Functionally-informed fine-mapping and polygenic localization of complex trait heritability

Fine-mapping aims to identify causal variants impacting complex traits. We propose PolyFun, a computationally scalable framework to improve fine-mapping accuracy by leveraging functional annotations across the entire genome—not just genome-wide significant loci—to specify prior probabilities for fine-mapping methods such as SuSiE or FINEMAP. In simulations, PolyFun+SuSiE and PolyFun+FINEMAP were well-calibrated and identified >20% more variants with posterior causal probability >0.95 than their non-functionally informed counterparts. In analyses of 49 UK Biobank traits (average N=318K), PolyFun+SuSiE identified 3,025 fine-mapped variant-trait pairs with posterior causal probability >0.95, a >32% improvement vs. SuSiE. We used posterior mean per-SNP heritabilities from PolyFun+SuSiE to perform polygenic localization, constructing minimal sets of common SNPs causally explaining 50% of common SNP heritability; these sets ranged in size from 28 (hair color) to 3,400 (height) to 2 million (number of children). In conclusion, PolyFun prioritizes variants for functional follow-up and provides insights into complex trait architectures.