Hum Hered 2005;59:118–124
(DOI:10.1159/000085226)

Linkage Disequilibrium: Ancient History Drives the New Genetics

Abecasis G.R. · Ghosh D. · Nichols T.E.
Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Mich., USA
email Corresponding Author


 goto top of outline Key Words

  • Linkage disequilibrium
  • Natural selection
  • Association mapping
  • Recombination rate

 goto top of outline Abstract

This brief review provides a summary of the biological causes of genetic association between tightly linked markers – termed linkage disequilibrium – and unlinked markers – termed population structure. We also review the utility of linkage disequilibrium data in gene mapping in isolated populations, in the estimation of recombination rates and in studying the history of particular alleles, including the detection of natural selection. We discuss current understanding of the extent and patterns of linkage disequilibrium in the genome, and its promise for genetic association studies in complex disease. Finally, we highlight the importance of using appropriate statistical procedures, such as the false discovery rate, to maximize the chances of success in large scale association studies.

Copyright © 2005 S. Karger AG, Basel


 goto top of outline References
  1. Abecasis GR, Cardon LR, Cookson WOC: A general test of association for quantitative traits in nuclear families. Am J Hum Genet 2000;66:279–292.
  2. Abecasis GR, Cookson WO, Cardon LR: Pedigree tests of transmission disequilibrium. Eur J Hum Genet 2000;8:545–551.
  3. Abecasis GR, Noguchi E, Heinzmann A, Traherne JA, Bhattacharyya S, Leaves NI, Anderson GG, Zhang Y, Lench NJ, Carey A, Cardon LR, Moffatt MF, Cookson WO: Extent and distribution of linkage disequilibrium in three genomic regions. Am J Hum Genet 2001;68:191–197.
  4. Benjamini Y, Hochberg Y: Controlling the false discovery rate: A practical and powerful approach to multiple testing. J R Stat Soc (B) 1995;57:289–300.
  5. Benjamini Y, Yekutieli D: The control of the false discovery rate in multiple testing under dependency. Ann Stat 2001;29:1165–1188.

