Skip to main content
SpringerLink
Log in

Linkage Disequilibrium Mapping for Complex Disease Genes

  • Protocol
Linkage Disequilibrium and Association Mapping

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

Abstract

In this chapter we lay out some background information about gene mapping for human complex traits. The chapter covers issues such as study design, high-throughput genotyping technologies, statistical analysis, and others. Many of the materials are based on and related to our recent experiences in case-control-association studies.

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

Access this chapter

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

Institutional subscriptions

References

  1. Cardon, L. R. and Bell, J. I. (2001) Association study designs for complex diseases. Nat. Rev. Genet. 2, 91–99.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Ioannidis, J. P., Ntzani, E. E., Trikalinos, T. A., and Contopoulos-Ioannidis, D. G. (2001) Replication validity of genetic association studies. Nat. Genet. 29, 306–309.

    Article  CAS  PubMed  Google Scholar 

  4. Risch, N. and Zhang, H. (1995) Extreme discordant sib pairs for mapping quantitative trait loci in humans. Science 268, 1584–1589.

    Article  CAS  PubMed  Google Scholar 

  5. 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 

  6. Botstein, D. and Risch, N. (2003) Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat. Genet. 33, 228–237.

    Article  CAS  PubMed  Google Scholar 

  7. Kruglyak, L. and Nickerson, D. A. (2001) Variation is the spice of life. Nat. Genet. 27, 234–236.

    Article  CAS  PubMed  Google Scholar 

  8. Hoh, J. and Ott, J. (2003) Mathematical multi-locus approaches to localizing complex human trait genes. Nat. Rev. Genet. 4, 701–709.

    Article  CAS  PubMed  Google Scholar 

  9. Cordell, H. J. and Clayton, D. G. (2005) Genetic association studies. Lancet 366, 1121–1131.

    Article  PubMed  Google Scholar 

  10. Palmer, L. J. and Cardon, L. R. (2005) Shaking the tree: mapping complex disease genes with linkage disequilibrium. Lancet 366, 1223–1234.

    Article  CAS  PubMed  Google Scholar 

  11. Romualdi, C., Balding, D., and Nasidze, E. S., et al. (2002) Patterns of human diversity, within and among continents, inferred from biallelic DNA polymorphisms. Genome Res. 12, 602–612.

    Article  CAS  PubMed  Google Scholar 

  12. Hinds, D. A., Stuve, L. L., Nilsen, G. B., et al. (2005) Whole-genome patterns of common DNA variation in three human populations. Science 307, 1072–1079.

    Article  CAS  PubMed  Google Scholar 

  13. Lewontin, R. (1972) The apportionment of human diversity. In: Evolutionary Biology, (Dobzhansky, T., Hecht, M., and Steere, W., eds.), Appleton-Century-Crofts, New York, NY, pp. 381–398.

    Google Scholar 

  14. Cooper, R.S., Kaufman, J. S., and Ward, R. (2003) Race and genomics. N. Engl. J. Med. 348, 1166–1170.

    Article  PubMed  Google Scholar 

  15. Haga, S. B. and Venter, J. C. (2003) Genetics. FDA races in wrong direction. Science 301, 466.

    Article  CAS  PubMed  Google Scholar 

  16. Wilson, J. F., Weale, M. E., Smith, A. C., et al. (2001) Population genetic structure of variable drug response. Nat. Genet. 29, 265–269.

    Article  CAS  PubMed  Google Scholar 

  17. Risch, N., Burchard, E., Ziv, E., and Tang, H. (2002) Categorization of humans in biomedical research: genes, race and disease. Genome Biol. 3, comment 2007.

    Google Scholar 

  18. Burchard, E. G., Ziv, E., Coyle, N., et al. (2003) The importance of race and ethnic background in biomedical research and clinical practice. N. Engl. J. Med. 348, 1170–1175.

    Article  PubMed  Google Scholar 

  19. Stephens, J. C., Schneider, J. A., Tanguay, D. A., et al. (2001) Haplotype variation and linkage disequilibrium in 313 human genes. Science 293, 489–493.

    Article  CAS  PubMed  Google Scholar 

  20. Rosenberg, N. A., Pritchard, J. K., Weber, J., et al. (2002) Genetic structure of human populations. Science 298, 2381–2385.

    Article  CAS  PubMed  Google Scholar 

  21. Tang, H., Quertermous, T., Rodriguez, B., et al. (2005) Genetic structure, self-identified race/ethnicity, and confounding in case-control association studies. Am. J. Hum. Genet. 76, 268–275.

