We developed Genomic Annotation Shifter (GoShifter), an enrichment test that controls for local genomic structure. GoShifter employs an intuitive method that locally shifts sites of tested features within each locus to generate a null distribution of annotations overlapping associated variants by chance. Other methods, such as Genome Structure Correction (GSC), assess the relationships between genomic features by shifting them.1,18–20 Although GSC can assess the significance of overlap between two genomic features, it does not provide a clear application to individual GWAS loci and their local LD structure. Here, we apply the shifting approach to identify informative annotations for fine mapping GWAS loci. We benchmark the performance of GoShifter against that of commonly employed matching-based methods. These methods rely on inferring the enrichment of the SNP-annotation overlap in the observed data by contrasting it with the overlap in the null set of SNPs derived by random sampling of variants from the genome. In order to control for plausible genomic confounders, these methods sample SNPs by matching for a selection of defined genomic parameters. The selection of these parameters is based on the assumptions about possible analytical confounders. In contrast, GoShifter does not require prior knowledge because the null distribution is derived within the tested loci, ensuring that the density of SNPs, annotations, and the spatial distribution of genomic features are preserved.