Genome association studies of complex diseases by case-control designs

One way to perform linkage-disequilibrium (LD) mapping of genetic traits is to use single markers. Since dense marker maps-such as single- nucleotide polymorphism and high-resolution microsatellite maps-are available, it is natural and practical to generalize single- marker LD mapping to high-resolution haplotype or multiple-marker LD mapping. This article investigates high-resolution LD-mapping methods, for complex diseases, based on haplotype maps or microsatellite marker maps. The objective is to explore test statistics that combine information from haplotype blocks or multiple markers. Based on two coding methods, genotype coding and haplotype coding, Hotelling's T-2 statistics T-G and T-H are proposed to test the association between a disease locus and two haplotype blocks or two markers. The validity of the two T-2 statistics is proved by theoretical calculations. A statistic T-C, an extension of the traditional method of comparing haplotype frequencies, is introduced by simply adding the chi(2) test statistics of the two haplotype blocks together. The merit of the three methods is explored by calculation and comparison of power and of type I errors. In the presence of LD between the two blocks, the type I error of T-C is higher than that of T-H and T-G, since T-C ignores the correlation between the two blocks. For each of the three statistics, the power of using two haplotype blocks is higher than that of using only one haplotype block. By power comparison, we notice that T-C has higher power than that of T-H, and T-H has higher power than that of T-G. In the absence of LD between the two blocks, the power of is similar to that of T-H and higher than that of T-G. Hence, we advocate use of T-H in the data analysis. In the presence of LD between the two blocks, takes into account the correlation between the two haplotype blocks and has a lower type I error and higher power than T-G. Besides, the feasibility of the methods is shown by sample-size calculation.