Skip to main content

SAGE Programs

Model-Free Linkage Analysis for Complex Cardiovascular Phenotypes

  • Protocol
Cardiovascular Disease

Part of the book series: Methods in Molecular Medicine™ ((MIMM,volume 128))

Abstract

A complex disease trait refers to a phenotype that does not follow simple Mendelian segregation attributable to a single gene locus, but instead may be caused by multiple disease loci, their interactions, polygenic inheritance, and environmental effects. Most cardiovascular disorders are thought to have a polygenic basis with complex interactions with environmental factors. A gene that increases or decreases the risk to a complex cardiovascular disease (susceptibility gene) can now be mapped to a specific chromosomal region by model-free linkage analysis, and follow-up molecular genetic studies can identify the specific gene at the locus. This chapter describes a protocol for model-free linkage analysis of a complex trait, as implemented in the popular genetic analysis software—SAGE. In particular, the Haseman-Elston sib-pair regression method is introduced and implemented with examples to demonstrate how to identify susceptibility loci for complex traits.

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

Access this chapter

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
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. Morton, N. E. (1955) Sequential tests for the detection of linkage. Am. J. Hum. Genet. 7, 277–318.

    PubMed  CAS  Google Scholar 

  2. Wang, Q., Rao, S., and Topol, E. J. (2004) Reply to newton-cheh et al. Am. J. Hum. Genet. 75, 152–154.

    Article  Google Scholar 

  3. Farrer, L. A. and Cupples, L. A. (1998) 5. Determining the genetic component of a disease, in Approaches to Gene Mapping in Complex Human Diseases, (Haines, J. L. and Pericak-Vance, M. A. eds.), Wiley-Liss, New York, pp. 93–129.

    Google Scholar 

  4. Haseman, J. K. and Elston, R. C. (1972) The investigation of linkage between a quantitative trait and a marker locus. Behav. Genet. 2, 3–19.

    Article  PubMed  CAS  Google Scholar 

  5. Amos, C. I. and Elston, R. C. (1989) Robust methods for the detection of genetic linkage for quantitative data from pedigrees. Genet. Epidemiol. 6, 349–360.

    Article  PubMed  CAS  Google Scholar 

  6. Wright, F. A. (1997) The phenotypic difference discards sib-pair QTL linkage information. Am. J. Hum. Genet. 60, 740–742.

    PubMed  CAS  Google Scholar 

  7. Fulker, D. W. and Cherny, S. S. (1996) An improved multipoint sib-pair analysis of quantitative traits. Behav. Genet. 26, 527–532.

    Article  PubMed  CAS  Google Scholar 

  8. Amos, C. I., Krushkal, J., Thiel, T. J., et al. (1997) Comparison of model-free linkage mapping strategies for the study of a complex trait. Genet. Epidemiol. 14, 743–748.

    Article  PubMed  CAS  Google Scholar 

  9. Single, R. M. and Finch, S. J. (1995) Gain in efficiency from using generalized least squares in the Haseman-Elston test. Genet. Epidemiol. 12, 889–894.

    Article  PubMed  CAS  Google Scholar 

  10. Karunaratne, P. M. and Elston, R. C. (1998) A multivariate logistic model (MLM) for analyzing binary family data. Am. J. Med. Genet. 76, 428–437.

    Article  PubMed  CAS  Google Scholar 

  11. SAGE (2004) SAGE Version 5.0. User Reference Manual, Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH.

    Google Scholar 

  12. Bonney, G. E. (1986) Regressive logistic models for familial disease and other binary traits. Biometrics 42, 611–625.

    Article  PubMed  CAS  Google Scholar 

  13. Hanson, R. L., Elston, R. C., Pettitt, D. J., Bennett, P. H., and Knowler, W. C. (1995) Segregation analysis of non-insulin-dependent diabetes mellitus in Pima Indians: evidence for a major-gene effect. Am. J. Hum. Genet. 57, 160–170.

