We validated the motivation for performing functionally-informed fine-mapping by verifying that fine-mapped SNPs are enriched for functional annotations, as previously shown for autoimmune diseases7,8,10 and blood traits12 (using non-functionally-informed SuSiE to avoid biasing the results). For each of 50 main binary annotations from the baseline-LF model24, for various PIP ranges, we computed the functional enrichment of fine-mapped common SNPs in the PIP range, defined as the proportion of common SNPs in the PIP range lying in the annotation divided by the proportion of genome-wide common SNPs lying in the annotation, and meta-analyzed the results across genetically uncorrelated traits (Methods, Figure 4, Supplementary Table 17). PIP>0.95 SNPs were strongly and significantly enriched for non-synonymous SNPs (51x enrichment, P=6.8×10−185) and SNPs in conserved regions (16x enrichment, P<10−300), significantly enriched for SNPs in various regulatory annotations (e.g. promoter-ExAC and H3K4me3), and significantly depleted for SNPs in repressed regions, consistent with previous literature on functional enrichment of fine-mapped SNPs7,8,10–12 and disease heritability17,24,25,33. We observed qualitatively similar but weaker enrichments at lower PIP ranges (Figure 4, Supplementary Table 17).
