• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of ajhgLink to Publisher's site
Am J Hum Genet. Dec 1998; 63(6): 1872–1885.
PMCID: PMC1377658

Genome screens using linkage disequilibrium tests: optimal marker characteristics and feasibility.

Abstract

Linkage disequilibrium (LD) testing has become a popular and effective method of fine-scale disease-gene localization. It has been proposed that LD testing could also be used for genome screening, particularly as dense maps of diallelic markers become available and automation allows inexpensive genotyping of diallelic markers. We compare diallelic markers and multiallelic markers in terms of sample sizes required for detection of LD, by use of a single marker locus in a case-control study, for rare monophyletic diseases with Mendelian inheritance. We extrapolate from our results to discuss the feasibility of single-marker LD screening in more-complex situations. We have used a deterministic population genetic model to calculate the expected power to detect LD as a function of marker density, age of mutation, number of marker alleles, mode of inheritance of a rare disease, and sample size. Our calculations show that multiallelic markers always have more power to detect LD than do diallelic markers (under otherwise equivalent conditions) and that the ratio of the number of diallelic to the number of multiallelic markers needed for equivalent power increases with mutation age and complexity of mode of inheritance. Power equivalent to that achieved by a multiallelic screen can theoretically be achieved by use of a more dense diallelic screen, but mapping panels of the necessary resolution are not currently available and may be difficult to achieve. Genome screening that uses single-marker LD testing may therefore be feasible only for young (<20 generations), rare, monophyletic Mendelian diseases, such as may be found in rapidly growing genetic isolates.

