Assume that J SNPs have been annotated to a gene or gene-set of interest. For each SNP j, the JLS-Fisher test statistic (e.g., WF,j) is first obtained and then the association evidence can be aggregated across the SNPs by considering, for example, the sum statistic,5 ∑jWF,j. To account for LD between SNPs, the overall association evidence can be evaluated by a phenotype-permutation approach where the empirical p value is the proportion of K permutation replicates with sum statistics more extreme than the observed value. Because this multivariate method analyzes all J SNPs simultaneously, the number of permutations need not be exceedingly large and K = 10,000 provides accurate estimates for p values in the range of 0.05. If multiple genes or gene-sets are of interest, more replicates would be required to adjust for the corresponding number of hypothesis tests.