Detecting Disease Associations due to Linkage Disequilibrium Using Haplotype Tags: A Class of Tests and the Determinants of Statistical Power

In the ‘indirect’ method of detecting genetic associations between a trait and a DNA variant, we type several markers in a gene or chromosome region of linkage disequilibrium. If there is association between markers and the trait, we presume the existence of one or more causal polymorphisms in the region. In order to obtain a sufficiently dense set of markers it will almost always be necessary to use single nucleotide polymorphisms (SNPs). Although there is an emerging literature on methods for choosing an optimal set of ‘haplotype tag SNPs’ (htSNPs) to detect association between a genetic region and a trait, less attention has been given to the problem of how such studies should be analysed when completed, and how the initial data which was used to select the htSNPs should be incorporated into the analysis. This paper discusses this problem for both population– and family-based association studies. The role of the R² measure of association between a causal locus and various methods of scoring of marker haplotypes is highlighted. In most cases, the simplest method of scoring (locus coding), which does not require phase resolution, is shown generally to be more powerful than scoring methods that include haplotype information. A new ‘multi-locus TDT’ is also proposed.