Full Text

The Full Text of this article is available as a PDF (371K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Arnheim N, Li H, Cui X. Genetic mapping by single sperm typing. Anim Genet. 1991;22(2):105–115. [PubMed]
  • Bird TD, Lampe TH, Nemens EJ, Miner GW, Sumi SM, Schellenberg GD. Familial Alzheimer's disease in American descendants of the Volga Germans: probable genetic founder effect. Ann Neurol. 1988 Jan;23(1):25–31. [PubMed]
  • Boehnke M. Limits of resolution of genetic linkage studies: implications for the positional cloning of human disease genes. Am J Hum Genet. 1994 Aug;55(2):379–390. [PMC free article] [PubMed]
  • Briscoe D, Stephens JC, O'Brien SJ. Linkage disequilibrium in admixed populations: applications in gene mapping. J Hered. 1994 Jan-Feb;85(1):59–63. [PubMed]
  • Brown PO, Hartwell L. Genomics and human disease--variations on variation. Nat Genet. 1998 Feb;18(2):91–93. [PubMed]
  • Casaubon LK, Melanson M, Lopes-Cendes I, Marineau C, Andermann E, Andermann F, Weissenbach J, Prévost C, Bouchard JP, Mathieu J, et al. The gene responsible for a severe form of peripheral neuropathy and agenesis of the corpus callosum maps to chromosome 15q. Am J Hum Genet. 1996 Jan;58(1):28–34. [PMC free article] [PubMed]
  • Chee M, Yang R, Hubbell E, Berno A, Huang XC, Stern D, Winkler J, Lockhart DJ, Morris MS, Fodor SP. Accessing genetic information with high-density DNA arrays. Science. 1996 Oct 25;274(5287):610–614. [PubMed]
  • Devlin B, Risch N. A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics. 1995 Sep 20;29(2):311–322. [PubMed]
  • Devlin B, Risch N, Roeder K. Disequilibrium mapping: composite likelihood for pairwise disequilibrium. Genomics. 1996 Aug 15;36(1):1–16. [PubMed]
  • Ellis NA, Roe AM, Kozloski J, Proytcheva M, Falk C, German J. Linkage disequilibrium between the FES, D15S127, and BLM loci in Ashkenazi Jews with Bloom syndrome. Am J Hum Genet. 1994 Sep;55(3):453–460. [PMC free article] [PubMed]
  • Escamilla MA, Spesny M, Reus VI, Gallegos A, Meza L, Molina J, Sandkuijl LA, Fournier E, Leon PE, Smith LB, et al. Use of linkage disequilibrium approaches to map genes for bipolar disorder in the Costa Rican population. Am J Med Genet. 1996 May 31;67(3):244–253. [PubMed]
  • Goddard KA, Yu CE, Oshima J, Miki T, Nakura J, Piussan C, Martin GM, Schellenberg GD, Wijsman EM. Toward localization of the Werner syndrome gene by linkage disequilibrium and ancestral haplotyping: lessons learned from analysis of 35 chromosome 8p11.1-21.1 markers. Am J Hum Genet. 1996 Jun;58(6):1286–1302. [PMC free article] [PubMed]
  • Hästbacka J, de la Chapelle A, Kaitila I, Sistonen P, Weaver A, Lander E. Linkage disequilibrium mapping in isolated founder populations: diastrophic dysplasia in Finland. Nat Genet. 1992 Nov;2(3):204–211. [PubMed]
  • Houwen RH, Baharloo S, Blankenship K, Raeymaekers P, Juyn J, Sandkuijl LA, Freimer NB. Genome screening by searching for shared segments: mapping a gene for benign recurrent intrahepatic cholestasis. Nat Genet. 1994 Dec;8(4):380–386. [PubMed]
  • Jorde LB. Linkage disequilibrium as a gene-mapping tool. Am J Hum Genet. 1995 Jan;56(1):11–14. [PMC free article] [PubMed]
  • Kalaydjieva L, Hallmayer J, Chandler D, Savov A, Nikolova A, Angelicheva D, King RH, Ishpekova B, Honeyman K, Calafell F, et al. Gene mapping in Gypsies identifies a novel demyelinating neuropathy on chromosome 8q24. Nat Genet. 1996 Oct;14(2):214–217. [PubMed]
  • Kaplan NL, Hill WG, Weir BS. Likelihood methods for locating disease genes in nonequilibrium populations. Am J Hum Genet. 1995 Jan;56(1):18–32. [PMC free article] [PubMed]
  • Kaplan NL, Martin ER, Weir BS. Power studies for the transmission/disequilibrium tests with multiple alleles. Am J Hum Genet. 1997 Mar;60(3):691–702. [PMC free article] [PubMed]
  • MacCluer JW, Blangero J, Dyer TD, Speer MC. GAW10: simulated family data for a common oligogenic disease with quantitative risk factors. Genet Epidemiol. 1997;14(6):737–742. [PubMed]
  • MacDonald ME, Novelletto A, Lin C, Tagle D, Barnes G, Bates G, Taylor S, Allitto B, Altherr M, Myers R, et al. The Huntington's disease candidate region exhibits many different haplotypes. Nat Genet. 1992 May;1(2):99–103. [PubMed]
  • Nickerson DA, Whitehurst C, Boysen C, Charmley P, Kaiser R, Hood L. Identification of clusters of biallelic polymorphic sequence-tagged sites (pSTSs) that generate highly informative and automatable markers for genetic linkage mapping. Genomics. 1992 Feb;12(2):377–387. [PubMed]
  • Olson JM, Wijsman EM. Design and sample-size considerations in the detection of linkage disequilibrium with a disease locus. Am J Hum Genet. 1994 Sep;55(3):574–580. [PMC free article] [PubMed]
  • Ott J, Rabinowitz D. The effect of marker heterozygosity on the power to detect linkage disequilibrium. Genetics. 1997 Oct;147(2):927–930. [PMC free article] [PubMed]
  • Pandolfo M, Sirugo G, Antonelli A, Weitnauer L, Ferretti L, Leone M, Dones I, Cerino A, Fujita R, Hanauer A, et al. Friedreich ataxia in Italian families: genetic homogeneity and linkage disequilibrium with the marker loci D9S5 and D9S15. Am J Hum Genet. 1990 Aug;47(2):228–235. [PMC free article] [PubMed]
  • Plomin R, Owen MJ, McGuffin P. The genetic basis of complex human behaviors. Science. 1994 Jun 17;264(5166):1733–1739. [PubMed]
  • Risch N, de Leon D, Ozelius L, Kramer P, Almasy L, Singer B, Fahn S, Breakefield X, Bressman S. Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population. Nat Genet. 1995 Feb;9(2):152–159. [PubMed]
  • Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science. 1996 Sep 13;273(5281):1516–1517. [PubMed]
  • Sham PC, Curtis D. Monte Carlo tests for associations between disease and alleles at highly polymorphic loci. Ann Hum Genet. 1995 Jan;59(Pt 1):97–105. [PubMed]
  • Shriver MD, Smith MW, Jin L, Marcini A, Akey JM, Deka R, Ferrell RE. Ethnic-affiliation estimation by use of population-specific DNA markers. Am J Hum Genet. 1997 Apr;60(4):957–964. [PMC free article] [PubMed]
  • Sulisalo T, Klockars J, Mäkitie O, Francomano CA, de la Chapelle A, Kaitila I, Sistonen P. High-resolution linkage-disequilibrium mapping of the cartilage-hair hypoplasia gene. Am J Hum Genet. 1994 Nov;55(5):937–945. [PMC free article] [PubMed]
  • Thompson EA, Deeb S, Walker D, Motulsky AG. The detection of linkage disequilibrium between closely linked markers: RFLPs at the AI-CIII apolipoprotein genes. Am J Hum Genet. 1988 Jan;42(1):113–124. [PMC free article] [PubMed]
  • Thompson EA, Neel JV. Allelic disequilibrium and allele frequency distribution as a function of social and demographic history. Am J Hum Genet. 1997 Jan;60(1):197–204. [PMC free article] [PubMed]
  • Varilo T, Savukoski M, Norio R, Santavuori P, Peltonen L, Järvelä I. The age of human mutation: genealogical and linkage disequilibrium analysis of the CLN5 mutation in the Finnish population. Am J Hum Genet. 1996 Mar;58(3):506–512. [PMC free article] [PubMed]
  • Votruba M, Moore AT, Bhattacharya SS. Genetic refinement of dominant optic atrophy (OPA1) locus to within a 2 cM interval of chromosome 3q. J Med Genet. 1997 Feb;34(2):117–121. [PMC free article] [PubMed]
  • Weber JL, May PE. Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am J Hum Genet. 1989 Mar;44(3):388–396. [PMC free article] [PubMed]
  • Weir BS, Cockerham CC. Testing Hypotheses about Linkage Disequilibrium with Multiple Alleles. Genetics. 1978 Mar;88(3):633–642. [PMC free article] [PubMed]
  • Yuan B, Vaske D, Weber JL, Beck J, Sheffield VC. Improved set of short-tandem-repeat polymorphisms for screening the human genome. Am J Hum Genet. 1997 Feb;60(2):459–460. [PMC free article] [PubMed]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...