Skip to main content
SpringerLink
Log in
Book cover

Linkage Disequilibrium and Association Mapping pp 23–45Cite as

Linkage Disequilibrium Maps and Location Databases

  • Protocol

Part of the book series: Methods in Molecular Biology™ ((MIMB,volume 376))

Abstract

Effective application of association mapping for complex traits requires characterization of linkage disequilibrium (LD) patterns that reflect the dominant process of recombination and its duration in addition to the more subtle influences of mutation, selection, and genetic drift. Maps expressed in linkage disequilibrium units (LDUs) reflect the influences of these factors with the use of a modified version of Malecot’s isolation-by-distance model. As a result, LDU maps are analogous to linkage maps in so far as their provision of an additive metric that is related to recombination and facilitates association-mapping studies. However, unlike linkage maps, LDUs also reflect the partly cumulative effects of multiple historical bottlenecks that account for substantial variations in LD patterns between populations. This chapter provides an overview of the data requirements and methodology used to construct LDU maps, their applications outside association mapping, and their integration into location databases.

This is a preview of subscription content, log in via an institution.

Protocol
USD   49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

References

  1. Morton, N. E., Zhang, W., Taillon-Miller, P., Ennis, S., Kwok, P. Y., and Collins, A. (2001) The optimal measure of allelic association. Proc. Natl. Acad. Sci. USA 98, 5217–5221.

    Article  CAS  PubMed  Google Scholar 

  2. Collins, A., Ennis, S., Taillon-Miller, P., Kwok, P. Y., and Morton, N. E. (2001) Allelic association with SNPs: metrics, populations, and the linkage disequilibrium map. Hum. Mutat. 17, 255–262.

    Article  CAS  PubMed  Google Scholar 

  3. Maniatis, N., Collins, A., Xu, C. F., et al. (2002) The first linkage disequilibrium (LD) maps: delineation of hot and cold blocks by diplotype analysis. Proc. Natl. Acad. Sci. USA 99, 2228–2233.

    Article  CAS  PubMed  Google Scholar 

  4. Zhang, W., Collins, A., Gibson, J., et al. (2004) Impact of population structure, effective bottleneck time, and allele frequency on linkage disequilibrium maps. Proc. Natl. Acad. Sci. USA 101, 18,075–18,080.

    Article  CAS  PubMed  Google Scholar 

  5. Jeffreys, A. J., Kauppi, L., and Neumann, R. (2001) Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nat. Genet. 29, 217–222.

    Article  CAS  PubMed  Google Scholar 

  6. Zhang, W., Collins, A., Maniatis, N., Tapper, W., and Morton, N. E. (2002) Properties of linkage disequilibrium (LD) maps. Proc. Natl. Acad. Sci. USA 99, 17,004–17,007.

    Article  CAS  PubMed  Google Scholar 

  7. Daly, M. J., Rioux, J. D., Schaffner, S. F., Hudson, T. J., and Lander, E. S. (2001) High-resolution haplotype structure in the human genome. Nat. Genet. 29, 229–232.

    Article  CAS  PubMed  Google Scholar 

  8. Lonjou, C., Zhang, W., Collins, A., et al. (2003) Linkage disequilibrium in human populations. Proc. Natl. Acad. Sci. USA 100, 6069–6074.

    Article  CAS  PubMed  Google Scholar 

  9. Gibson, J., Tapper, W., Zhang, W., Morton, N., and Collins, A. (2005) Cosmopolitan linkage disequilibrium maps. Hum. Genomics 2, 20–27.

    CAS  PubMed  Google Scholar 

  10. Jeffreys, A. J. and Neumann, R. (2002) Reciprocal crossover asymmetry and meiotic drive in a human recombination hot spot. Nat. Genet. 31, 267–271.

    Article  CAS  PubMed  Google Scholar 

  11. Tapper, W., Collins, A., Gibson, J., Maniatis, N., Ennis, S., and Morton, N. E. (2005) A map of the human genome in linkage disequilibrium units. Proc. Natl. Acad. Sci. USA 102, 11,835–11,839.

    Article  CAS  PubMed  Google Scholar 

  12. Collins, F. S., Green, E. D., Guttmacher, A. E., and Guyer, M. S. (2003) A vision for the future of genomics research. Nature 422, 835–847.

    Article  CAS  PubMed  Google Scholar 

  13. Dawson, E., Abecasis, G. R., Bumpstead, S., et al. (2002) A first-generation linkage disequilibrium map of human chromosome 22. Nature 418, 544–548.

