Urolithiasis is a complex disease influenced by genetic and metabolic factors. Although genome-wide association studies (GWAS) have identified susceptibility loci, the causal genes and mechanisms remain unclear. This study aimed to identify genes whose genetically regulated expression contributes to urolithiasis risk and clarify their potential biological roles. We integrated two independent European-ancestry GWAS datasets with multi-tissue expression quantitative trait loci (eQTL) data from genotype-tissue expression project (GTEx) V8. Cross-tissue and single-tissue transcriptome-wide association studies, conditional and joint analyses, gene-level association, and fine-mapping were applied to prioritize candidate genes. Mendelian randomization and Bayesian colocalization were used to assess causality and shared genetic signals. Functional networks were explored using GeneMANIA. Multi-layer analyses identified GCAT and UGT8 as independent causal genes. MR analyses confirmed significant causal effects, supported by colocalization (PPH4 > 0.80). GCAT regulates glycine metabolism and oxalate production, linking systemic metabolic status to urinary microenvironment, whereas UGT8 modulates glucuronidation in fibroblasts, influencing local metabolic conditions relevant to stone formation. This study establishes GCAT and UGT8 as causal genes for urolithiasis, providing mechanistic insight into glycine/oxalate metabolism and glucuronidation pathways. These findings expand understanding of genetic regulation in stone formation and highlight potential targets for preventive and therapeutic interventions.
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