Gains in power for exhaustive analyses of haplotypes using variable-sized sliding window strategy: a comparison of association-mapping strategies

Linkage disequilibrium (LD)-based association mapping is often performed by analyzing either individual SNPs or block-based multi-SNP haplotypes. Sliding windows of several fixed sizes (in terms of SNP numbers) were also applied to a few simulated or real data sets. In comparison, exhaustively testing based on variable-sized sliding windows (VSW) of all possible sizes of SNPs over a genomic region has the best chance to capture the optimum markers (single SNPs or haplotypes) that are most significantly associated with the traits under study. However, the cost is the increased number of multiple tests and computation. Here, a strategy of VSW of all possible sizes is proposed and its power is examined, in comparison with those using only haplotype blocks (BLK) or single SNP loci (SGL) tests. Critical values for statistical significance testing that account for multiple testing are simulated. We demonstrated that, over a wide range of parameters simulated, VSW increased power for the detection of disease variants by similar to 1-15% over the BLK and SGL approaches. The improved performance was more significant in regions with high recombination rates. In an empirical data set, VSW obtained the most significant signal and identified the LRP5 gene as strongly associated with osteoporosis. With the use of computational techniques such as parallel algorithms and clustering computing, it is feasible to apply VSW to large genomic regions or those regions preliminarily identified by traditional SGL/BLK methods. European Journal of Human Genetics (2009) 17, 785-792; doi: 10.1038/ejhg.2008.244; published online 17 December 2008