Integrated multi-omics profiling identifies genetic loci of African swine fever resistance in pigs

African swine fever (ASF) remains a persistent threat to global pig production, with no licensed vaccines or effective treatments available. Observations of surviving individuals within low-virulence infected herds suggest that host genetic resistance plays a crucial role. Here, we present a multi-dimensional integrative analysis to uncover host genomic variants associated with ASF resistance. Combining genome-wide association studies (GWAS), genetic differentiation, and functional genomic approaches, including TWAS, SMR, colocalization, and Bayesian network GWAS, we prioritized 135 high-priority candidate resistance genes from an initial gene set of 1,102 candidates. These prioritized genes are enriched in immune-related pathways, such as chemokine signaling and IL-15-mediated activation. Heritability enrichment and transcriptomic analyses further revealed tissue- and cell-type-specific expression patterns, particularly in peripheral immune organs and pulmonary alveolar macrophages. Dynamic infection-responsive genes, including CXCL10, CXCL11 and IL15, exhibited robust antiviral signatures, which highlighted Mac_CD163 as key cellular mediators in the immune response to ASF. Moreover, multiple genes (such as SOS1, FCGR2B, FCGR3) converged on the PI3K-AKT and Fcγ receptor signaling axes pathways, underscoring their functional importance. Finally, we developed a polygenic resistance score using 40 prioritized independent SNPs, which effectively discriminates phenotypic outcomes and showed a positive correlation with health traits such as platelet distribution width. These findings provided a genomic foundation for the precision breeding of ASF-resistant pigs and inform host-targeted disease control strategies.