Protocol for constructing multi-ancestry polygenic models using S4-Multi

Here, we present a protocol to construct multi-ancestry polygenic models using S4-Multi and generate polygenic risk scores. We describe steps for preparing reference genotype files, formatting genome-wide association stud (GWAS) summary statistics, and selecting SNPs using S4_select. We then perform Bayesian shrinkage with S4_shrink and describe procedures for polygenic score generation and performance evaluation. This workflow supports single- and multi-ancestry analyses and uses linkage disequilibrium information to improve prediction accuracy. For complete details on the use and execution of this protocol, please refer to Baierl et al.¹.