Testing Association of Statistically Inferred Haplotypes with Discrete and Continuous Traits in Samples of Unrelated IndividualsZaykin D.V. · Westfall P.H. · Young S.S. · Karnoub M.A. · Wagner M.J. · Ehm M.G.
GlaxoSmithKline Inc.,aDiscovery Genetics and bResearch Statistics Unit, Research Triangle Park, N.C. and cTexas Tech University, Lubbock, Tex., USA
There have been increasing efforts to relate drug efficacy and disease predisposition with genetic polymorphisms. We present statistical tests for association of haplotype frequencies with discrete and continuous traits in samples of unrelated individuals. Haplotype frequencies are estimated through the expectation-maximization algorithm, and each individual in the sample is expanded into all possible haplotype configurations with corresponding probabilities, conditional on their genotype. A regression-based approach is then used to relate inferred haplotype probabilities to the response. The relationship of this technique to commonly used approaches developed for case-control data is discussed. We confirm the proper size of the test under H0 and find an increase in power under the alternative by comparing test results using inferred haplotypes with single-marker tests using simulated data. More importantly, analysis of real data comprised of a dense map of single nucleotide polymorphisms spaced along a 12-cM chromosomal region allows us to confirm the utility of the haplotype approach as well as the validity and usefulness of the proposed statistical technique. The method appears to be successful in relating data from multiple, correlated markers to response.
Dmitri V. Zaykin
GlaxoSmithKline Inc., Department of Population Genetics
Five Moore Drive, PO Box 13398
Research Triangle Park, NC 27709 (USA)
Tel. +1 919 483 9391, Fax +1 919 315 4170, E-Mail firstname.lastname@example.org
Received: Received: September 24, 2001
Revision received: January 11, 2002
Accepted: January 23, 2002
Number of Print Pages : 13
Number of Figures : 6, Number of Tables : 4, Number of References : 41
Human Heredity (International Journal of Human and Medical Genetics)
Founded 1950 as Acta Genetica et Statistica Medica by Gunnar Dahlberg; Continued by M. Hauge (1965–1983)
Vol. 53, No. 2, Year 2002 (Cover Date: Released May 2002)
Journal Editor: J. Ott, New York, N.Y.
ISSN: 0001–5652 (print), 1423–0062 (Online)
For additional information: http://www.karger.ch/journals/hhe