Sister haplotypes and recombination disequilibrium: a new approach to identify associations of haplotypes with complex diseases.

Haplotype-based association analysis has several advantages over single-SNP association analysis. However, to date all haplotype-disease associations have not excluded recombination interference among multiple loci and hence some results might be confounded by recombination interference. Association of sister haplotypes with a complex disease, based on recombination disequilibrium (RD) was presented. Sister haplotypes can be determined by translating notation of DNA base haplotypes to notation of genetic genotypes. Sister haplotypes provide haplotype pairs available for haplotype-disease association analysis. After performing RD tests in control and case cohorts, a two-by-two contingency table can be constructed using sister haplotype pair and case-control pair. With this standard two-by-two table, one can perform classical Chi-square test to find statistical haplotype-disease association. Applying this method to a haplotype dataset of Alzheimer disease (AD), association of sister haplotypes containing ApoE3/4 with risk for AD was identified under no RD. Haplotypes within gene IL-13 were not associated with risk for breast cancer in the case of no RD and no association of haplotypes in gene IL-17A with risk for coronary artery disease were detected without RD. The previously reported associations of haplotypes within these genes with risk for these diseases might be due to strong RD and/or inappropriate haplotype pairs.