UNLABELLED: It has been argued that the missing heritability in common diseases may be in part due to rare variants and gene-gene effects. Haplotype analyses provide more power for rare variants and joint analyses across genes can address multi-gene effects. Currently, methods are lacking to perform joint multi-locus association analyses across more than one gene/region. Here, we present a haplotype-mining gene-gene analysis method, which considers multi-locus data for two genes/regions simultaneously. This approach extends our single region haplotype-mining algorithm, hapConstructor, to two genes/regions. It allows construction of multi-locus SNP sets at both genes and tests joint gene-gene effects and interactions between single variants or haplotype combinations. A Monte Carlo framework is used to provide statistical significance assessment of the joint and interaction statistics, thus the method can also be used with related individuals. This tool provides a flexible data-mining approach to identifying gene-gene effects that otherwise is currently unavailable. AVAILABILITY: http://bioinformatics.med.utah.edu/Genie/hapConstructor.html.

SUMMARY: Haplotypes carry important information that can direct investigators towards underlying susceptibility variants, and hence multiple tagging single nucleotide polymorphisms (tSNPs) are usually studied in candidate gene association studies. However, it is often unknown which SNPs should be included in haplotype analyses, or which tests should be performed for maximum power. We have developed a program, hapConstructor, which automatically builds multi-locus SNP sets to test for association in a case-control framework. The multi-SNP sets considered need not be contiguous; they are built based on significance. An important feature is that the missing data imputation is carried out based on the full data, for maximal information and consistency. HapConstructor is implemented in a Monte Carlo framework and naturally extends to allow for significance testing and false discovery rates that account for the construction process and to related individuals. HapConstructor is a useful tool for exploring multi-locus associations in candidate genes and regions. AVAILABILITY: http://www-genepi.med.utah.edu/Genie.