The alternative distribution16 and LRT17 joint testing methods were proposed for analysis of single SNPs. In principle, they can be extended to gene-set or pathway analysis, but multiple issues arise in implementation. The distribution test statistic depends on the size of the genotype groups for each variant, so it is not clear what the best strategy is to combine the statistics across SNPs with different MAFs. The LRT method is sensitive to the normality assumption of the phenotype distribution and to small group size of the genotype distribution (Tables S1 and S2).