Although our polygenic approach has enabled a powerful analysis of genome-wide summary statistics, it has several limitations. First, for the method to have reasonable power, the dataset analyzed must have a very large sample size and/or large SNP-heritability, and the trait analyzed must be polygenic (Figure 1). Second, the method requires an LD reference panel matched to the population studied to give accurate results; all results here are from European datasets and use 1000G Europeans as a reference panel (see Online Methods and Supplementary Figure 4). Third, our method is currently not applicable to studies using custom genotyping arrays (e.g., Metabochip; see Supplementary Note). Fourth, our method is based on an additive model and does not consider the contribution of epistatic or other non-additive effects, nor does it model causal contributions of SNPs not in the reference panel; in particular, it is possible that patterns of enrichment at extremely rare variants may be different from those inferred using this method (see Online Methods). Fifth, the method is limited by available functional data: if a trait is enriched in a cell