    Article  CAS  PubMed  Google Scholar 

  22. Helgason, A., Yngvadottir, B., Hrafnkelsson, B., Gulcher, J., and Stefansson, K. (2005) An Icelandic example of the impact of population structure on association studies. Nat. Genet. 37, 90–95.

    CAS  PubMed  Google Scholar 

  23. Bersaglieri, T., Saberti, P. C., Patterson, N., et al. (2004) Genetic signatures of strong recent positive selection at the lactase gene. Am. J. Hum. Genet. 74, 1111–1120.

    Article  CAS  PubMed  Google Scholar 

  24. Campbell, C. D., Ogburn, E. L., Lunetta, K. L., et al. (2005) Demonstrating stratification in a European American population. Nat. Genet. 37, 868–872.

    Article  CAS  PubMed  Google Scholar 

  25. International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437, 1299–1320.

    Article  Google Scholar 

  26. Ingman, M., Kaessmann, H., Paabo, S., and Gyllensten, U. (2000) Mitochondrial genome variation and the origin of modern humans. Nature 408, 708–713.

    Article  CAS  PubMed  Google Scholar 

  27. Herrnstadt, C., Elson, J. L., Fahy, E., et al. (2002) Reduced-median-network analysis of complete mitochondrial DNA coding-region sequences for the major African, Asian, and European haplogroups. Am. J. Hum. Genet. 70, 1152–1171.

    Article  CAS  PubMed  Google Scholar 

  28. Taylor, R. W. and Turnbull, D. M. (2005) Mitochondrial DNA mutations in human disease. Nat. Rev. Genet. 6, 389–402.

    Article  CAS  PubMed  Google Scholar 

  29. Matsuzaki, H., Dong, S., Loi, H., et al. (2004) Genotyping over 100,000 SNPs on a pair of oligonucleotide arrays. Nat. Methods 1, 109–111.

    Article  CAS  PubMed  Google Scholar 

  30. Matsuzaki, H., Loi, H., Dong, S., et al. (2004) Parallel genotyping of over 10,000 SNPs using a one-primer assay on a high-density oligonucleotide array. Genome Res. 14, 414–425.

    Article  CAS  PubMed  Google Scholar 

  31. Gunderson, K. L., Steemers, F. J., Lee, G., Mendoza, L. G., and Chee, M. S. (2005) A genome-wide scalable SNP genotyping assay using microarray technology. Nat. Genet. 37, 549–554.

    Article  CAS  PubMed  Google Scholar 

  32. Steemers, F. J., Chang, W., Lee, G., Barker, D. L., Shen, R., and Gunderson, K. L. (2006) Whole-genome genotyping with the single-base extension assay. Nat. Methods 3, 31–33.

    Article  CAS  PubMed  Google Scholar 

  33. Deloukas, P., Earthrowl, M. E., Grafham, D. V., et al. (2004) The DNA sequence and comparative analysis of human chromosome 10. Nature 429, 375–381.

    Article  CAS  PubMed  Google Scholar 

  34. Klein, R. S. (Unpublished).

    Google Scholar 

  35. Rice, J. (1995) Mathematical Statistics and Data Analysis. 2nd ed., Duxbury Press, Belmont, CA.

    Google Scholar 

  36. McIntyre, L. M., Martin, E. R., Simonsen, K. L., and Kaplan, N. L. (2000) Circumventing multiple testing: a multilocus Monte Carlo approach to testing for association. Genet. Epidemiol. 19, 18–29.

    Article  CAS  PubMed  Google Scholar 

  37. Benjamini, Y. and Hochberg, Y. (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Statist. Soc. B. 57, 289–300.

    Google Scholar 

  38. Devlin, B., Roeder, K., and Wasserman, L. (2003) Analysis of multilocus models of association. Genet. Epidemiol. 25, 36–47.

    Article  CAS  PubMed  Google Scholar 

  39. Westfall, P. and Young, S. (1989) pValue adjustments for multiple tests in multivariate binomial models. J. Am. Stat. Assoc. 84, 780–786.

    Article  Google Scholar 

  40. 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 

  41. Lin, S., Chakravarti, A., and Cutler, D. J. (2004) Exhaustive allelic transmission disequilibrium tests as a new approach to genome-wide association studies. Nat. Genet. 36, 1181–1188.

