A cross-ancestry genetic atlas of shared susceptibility between infectious diseases and cancer

Extensive epidemiological and mechanistic studies have established links between specific infections and cancer, but the inherited host-genetic contribution to broader infection-cancer relationships remains incompletely characterized. Here, we integrated genome-wide association study summary statistics for multiple infectious diseases and cancers from European- and East Asian-ancestry populations and evaluated shared host genetic architecture across genome-wide and local genetic sharing, tissue- and cell-type enrichment, cross-trait locus discovery, functional gene prioritization, proteome-level integration and exploratory bidirectional Mendelian randomization. In the European ancestry analyses, four complementary genome-wide approaches identified 11, 21, 44 and 11 significant infection-cancer trait pairs, respectively; 11 pairs were supported by at least three approaches, and sepsis-lung cancer, pneumonia-kidney cancer and sepsis-colorectal cancer were supported by all four. In the East Asian-ancestry analyses, tuberculosis-lung cancer showed the most prominent regional shared genetic architecture. Local analyses further showed that genetic overlap was not uniformly distributed across the genome, but was concentrated in specific regions with heterogeneous directions of effect. Tissue- and cell-type enrichment analyses indicated that shared signals were primarily concentrated in mucosal and epithelial barrier-related tissues and immune-cell compartments. Cross-trait analyses identified 396 potential pleiotropic independent risk loci, 14 colocalized variants, and 86 high-confidence pleiotropic genes, while proteome-level analysis identified 83 pleiotropic proteins, including MORF4L1, which was associated with five trait pairs. Exploratory Mendelian randomization provided directional genetic-liability evidence, with the strongest European-ancestry signal linking lung cancer liability to sepsis. Together, these findings support a shared host-genetic component underlying part of the relationship between infections and cancers, involving immune regulation, barrier homeostasis and cellular stress adaptation.