Mapping Genetic Susceptibility to Urinary Tract Infection from Kidney Papilla to Bladder

Urinary tract infections (UTIs) are among the most common bacterial infections, yet the genetic factors influencing susceptibility remain poorly understood. We performed a genome-wide association study of recurrent UTI involving 1,860,836 individuals (213,869 cases and 1,646,967 controls). We identified 36 independent non-HLA genome-wide significant loci encoding kidney epithelial and immune response genes and demonstrated that some loci have sex-specific effects. Integrative functional annotation, expression and protein quantitative trait locus colocalization, and single-cell multi-omic analyses revealed that UTI risk alleles preferentially modulated gene expression in kidney, ureter, and bladder epithelia. Multi-omic prioritization converged on a number of pathogenic pathways: epithelial barrier and mucosal glycocalyx defense (PSCA, UMOD, CLPTM1L, FUT2), innate immune regulation (FES, PTPRC, NEK7, HOTAIR, NFATC1, BTN3A2), infection resolution and regulated cell death (STK3, CASP7, TAX1BP1, ZFP36L2), epithelial identity maintenance (GLIS2, CLDN10, ZFHX3, SPDEF, MPP7), urinary tract development (FGFR2, BMP7, HGF, MET, HOXA9, TSHZ2, WNT7B/LINC00899), and nutritional immunity through iron sequestration (SLC11A2, FAM210B, RPS10). Approximately one-third of loci colocalized with gene expression in kidney tubules, suggesting direct modulation of epithelial host-defense programs. Among all loci, PSCA, which encodes a GPI-anchored epithelial surface protein expressed in the kidney papilla and urinary tract epithelia, emerged as the strongest candidate causal gene. We demonstrated that PSCA was secreted into urine, bound uropathogenic E. coli, and inhibited bacterial growth in vitro, implicating it as a constitutive epithelial defense factor. We also demonstrated that while PSCA was protective against urinary infections and duodenal ulcers, it was associated with increased risk of bladder, prostate, and gastric cancers, suggesting antagonistic pleiotropy between mucosal defenses and oncogenesis. Together, our findings define the polygenic architecture of UTI susceptibility, highlighting epithelial surface defense, innate immune regulation, developmental patterning, and nutritional immunity as central components of host defense, providing a new framework for host-directed, non-antibiotic interventions.