    Article  CAS  PubMed  Google Scholar 

  14. Tapper, W. J., Maniatis, N., Morton, N. E., and Collins, A. (2003) A metric linkage disequilibrium map of a human chromosome. Ann. Hum. Genet. 67, 487–494.

    Article  CAS  PubMed  Google Scholar 

  15. Ke, X., Tapper, W., and Collins, A. (2001) LDB2000: sequence-based integrated maps of the human genome. Bioinformatics 17, 581–586.

    Article  CAS  PubMed  Google Scholar 

  16. Gusella, J. F., Wexler, N. S., Conneally, P. M., et al. (1983) A polymorphic DNA marker genetically linked to Huntington’s disease. Nature 306, 234–238.

    Article  CAS  PubMed  Google Scholar 

  17. Matise, T. C., Sachidanandam, R., Clark, A. G., et al. (2003) A 3.9-centimorganresolution human single-nucleotide polymorphism linkage map and screening set. Am. J. Hum. Genet. 73, 271–284.

    Article  CAS  PubMed  Google Scholar 

  18. Kong, A., Gudbjartsson, D. F., Sainz, J., et al. (2002) A high-resolution recombination map of the human genome. Nat. Genet. 31, 241–247.

    CAS  PubMed  Google Scholar 

  19. Kong, X., Murphy, K., Raj, T., He, C., White, P. S., and Matise, T. C. (2004) A combined linkage-physical map of the human genome. Am. J. Hum. Genet. 75, 1143–1148.

    Article  CAS  PubMed  Google Scholar 

  20. Collins, F. S. (1992) Positional cloning: let’s not call it reverse anymore. Nat. Genet. 1, 3–6.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. Altshuler, D., Brooks, L. D., Chakravarti, A., Collins, F. S., Daly, M. J., and Donnelly, P. (2005) A haplotype map of the human genome. Nature 437, 1299–1320.

    Article  Google Scholar 

  23. Thompson, E. A., Deeb, S., Walker, D., and Motulsky, A. G. (1988) The detection of linkage disequilibrium between closely linked markers: RFLPs at the AI-CIII apolipoprotein genes. Am. J. Hum. Genet. 42, 113–124.

    CAS  PubMed  Google Scholar 

  24. Gomes, I., Collins, A., Lonjou, C., et al. (1999) Hardy-Weinberg quality control. Ann. Hum. Genet. 63, 535–538.

    Article  CAS  PubMed  Google Scholar 

  25. Ke, X., Hunt, S., Tapper, W., et al. (2004) The impact of SNP density on fine-scale patterns of linkage disequilibrium. Hum. Mol. Genet. 13, 577–588.

    Article  CAS  PubMed  Google Scholar 

  26. Gabriel, S. B., Schaffner, S. F., Nguyen, H., et al. (2002) The structure of haplotype blocks in the human genome. Science 296, 2225–2229.

    Article  CAS  PubMed  Google Scholar 

  27. Phillips, M. S., Lawrence, R., Sachidanandam, R., et al. (2003) Chromosome-wide distribution of haplotype blocks and the role of recombination hot spots. Nat. Genet. 33, 382–387.

    Article  CAS  PubMed  Google Scholar 

  28. Wang, N., Akey, J. M., Zhang, K., Chakraborty, R., and Jin, L. (2002) Distribution of recombination crossovers and the origin of haplotype blocks: the interplay of population history, recombination, and mutation. Am. J. Hum. Genet. 71, 1227–1234.

    Article  CAS  PubMed  Google Scholar 

  29. Service, S., DeYoung, J., Karayiorgou, M., et al. (2006) Magnitude and distribution of linkage disequilibrium in population isolates and implications for genome-wide association. Nat. Genet. 38, 556–560.

    Article  CAS  PubMed  Google Scholar 

  30. Teare, M. D., Dunning, A. M., Durocher, F., Rennart, G., and Easton, D. F. (2002) Sampling distribution of summary linkage disequilibrium measures. Ann. Hum. Genet. 66, 223–233.

    Article  CAS  PubMed  Google Scholar 

  31. Tenesa, A., Wright, A. F., Knott, S. A., et al. (2004) Extent of linkage disequilibrium in a Sardinian sub-isolate: sampling and methodological considerations. Hum. Mol. Genet. 13, 25–33.

    Article  CAS  PubMed  Google Scholar 

  32. Collins, A. and Morton, N. E. (1998) Mapping a disease locus by allelic association. Proc. Natl. Acad. Sci. USA 95, 1741–1745.

