Abstract
Fine-mapping refines genotype-phenotype association signals to identify causal variants underlying complex traits. However, current methods typically focus on individual genomic loci and do not account for the global genetic architecture. Here, we demonstrate the advantages of performing genome-wide fine-mapping (GWFM) with functional annotations and develop methods to facilitate GWFM. In simulations and real data analyses, GWFM outperforms current methods across multiple metrics, including error control, mapping power, resolution, precision, replication rate, and trans-ancestry phenotype prediction. Across 48 complex traits, we identify credible sets that collectively explain 18% of the SNP-based heritability ( hSNP2 ) on average, with 30% credible sets located outside genome-wide significant loci. Leveraging the genetic architecture estimated from GWFM, we predict that fine-mapping over 50% of hSNP2 would require an average of 2 million samples. Finally, as proof-of-principle, we highlight a known causal variant at FTO for body mass index and identify novel missense causal variants for schizophrenia and Crohn's disease.