Inherited Susceptibility to Urinary Tract Infections from Kidney Papilla to Bladder.

Urinary tract infections (UTIs) are traditionally viewed as environmentally driven, yet their inherited susceptibility remains largely unexplored. We conducted a cross-biobank genome-wide association study of recurrent UTIs in 1,860,836 individuals (213,869 cases and 1,646,967 controls). We identified 36 genetic susceptibility loci and performed tissue-based multi-omic mapping to prioritize candidate causal genes. UTI risk alleles preferentially modulated epithelial gene expression in kidney and bladder, converging on urinary epithelia structure and function. PSCA, encoding a secreted epithelial surface protein, emerged as the strongest candidate under genetic control; the gene product is constitutively secreted into the urine from kidney papilla and bladder epithelia, binds uropathogenic E. coli, and inhibits bacterial growth in vitro. Our findings define the polygenic architecture of UTIs and highlight the critical role of uroepithelial surface defenses, providing a new framework for host-directed, non-antibiotic interventions.