Powerful testing via hierarchical linkage disequilibrium in haplotype association studies

Marginal tests based on individual SNPs are routinely used in genetic association studies. Studies have shown that haplotype-based methods may provide more power in disease mapping than methods based on single markers when, for example, multiple disease-susceptibility variants occur within the same gene. A limitation of haplotype-based methods is that the number of parameters increases exponentially with the number of SNPs, inducing a commensurate increase in the degrees of freedom and weakening the power to detect associations. To address this limitation, we introduce a hierarchical linkage disequilibrium model for disease mapping, based on a reparametrization of the multinomial haplotype distribution, where every parameter corresponds to the cumulant of each possible subset of a set of loci. This hierarchy present in the parameters enables us to employ flexible testing strategies over a range of parameter sets: from standard single SNP analyses through the full haplotype distribution tests, reducing degrees of freedom and increasing the power to detect associations. We show via extensive simulations that our approach maintains the type I error at nominal level and has increased power under many realistic scenarios, as compared to single SNP and standard haplotype-based studies. To evaluate the performance of our proposed methodology in real data, we analyze genome-wide data from the Wellcome Trust Case-Control Consortium.