Human mitochondrial DNA variation and the origin of Basques. Ann. Hum. Genet. 59, 63– 81 (1995).
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).
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).
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.
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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
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DOI: https://doi.org/10.1038/70501
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