    PubMed  CAS  Google Scholar 

  14. Elston, R. C. (1981) Segregation analysis. Adv. Hum. Genet. 11, 63–120, 372–123.

    PubMed  CAS  Google Scholar 

  15. Olson, J. M. (1999) Relationship estimation by Markov-process models in a sibpair linkage study. Am. J. Hum. Genet. 64, 1464–1472.

    Article  PubMed  CAS  Google Scholar 

  16. Topol, E. J., McCarthy, J., Gabriel, S., et al. (2001) Single nucleotide polymorphisms in multiple novel thrombospondin genes may be associated with familial premature myocardial infarction. Circulation 104, 2641–2644.

    Article  PubMed  CAS  Google Scholar 

  17. Wang, Q., Rao, S., Shen, G. Q., et al. (2004) Premature myocardial infarction novel susceptibility locus on chromosome 1P34-36 identified by genomewide linkage analysis. Am. J. Hum. Genet. 74, 262–271.

    Article  PubMed  CAS  Google Scholar 

  18. Elston, R. C., Buxbaum, S., Jacobs, K. B., and Olson, J. M. (2000) Haseman and Elston revisited. Genet. Epidemiol. 19, 1–17.

    Article  PubMed  CAS  Google Scholar 

  19. Risch, N., Claus, E., and Giuffra, L. (1989) Linkage and mode of inheritance in complex traits. Prog. Clin. Biol. Res. 329, 183–188.

    PubMed  CAS  Google Scholar 

  20. Hodge, S. E. and Elston, R. C. (1994) Lods, wrods, and mods: the interpretation of lod scores calculated under different models. Genet. Epidemiol. 11, 329–342.

    Article  PubMed  CAS  Google Scholar 

  21. Lange, K. (1986) The affected sib-pair method using identity by state relations. Am. J. Hum. Genet. 39, 148–150.

    PubMed  CAS  Google Scholar 

  22. Kruglyak, L. and Lander, E. S. (1995) Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am. J. Hum. Genet. 57, 439–454.

    PubMed  CAS  Google Scholar 

  23. Sobel, E. and Lange, K. (1996) Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am. J. Hum. Genet. 58, 1323–1337.

    PubMed  CAS  Google Scholar 

  24. Olson, J. M. (1999) A general conditional-logistic model for affected-relative-pair linkage studies. Am. J. Hum. Genet. 65, 1760–1769.

    Article  PubMed  CAS  Google Scholar 

  25. Weeks, D. E. and Lange, K. (1988) The affected-pedigree-member method of linkage analysis. Am. J. Hum. Genet. 42, 315–326.

    PubMed  CAS  Google Scholar 

  26. Davis, S., Schroeder, M., Goldin, L. R., and Weeks, D. E. (1996) Nonparametric simulation-based statistics for detecting linkage in general pedigrees. Am. J. Hum. Genet. 58, 867–880.

    PubMed  CAS  Google Scholar 

  27. Kruglyak, L., Daly, M. J., Reeve-Daly, M. P., and Lander, E. S. (1996) Parametric and nonparametric linkage analysis: a unified multipoint approach. Am. J. Hum. Genet. 58, 1347–1363.

    PubMed  CAS  Google Scholar 

  28. Commenges, D. (1994) Robust genetic linkage analysis based on a score test of homogeneity: the weighted pairwise correlation statistic. Genet. Epidemiol. 11, 189–200.

    Article  PubMed  CAS  Google Scholar 

  29. Almasy, L. and Blangero, J. (1998) Multipoint quantitative-trait linkage analysis in general pedigrees. Am. J. Hum. Genet. 62, 1198–1211.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Humana Press Inc.

About this protocol

Cite this protocol

Rao, S., Wang, Q.K. (2006). SAGE Programs. In: Wang, Q.K. (eds) Cardiovascular Disease. Methods in Molecular Medicine™, vol 128. Humana Press. https://doi.org/10.1007/978-1-59745-159-8_6

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-159-8_6

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-572-9

  • Online ISBN: 978-1-59745-159-8

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics