PolyFun prioritizes variants in enriched functional annotations by specifying prior causal probabilities in proportion to predicted per-SNP heritabilities and providing them as input to fine-mapping methods such as SuSiE21or FINEMAP22,23. For each target locus, PolyFun robustly specifies prior causal probabilities for all SNPs on the corresponding odd (resp. even) target chromosome by (1) estimating functional enrichments for a broad set of coding, conserved, regulatory and LD-related annotations from the baseline-LF 2.2.UKB model25 (187 annotations; Methods, Supplementary Table 1) using an L2-regularized extension of S-LDSC17, restricted to even (resp. odd) chromosomes; (2) estimating per-SNP heritabilities for SNPs on odd (resp. even) chromosomes using the functional enrichment estimates from step 1; (3) partitioning all SNPs into 20 bins of similar estimated per-SNP heritabilities from step 2; (4) re-estimating per-SNP heritabilities for all SNPs on the target chromosome by applying S-LDSC to the 20 bins, restricted to odd (resp. even) chromosomes excluding the target chromosome; and (5) setting prior causal probabilities for SNPs on the target chromosome proportional to per-SNP heritabilities from step 4. The L2 regularization in step 1 improves the accuracy
