We propose a weighted-sum method in which mutations are grouped according to function (e.g. gene), and each individual is scored by a weighted sum of the mutation counts. To test for an excess of mutations in affected individuals, we use permutation of disease status among affected and unaffected individuals. By using permutation, the method adjusts for the weighting of the mutations and the requirement that a mutation must be observed to be included in the study. Note that permutation of disease status results in correct type I error even in the presence of linkage disequilibrium (LD) [29],[30], although relatively low LD is expected between rare variants [26],[31],[32].
