Sequential haplotype scan methods for association analysis

Multi-locus association analyses, including haplotype-based analyses, can sometimes provide greater power than single-locus analyses for detecting disease susceptibility loci. This potential gain, however, can be compromised by the large number of degrees of freedom caused by irrelevant markers. Exhaustive search for the optimal set of markers might be possible for a small number of markers, yet it is computationally inefficient. In this paper, we present a sequential haplotype scan method to search for combinations of adjacent markers that are jointly associated with disease status. When evaluating each marker, we add markers close to it in a sequential manner: a marker is added if its contribution to the haplotype association with disease is warranted, conditional on current haplotypes. This conditional evaluation is based on the well-known Mantel-Haenszel statistic. We propose two permutation based methods to evaluate the growing haplotypes: a haplotype method for the combined markers, and a summary method that sums conditional statistics. We compared our proposed methods, the single-locus method, and a sliding window method using simulated data. We also applied our sequential haplotype scan algorithm to experimental data for CYP2D6. The results indicate that the sequential scan procedure can identify a set of adjacent markers whose haplotypes might have strong genetic effects or be in linkage disequilibrium with disease predisposing variants. As a result, our methods can achieve greater power than the single-locus method, yet is much more computationally efficient than sliding window methods.