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. 2002 Feb;70(2):425-34.
doi: 10.1086/338688. Epub 2001 Dec 27.

Score tests for association between traits and haplotypes when linkage phase is ambiguous

Daniel J Schaid  1 , Charles M Rowland, David E Tines, Robert M Jacobson, Gregory A Poland
Affiliations

Score tests for association between traits and haplotypes when linkage phase is ambiguous

Daniel J Schaid et al. Am J Hum Genet. 2002 Feb.

Abstract

A key step toward the discovery of a gene related to a trait is the finding of an association between the trait and one or more haplotypes. Haplotype analyses can also provide critical information regarding the function of a gene; however, when unrelated subjects are sampled, haplotypes are often ambiguous because of unknown linkage phase of the measured sites along a chromosome. A popular method of accounting for this ambiguity in case-control studies uses a likelihood that depends on haplotype frequencies, so that the haplotype frequencies can be compared between the cases and controls; however, this traditional method is limited to a binary trait (case vs. control), and it does not provide a method of testing the statistical significance of specific haplotypes. To address these limitations, we developed new methods of testing the statistical association between haplotypes and a wide variety of traits, including binary, ordinal, and quantitative traits. Our methods allow adjustment for nongenetic covariates, which may be critical when analyzing genetically complex traits. Furthermore, our methods provide several different global tests for association, as well as haplotype-specific tests, which give a meaningful advantage in attempts to understand the roles of many different haplotypes. The statistics can be computed rapidly, making it feasible to evaluate the associations between many haplotypes and a trait. To illustrate the use of our new methods, they are applied to a study of the association of haplotypes (composed of genes from the human-leukocyte-antigen complex) with humoral immune response to measles vaccination. Limited simulations are also presented to demonstrate the validity of our methods, as well as to provide guidelines on how our methods could be used.

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Figures

Figure 1
Figure 1
Comparison of P values for haplotype-specific score statistics. P values were computed by the χ2 distribution (i.e., χ21) versus simulations, to test the association of HLA haplotypes with failure to demonstrate an immune response (binary trait [A]) or with a quantitative antibody level (quantitative trait [B]).
See this image and copyright information in PMC

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References

Electronic-Database Information

    1. Insightful, http://www.insightful.com/default_class5.asp (for the programming language S-PLUS)
    1. Statistical and Genetic Epidemiology, Health Sciences Research–Mayo Clinic, http://www.mayo.edu/statgen/ (for software that implements computation of score statistics)

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