Incorporating Single-Locus Tests into Haplotype Cladistic Analysis in Case-Control Studies

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Abstract
In case-control studies, genetic associations for complex diseases may be probed either with single-locus tests or with haplotype-based tests. Although there are different views on the relative merits and preferences of the two test strategies, haplotype-based analyses are generally believed to be more powerful to detect genes with modest effects. However, a main drawback of haplotype-based association tests is the large number of distinct haplotypes, which increases the degrees of freedom for corresponding test statistics and thus reduces the statistical power. To decrease the degrees of freedom and enhance the efficiency and power of haplotype analysis, we propose an improved haplotype clustering method that is based on the haplotype cladistic analysis developed by Durrant et al. In our method, we attempt to combine the strengths of single-locus analysis and haplotype-based analysis into one single test framework. Novel in our method is that we develop a more informative haplotype similarity measurement by using p-values obtained from single-locus association tests to construct a measure of weight, which to some extent incorporates the information of disease outcomes. The weights are then used in computation of similarity measures to construct distance metrics between haplotype pairs in haplotype cladistic analysis. To assess our proposed new method, we performed simulation analyses to compare the relative performances of (1) conventional haplotype-based analysis using original haplotype, (2) single-locus allele-based analysis, (3) original haplotype cladistic analysis (CLADHC) by Durrant et al., and (4) our weighted haplotype cladistic analysis method, under different scenarios. Our weighted cladistic analysis method shows an increased statistical power and robustness, compared with the methods of haplotype cladistic analysis, single-locus test, and the traditional haplotype-based analyses. The real data analyses also show that our proposed method has practical significance in the human genetics field. Methods of haplotype-based analysis and single-locus analysis are widely used in genetic association studies. There is no consensus as to the best strategy for the performance of the two methods. Although haplotype-based analysis is a powerful tool, the large number of distinct haplotypes may reduce its efficiency. Haplotype clustering analysis is a promising way of decreasing haplotype dimensionality. A potential limitation of many existing clustering methods is that they do not allow the clustering to adapt to the position of the underlying trait locus. In this study, we proposed a weighted haplotype cladistic analysis method by incorporating a single-locus test into haplotype clustering. Under this framework, relationships between single loci and the disease outcomes can be considered when creating the hierarchical tree of haplotypes. The extensive simulations show that our method is robust against varied simulation conditions and is more powerful than either the original unweighted cladistic analysis method or single-locus analysis methods in case-control studies. Our hybrid method combining haplotype-based and single-locus analyses can be readily extended to whole genome association studies.