Advertisement

Family-Based Association Studies

  • Frank DudbridgeEmail author
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 713)

Abstract

Family-based association methods are useful because they offer improved matching of controls to cases, with the result that they are not susceptible to confounding by population stratification. They also allow analysis of parent-of-origin effects and maternal–fetal interactions. The transmission/disequilibrium test (TDT) is a test of linkage and association that is equivalent to a matched case/control analysis, from which various extensions are possible. A logistic regression formulation leads to modifications for multiallelic markers, haplotypes, and quantitative traits. Some pitfalls are described, for the situations in which one parent is missing, genotyping errors have occurred, and haplotype phase is uncertain. The problem of testing association in general pedigrees is discussed, with particular reference to sib pairs without parents.

Key words

TDT Matched case/control Population stratification Linkage Within-family test 

References

  1. 1.
    Spielman, R.S., McGinnis, R.E. and Ewens, W.J. (1993). Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 52, 506–516.PubMedGoogle Scholar
  2. 2.
    Ewens, W.J. and Spielman, R.S. (1995). The transmission/disequilibrium test: history, subdivision, and admixture. Am J Hum Genet 57, 455–464.PubMedCrossRefGoogle Scholar
  3. 3.
    Cordell, H.J., Barratt, B.J. and Clayton, D.G. (2004). Case/pseudocontrol analysis in genetic association studies: a unified framework for detection of genotype and haplotype associations, gene–gene and gene–environment interactions, and parent-of-origin effects. Genet Epidemiol 26, 167–185.PubMedCrossRefGoogle Scholar
  4. 4.
    Waldman, I.D., Robinson, B.F. and Rowe, D.C. (1999). A logistic regression based extension of the TDT for continuous and categorical traits. Ann Hum Genet 63, 329–340.PubMedCrossRefGoogle Scholar
  5. 5.
    Abecasis, G.R., Cardon, L.R. and Cookson, W.O. (2000). A general test of association for quantitative traits in nuclear families. Am J Hum Genet 66, 279–292.PubMedCrossRefGoogle Scholar
  6. 6.
    Curtis, D. and Sham P.C. (1995). A note on the application of the transmission disequilibrium test when a parent is missing. Am J Hum Genet 56, 811–812.PubMedGoogle Scholar
  7. 7.
    Lake, S.L., Blacker, D. and Laird, N.M. (2000). Family-based tests of association in the presence of linkage. Am J Hum Genet 67, 1515–1525.PubMedCrossRefGoogle Scholar
  8. 8.
    Dudbridge, F. (2008). Likelihood-based association analysis in nuclear families and unrelated subjects with missing genotype data. Hum Hered 66, 89–98.CrossRefGoogle Scholar
  9. 9.
    Mitchell, A.A., Cutler, D.J. and Chakravarti, A. (2003). Undetected genotyping errors cause apparent overtransmission of common alleles in the transmission/disequilibrium test. Am J Hum Genet 72, 598–610.PubMedCrossRefGoogle Scholar
  10. 10.
    Clayton, D. (1999). A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission. Am J Hum Genet 65, 1170–1177.PubMedCrossRefGoogle Scholar
  11. 11.
    Dudbridge, F., Koeleman, B.P., Todd, J.A. and Clayton, D.G. (2000). Unbiased application of the transmission/disequilibrium test to multilocus haplotypes. Am J Hum Genet 66, 2009–2012.PubMedCrossRefGoogle Scholar
  12. 12.
    Horvath, S., Xu, X., Lake, S.L., Silverman, E.K., Weiss, S.T. and Laird, N.M. (2004). Family-based tests for associating haplotypes with general phenotype data: application to asthma genetics. Genet Epidemiol 26, 61–69.PubMedCrossRefGoogle Scholar
  13. 13.
    Martin, E.R., Bass, M.P., Hauser, E.R. and Kaplan, N.L. (2003). Accounting for linkage in family-based tests of association with missing parental genotypes. Am J Hum Genet 73, 1016–1026.PubMedCrossRefGoogle Scholar
  14. 14.
    Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. et al. (2007). PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81, 559–575.PubMedCrossRefGoogle Scholar
  15. 15.
    Spielman, R.S. and Ewens, W.J. (1998). A sibship test for linkage in the presence of association: the sib transmission/disequilibrium test. Am J Hum Genet 62, 450–458.PubMedCrossRefGoogle Scholar
  16. 16.
    Laird, N.M. and Lange, C. (2006). Family-based designs in the age of large-scale gene-association studies. Nat Rev Genet 7, 385–394.PubMedCrossRefGoogle Scholar
  17. 17.
    Tiwari, H.K., Barnholtz-Sloan, J., Wineinger, N., Padilla, M.A., Vaughan, L.K. and Allison, D.B. (2008). Review and evaluation of methods correcting for population stratification with a focus on underlying statistical principles. Hum Hered 66, 67–86.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department Non-communicable Disease EpidemiologyLondon School of Hygiene and Tropical MedicineLondonUK

Personalised recommendations