    Article  CAS  PubMed  Google Scholar 

  33. Collins, A., Lonjou, C., and Morton, N. E. (1999) Genetic epidemiology of singlenucleotide polymorphisms. Proc. Natl. Acad. Sci. USA 96, 15,173–15,177.

    Article  CAS  PubMed  Google Scholar 

  34. Lewontin, R. C. (1964) The interaction of selection and linkage. I. General considerations. Genetics 49, 49–67.

    CAS  PubMed  Google Scholar 

  35. Hill, W. G. (1974) Estimation of linkage disequilibrium in randomly mating populations. Heredity 33, 229–239.

    Article  CAS  PubMed  Google Scholar 

  36. Collins, A., Lau, W., and De La Vega, F. M. (2004) Mapping genes for common diseases: the case for genetic (LD) maps. Hum. Hered. 58, 2–9.

    Article  PubMed  Google Scholar 

  37. Altschul, S. F., Gish, W., Miller, W., Myers, E. W., and Lipman, D. J. (1990) Basic local alignment search tool. J. Mol. Biol. 215, 403–410.

    CAS  PubMed  Google Scholar 

  38. White, J. A., McAlpine, P. J., Antonarakis, S., et al. (1997) Guidelines for human gene nomenclature (1997). HUGO Nomenclature Committee. Genomics 45, 468–471.

    Article  CAS  PubMed  Google Scholar 

  39. Cheung, V. G., Nowak, N., Jang, W., et al. (2001) Integration of cytogenetic landmarks into the draft sequence of the human genome. Nature 409, 953–958.

    Article  CAS  PubMed  Google Scholar 

  40. De La Vega, F. M., Isaac, H., Collins, A., et al. (2005) The linkage disequilibrium maps of three human chromosomes across four populations reflect their demographic history and a common underlying recombination pattern. Genome Res. 15, 454–462.

    Article  Google Scholar 

  41. Jeffreys, A. J., Neumann, R., Panayi, M., Myers, S., and Donnelly, P. (2005) Human recombination hot spots hidden in regions of strong marker association. Nat. Genet. 37, 601–606.

    Article  CAS  PubMed  Google Scholar 

  42. Rao, D. C., Morton, N. E., Lindsten, J., Hulten, M., and Yee, S. (1977) A mapping function for man. Hum. Hered. 27, 99–104.

    Article  CAS  PubMed  Google Scholar 

  43. Collins, A., Teague, J., Keats, B. J., and Morton, N. E. (1996) Linkage map integration. Genomics 36, 157–162.

    Article  CAS  PubMed  Google Scholar 

  44. Broman, K. W., Rowe, L. B., Churchill, G. A., and Paigen, K. (2002) Crossover interference in the mouse. Genetics 160, 1123–1131.

    PubMed  Google Scholar 

  45. Charlesworth, B., Borthwick, H., Bartolome, C., and Pignatelli, P. (2004) Estimates of the genomic mutation rate for detrimental alleles in Drosophila melanogaster. Genetics 167, 815–826.

    Article  CAS  PubMed  Google Scholar 

  46. Giannelli, F. and Green, P. M. (2000) The X chromosome and the rate of deleterious mutations in humans. Am. J. Hum. Genet. 67, 515–517.

    Article  CAS  PubMed  Google Scholar 

  47. Ozaki, K., Ohnishi, Y., Iida, A., et al. (2002) Functional SNPs in the lymphotoxinalpha gene that are associated with susceptibility to myocardial infarction. Nat. Genet. 32, 650–654.

    Article  CAS  PubMed  Google Scholar 

  48. Klein, R. J., Zeiss, C., Chew, E. Y., et al. (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308, 385–389.

    Article  CAS  PubMed  Google Scholar 

  49. McVean, G. A., Myers, S. R., Hunt, S., Deloukas, P., Bentley, D. R., and Donnelly, P. (2004) The fine-scale structure of recombination rate variation in the human genome. Science 304, 581–584.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Genetic Epidemiology and Bioinformatics Group, Human Genetics Division, Southampton General Hospital, Southampton, UK

    William Tapper

Authors
  1. William Tapper
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Genetic Epidemiology and Bioinformatics Group, Human Genetics Division Southampton General Hospital, Southampton, UK

    Andrew R. Collins

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Humana Press Inc.

About this protocol

Cite this protocol

Tapper, W. (2007). Linkage Disequilibrium Maps and Location Databases. In: Collins, A.R. (eds) Linkage Disequilibrium and Association Mapping. Methods in Molecular Biology™, vol 376. Humana Press. https://doi.org/10.1007/978-1-59745-389-9_3

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-389-9_3

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-669-6

  • Online ISBN: 978-1-59745-389-9

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation