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Biostatistics 3:195-211 (2002)
© 2002 Oxford University Press

Multipoint linkage detection in the presence of heterogeneity

Yen-Feng Chiu, Kung-Yee Liang and Terri H. Beaty

Yen-Feng Chiu. Department of Biostatistics, School of Public Health, CB #7420, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7420, USA yfchiu{at}bios.unc.edu
Kung-Yee Liang. Department of Biostatistics, School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
Terri H. Beaty. Department of Epidemiology, School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA

Linkage heterogeneity is common for complex diseases. It is well known that loss of statistical power for detecting linkage will result if one assumes complete homogeneity in the presence of linkage heterogeneity. To this end, Smith (1963, Annals of Human Genetics 27, 175–182) proposed an admixture model to account for linkage heterogeneity. It is well known that for this model, the conventional chisquared approximation to the likelihood ratio test for no linkage does not apply even when the sample size is large. By dealing with nuclear families and one marker at a time for genetic diseases with simple modes of inheritance, score-based test statistics (Liang and Rathouz, 1999, Biometrics 55, 65–74) and likelihoodratio- based test statistics (Lemdani and Pons, 1995, Biometrics 51, 1033–1041) have been proposed which have a simple large-sample distibution under the null hypothesis of linkage. In this paper, we extend their work to more practical situations that include information from multiple markers and multi-generational pedigrees while allowing for a class of general genetic models. Three different approaches are proposed to eliminate the nuisance parameters in these test statistics. We show that all three approaches lead to the same asymptotic distribution under the null hypothesis of no linkage. Simulation results show that the proposed test statistics have adequate power to detect linkage and that the performances of these two classes of test statistics are quite comparable. We have applied the proposed method to a family study of asthma (Barnes et al., 1996), in which the score-based test shows evidence of linkage with p-value <0.0001 in the region of interest on chromosome 12. Additionally, we have implemented this score-based test within the frequently used computer package GENEHUNTER.

Keywords: Admixture model; Asymptotic; Genetic heterogeneity; Genetic linkage; Multipoint analysis


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