Integrative multi-layer genetic analysis identifies novel susceptibility genes for urolithiasis

Area of Science:

• Genetics
• Metabolic Diseases
• Urology

Background:

• Urolithiasis (kidney stones) is a complex condition with unclear genetic causes despite GWAS findings.
• Identifying causal genes and their mechanisms is crucial for understanding urolithiasis pathogenesis.

Purpose of the Study:

• To identify genes whose genetically regulated expression contributes to urolithiasis risk.
• To clarify the biological roles of these genes in stone formation.

Main Methods:

• Integrated European-ancestry GWAS data with GTEx V8 eQTL data.
• Applied transcriptome-wide association studies, conditional/joint analyses, and fine-mapping.
• Utilized Mendelian randomization and Bayesian colocalization to assess causality.

Main Results:

• Identified GCAT and UGT8 as independent causal genes for urolithiasis.
• Confirmed causal effects using Mendelian randomization and colocalization.
• GCAT links glycine metabolism and oxalate production; UGT8 modulates fibroblast glucuronidation.

Conclusions:

• GCAT and UGT8 are established as causal genes in urolithiasis.
• Mechanistic insights into glycine/oxalate metabolism and glucuronidation pathways are provided.
• Findings highlight potential targets for urolithiasis prevention and treatment.