    External Resources

  6. Botstein D, Risch N: Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat Genet 2003;33(suppl):228–237.
  7. Cardon LR, Abecasis GR: Using haplotype blocks to map human complex trait loci. Trends Genet 2003;19:135–140.
  8. Carlson CS, Eberle MA, Rieder MJ, Smith JD, Kruglyak L, Nickerson DA: Additional SNPs and linkage-disequilibrium analyses are necessary for whole-genome association studies in humans. Nat Genet 2003;33:518–521.
  9. Carlson CS, Eberle MA, Rieder MJ, Yi Q, Kruglyak L, Nickerson DA: Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet 2004;74:106–120.
  10. Chakravarti A, Buetow KH, Antonarakis SE, Waber PG, Boehm CD, Kazazian HH: Nonuniform recombination within the human beta-globin gene cluster. Am J Hum Genet 1984;36:1239–1258.
  11. Chakravarti A, Phillips JA, 3rd, Mellits KH, Buetow KH, Seeburg PH: Patterns of polymorphism and linkage disequilibrium suggest independent origins of the human growth hor mone gene cluster. Proc Natl Acad Sci USA 1984;81:6085–6089.
  12. Daly MJ, Rioux JD, Schaffner SE, Hudson TJ, Lander ES: High-resolution haplotype structure in the human genome. Nat Genet 2001;29:229–232.
  13. Dawson E, Abecasis GR, Bumpstead S, Chen Y, Hunt S, Beare DM, Pabial J, et al: A linkage disequilibrium map of chromosome 22. Nature 2002;418:544–548.
  14. Devlin B, Roeder K, Wasserman L: False discovery or missed discovery? Heredity 2003;91:537–538.
  15. Dudbridge F, Koeleman BP: Efficient computation of significance levels for multiple associations in large studies of correlated data, including genomewide association studies. Am J Hum Genet 2004;75:424–435.
  16. Durrant C, Zondervan KT, Cardon LR, Hunt S, Deloukas P, Morris AP: Linkage disequilibrium mapping via cladistic analysis of single-nucleotide polymorphism haplotypes. Am J Hum Genet 2004;75:35–43.
  17. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D: The structure of haplotype blocks in the human genome. Science 2002;296:2225–2229.
  18. Genovese C, Wasserman L: Operating characteristics and extensions of the false discovery rate procedure. J R Stat Soc (B) 2002;64:499–517.
  19. Hinds DA, Stuve LL, Nilsen GB, Halperin E, Eskin E, Ballinger DG, Frazer KA, Cox DR: Whole-genome patterns of common DNA variation in three human populations. Science 2005;307:1072–1079.
  20. Jeffreys AJ, Kauppi L, Neumann R: Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nat Genet 2001;29:217–222.
  21. Johnson GCL, Esposito L, Barratt BJ, Smith AN, Heward J, Di Genova G, Ueda H, Cordell HJ, Eaves IA, Dudbridge F, Twells RCJ, Payne F, Hughes W, Nutland S, Stevens H, Carr P, Tuomilehto-Wolf E, Tuomilehto J, Gough SCL, Clayton DG, Todd JA: Haplotype tagging for the identification of common disease genes. Nat Genet 2001;29:233–237.
  22. Jorde LB, Watkins WS, Carlson M, Groden J, Albertsen H, Thliveris A, Leppert M: Linkage disequilibrium predicts physical distance in the adenomatous polyposis coli region. Am J Hum Genet 1994;54:884–898.
  23. Lin S, Chakravarti A, Cutler DJ: Exhaustive allelic transmission disequilibrium tests as a new approach to genome-wide association studies. Nat Genet 2004;36:1181–1188.
  24. Martin ER, Lai EH, Gilbert JR, Rogala AR, Afshari AJ, Riley J, Finch KL, Stevens JF, Livak KJ, Slotterbeck BD, Slifer SH, Warren LL, Conneally PM, Schmechel DE, Purvis I, Pericak-Vance MA, Roses AD, Vance JM: SNPing away at complex diseases: analysis of single-nucleotide polymorphisms around APOE in Alzheimer disease. Am J Hum Genet 2000;67:383–394.
  25. Matsuzaki H, Dong S, Loi H, Di X, Liu G, Hubbell E, Law J, Bernsten T, Chadha M, Hui H, Yang G, Webster T, Cawley S, Walsh P, Jones K, Mei R: Genotyping over 100,000 SNPs on a pair of oligonucleotide arrays. Nature Methods 2004;1:109–111.
  26. McKenzie CA, Abecasis GR, Keavney B, Forrester T, Ratcliffe PJ, Julier C, Connell JM, Bennett F, McFarlane-Anderson N, Lathrop GM, Cardon LR: Trans-ethnic fine mapping of a quantitative trait locus for circulating angiotensin I-converting enzyme (ACE). Hum Mol Genet 2001;10:1077–1084.
  27. McVean GA, Myers SR, Hunt S, Deloukas P, Bentley DR, Donnelly P: The fine-scale structure of recombination rate variation in the human genome. Science 2004;304:581–584.
  28. Morley M, Molony CM, Weber TM, Devlin JL, Ewens KG, Spielman RS, Cheung VG: Genetic analysis of genome-wide variation in human gene expression. Nature 2004;430:743–747.
  29. Morris AP, Whittaker JC, Balding DJ: Fine-scale mapping of disease loci via shattered coalescent modeling of genealogies. Am J Hum Genet 2002;70:686–707.
  30. Peltonen L, Palotie A, Lange K, Department of Medical Genetics UoH, National Public Health Institute FLmue: Use of population isolates for mapping complex traits. Nature reviews Genetics 2000;1:182–190.
  31. Reich DE, Cargill M, Bolk S, Ireland J, Sabeti PC, Richter DJ, Lavery T, Kouyoumjian R, Farhadian SF, Ward R, Lander ES: Linkage disequilibrium in the human genome. Nature 2001;411:199–204.
