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We develop a method, SBayesRC, that integrates genome-wide association study (GWAS) summary statistics with functional genomic annotations to improve polygenic prediction of complex traits. Our method is scalable to whole-genome variant analysis and refines signals from functional annotations by allowing them to affect both causal variant probability and causal effect distribution. We analyze 50 complex traits and diseases using ∼7 million common single-nucleotide polymorphisms (SNPs) and 96 annotations. SBayesRC improves prediction accuracy by 14% in European ancestry and up to 34% in cross-ancestry prediction compared to the baseline method SBayesR, which does not use annotations, and outperforms other methods, including LDpred2, LDpred-funct, MegaPRS, PolyPred-S and PRS-CSx. Investigation of factors affecting prediction accuracy identifies a significant interaction between SNP …