In this study, we focus on a scenario in which a group of multiple rare mutations has been identified. In functional regions, one may choose to include only probable disease susceptibility mutations (non-synonymous substitutions, frame shift mutations, etc) in the group of mutations. Using only probable disease susceptibility mutations has the benefit that random variation due to non-associated variants may decrease. In this manner, association studies of groups of rare probable disease-susceptibility variants may be able to identify genetically heterogeneous mutations, and hence complement genome-wide analysis of common SNPs. Grouping of mutations according to functional elements, such as genes, has the added advantage of focusing on causal relations between genes and diseases, rather than just identifying highly associated genomic regions. Furthermore, since many (millions of) mutations are expected to be identified in a resequencing study of thousands of individuals [28], grouping lowers the burden of multiple testing.