  32. Rhodes DR, Barrette TR, Rubin MA, Ghosh D, Chinnaiyan AM: Meta-analysis of microarrays: interstudy validation of gene expression profiles reveals pathway dysregulation in prostate cancer. Cancer Res 2002;62:4427–4433.
  33. Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A, Chinnaiyan AM: Large-scale meta-analysis of cancer microarray data identifies common transcriptional profiles of neoplastic transformation and progression. Proc Natl Acad Sci USA 2004;101:9309–9314.
  34. Rosenberg NA, Pritchard JK, Weber JL, Cann HM, Kidd KK, Zhivotovsky LA, Feldman MW: Genetic structure of human populations. Science 2002;298:2381–2385.
  35. Sabatti C, Service S, Freimer N: False discovery rate in linkage and association genome screens for complex disorders. Genetics 2003;164:829–833.
  36. Sabeti PC, Reich DE, Higgins JM, Levine HZ, Richter DJ, Schaffner SF, Gabriel SB, Platko JV, Patterson NJ, McDonald GJ, Ackerman HC, Campbell SJ, Altshuler D, Cooper R, Kwiatkowski D, Ward R, Lander ES: Detecting recent positive selection in the human genome from haplotype structure. Nature 2002;419:832–837.
  37. Sachidanandam R, Weissman D, Schmidt SC, Kakol JM, Stein LD, Marth G, Sherry S, et al: A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 2001;409:928–933.
  38. Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA: Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 2002;70:425–434.
  39. Stephens JC, Reich DE, Goldstein DB, Shin HD, Smith MW, Carrington M, Winkler C, et al: Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes. Am J Hum Genet 1998;62:1507–1515.
  40. Storey JD: A direct approach to false discovery rates. J R Stat Soc (B) 2002;64:479–498.
  41. Storey JD, Tibshirani R: Statistical significance for genomewide studies. Proc Natl Acad Sci USA 2003;100:9440–9445.
  42. The International HapMap Consortium: The International HapMap Project. Nature 2003;426:789–796.
  43. Tomlinson IP, Bodmer WF: The HLA system and the analysis of multifactorial genetic disease. Trends Genet 1995;11:493–498.
  44. Tusher VG, Tibshirani R, Chu G: Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 2001;98:5116–5121.
  45. Underhill PA, Shen P, Lin AA, Jin L, Passarino G, Yang WH, Kauffman E, Bonne-Tamir B, Bertranpetit J, Francalacci P, Ibrahim M, Jenkins T, Kidd JR, Mehdi SQ, Seielstad MT, Wells RS, Piazza A, Davis RW, Feldman MW, Cavalli-Sforza LL, Oefner PJ: Y chromosome sequence variation and the history of human populations. Nat Genet 2000;26:358–361.
  46. Wille A, Hoh J, Ott J: Sum statistics for the joint detection of multiple disease loci in case-control association studies with SNP markers. Genet Epidemiol 2003;25:350–359.
  47. Wootton JC, Feng X, Ferdig MT, Cooper RA, Mu J, Baruch DI, Magill AJ, Su XZ: Genetic diversity and chloroquine selective sweeps in Plasmodium falciparum. Nature 2002;418:320–323.
  48. Zabetian CP, Anderson GM, Buxbaum SG, Elston RC, Ichinose H, Nagatsu T, Kim KS, Kim CH, Malison RT, Gelernter J, Cubells JF: A quantitative-trait analysis of human plasma-dopamine beta-hydroxylase activity: Evidence for a major functional polymorphism at the DBH locus. Am J Hum Genet 2001;68:515–522.
  49. Zabetian CP, Buxbaum SG, Elston RC, Kohnke MD, Anderson GM, Gelernter J, Cubells JF: The structure of linkage disequilibrium at the DBH locus strongly influences the magnitude of association between diallelic markers and plasma dopamine beta-hydroxylase activity. Am J Hum Genet 2003;72:1389–1400.
  50. Zaykin DV, Westfall PH, Young SS, Karnoub MA, Wagner MJ, Ehm MG: Testing association of statistically inferred haplotypes with discrete and continuous traits in samples of unrelated individuals. Hum Hered 2002;53:79–91.
  51. Zhang W, Collins A, Maniatis N, Tapper W, Morton NE: Properties of linkage disequilibrium (LD) maps. Proc Natl Acad Sci USA 2002;99:17004–17007.
  52. Zhu X, Luke A, Cooper RS, Quertermous T, Hanis C, Mosley T, Gu CC, Tang H, Rao DC, Risch N, Weder A: Admixture mapping for hypertension loci with genome-scan markers. Nat Genet 2005;37:177–181.
  53. Zollner S, Pritchard JK: Coalescent-based association mapping and fine mapping of complex trait loci. Genetics 2005;169:1071–1092.

 goto top of outline Author Contacts

Dr. G.R. Abecasis
Department of Biostatistics, School of Public Health
University of Michigan
Ann Arbor, MI (USA)
Tel. +1 734 763 4901, Fax +1 734 615 8322, E-Mail goncalo@umich.edu


 goto top of outline Article Information

Received: January 25, 2005
Accepted after revision: February 22, 2005
Published online: April 18, 2005
Number of Print Pages : 7
Number of Figures : 2, Number of Tables : 0, Number of References : 53


 goto top of outline Publication Details

Human Heredity (International Journal of Human and Medical Genetics)

Vol. 59, No. 2, Year 2005 (Cover Date: Released May 2005)

Journal Editor: Devoto, M. (Wilmington, Del.)
ISSN: 0001–5652 (print), 1423–0062 (Online)

For additional information: http://www.karger.com/hhe


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