Objective: The potential value of haplotypes has attracted widespread interest in the mapping of complex traits. Haplotype sharing methods take the linkage disequilibrium information between multiple markers into account, and may have good power to detect predisposing genes. We present a new approach based on Mantel statistics for spacetime clustering, which is developed in order to improve the power of haplotype sharing analysis for gene mapping in complex disease. Methods: The new statistic correlates genetic similarity and phenotypic similarity across pairs of haplotypes for case-only and case-control studies. The genetic similarity is measured as the shared length between haplotypes around a putative disease locus. The phenotypic similarity is measured as the mean-corrected cross-product based on the respective phenotypes. We analyzed two tests for statistical significance with respect to type I error: (1) assuming asymptotic normality, and (2) using a Monte Carlo permutation procedure. The results were compared to the χ2 test for association based on 3-marker haplotypes. Results: The results of the type I error rates for the Mantel statistics using the permutational procedure yielded pointwise valid tests. The approach based on the assumption of asymptotic normality was seriously liberal. Conclusion: Power comparisons showed that the Mantel statistics were better than or equal to the χ2 test for all simulated disease models.

Keywords:
Haplotype sharing, Mantel statistics, Case-control studies, Genetic association studies, Complex disease
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© 2005 S. Karger AG, Basel
2005
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