    Article  CAS  PubMed  Google Scholar 

  42. 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 

  43. Stephens, M. and Donnelly, P. (2003) A comparison of bayesian methods for haplotype reconstruction from population genotype data. Am. J. Hum. Genet. 73, 1162–1169.

    Article  CAS  PubMed  Google Scholar 

  44. Stephens, M., Smith, N. J., and Donnelly, P. (2001) A new statistical method for haplotype reconstruction from population data. Am. J. Hum. Genet. 68, 978–989.

    Article  CAS  PubMed  Google Scholar 

  45. Marchini, J., Cutler, D., Patterson, N., et al. (2006) A comparison of phasing algorithms for trios and unrelated individuals. Am. J. Hum. Genet. 78, 437–450.

    Article  CAS  PubMed  Google Scholar 

  46. Templeton, A. R., Boerwinkle, E., and Sing, C. F. (1987) A cladistic analysis of phenotypic associations with haplotypes inferred from restriction endonuclease mapping. I. Basic theory and an analysis of alcohol dehydrogenase activity in Drosophila. Genetics 117, 343–351.

    CAS  PubMed  Google Scholar 

  47. Culverhouse, R., Suarez, B. K., Lin, J., and Reich, T. (2002) A perspective on epistasis: limits of models displaying no main effect. Am. J. Hum. Genet. 70, 461–471.

    Article  PubMed  Google Scholar 

  48. Ritchie, M. D., Hahn, L. W., Roodi, N., et al. (2001) Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am. J. Hum. Genet. 69, 138–147.

    Article  CAS  PubMed  Google Scholar 

  49. Cockerham, C. C. (1954) An extension of the concept of partitioning hereditary variance for analysis of covariates among relatives when epistasis is present. Genetics 39, 859–882.

    CAS  PubMed  Google Scholar 

  50. Cordell, H. J. (2002) Epistasis: what it means, what it doesn’t mean, and statistical methods to detect it in humans. Hum. Mol. Genet. 11, 2463–2468.

    Article  CAS  PubMed  Google Scholar 

  51. North, B. V., Curtis, D., and Sham, P. C. (2005) Application of logistic regression to case-control association studies involving two causative loci. Hum. Hered. 59, 79–87.

    Article  PubMed  Google Scholar 

  52. Glass, B. and Li, C. C. (1953) The dynamics of racial intermixture; an analysis based on the American Negro. Am. J. Hum. Genet. 5, 1–20.

    CAS  PubMed  Google Scholar 

  53. Marchini, J., Cardon, L. R., Phillips, M. S., and Donnelly, P. (2004) The effects of human population structure on large genetic association studies. Nat. Genet. 36, 512–517.

    Article  CAS  PubMed  Google Scholar 

  54. Long, J. C. (1991) The genetic structure of admixed populations. Genetics 127, 417–428.

    CAS  PubMed  Google Scholar 

  55. Long, J. C., Williams, R. C., and Urbanek, M. (1995) An E-M algorithm and testing strategy for multiple-locus haplotypes. Am. J. Hum. Genet. 56, 799–810.

    CAS  PubMed  Google Scholar 

  56. Smith, M. W., Patterson, N., Lautenberger, J. A., et al. (2004) A high-density admixture map for disease gene discovery in african americans. Am. J. Hum. Genet. 74, 1001–1013.

    Article  CAS  PubMed  Google Scholar 

  57. Patterson, N., Hattangadi, N., Lane, B., et al. (2004) Methods for high-density admixture mapping of disease genes. Am. J. Hum. Genet. 74, 979–1000.

    Article  CAS  PubMed  Google Scholar 

  58. Hoggart, C. J., Parra, E. J., Shriver, M. D., et al. (2003) Control of confounding of genetic associations in stratified populations. Am. J. Hum. Genet. 72, 1492–1504.

    Article  CAS  PubMed  Google Scholar 

  59. Stewart, C. A., Horton, R., Allcock, R. J., et al. (2004) Complete MHC haplotype sequencing for common disease gene mapping. Genome Res. 14, 1176–1187.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT

    Andrew DeWan & Josephine Hoh

  2. Laboratory of Statistical Genetics, Rockefeller University, New York, NY

    Robert J. Klein

Authors
  1. Andrew DeWan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert J. Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Josephine Hoh
    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

DeWan, A., Klein, R.J., Hoh, J. (2007). Linkage Disequilibrium Mapping for Complex Disease Genes. 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_7

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-389-9_7

  • 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