Identification of potential oxidative stress-related causal genes for calculus of kidney and ureter: a multi-omics Mendelian Randomization analysis

Introduction: Oxidative stress contributes to kidney and ureteral calculi, but the specific genes and mechanisms remain unclear. This study integrates methylation quantitative trait loci (mQTL), expression QTL (eQTL), and protein QTL (pQTL) data with genome-wide association study (GWAS) data to identify oxidative stress-related genes linked to calculi. Methods: Summary-data-based Mendelian randomization (SMR) and colocalization analyses were performed using GWAS data from FinnGen (discovery) and UK Biobank (UKB; validation) to identify oxidative stress-related genes associated with calculus risk. External validation employed a genetic hypercalciuric stone-forming (GHS) rat transcriptomic dataset. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, together with protein–protein interaction (PPI) network, were used to characterize functional pathways and central regulators. Results: SMR and colocalization analyses in FinnGen identified 172 mQTLs, 27 eQTLs, and 5 pQTLs associated with calculus risk, with subsets validated in UKB. Multi-omics integration highlighted CREM (cg26679713) and MAPT (cg21705961) as key candidates, showing hypermethylation-associated upregulation. CREM was consistently associated with increased risk in both SMR analysis and the GHS model, whereas MAPT showed a protective association in SMR but was upregulated in GHS kidneys. GO and KEGG enrichment of 75 nonredundant genes from eQTL- and pQTL-level associations indicated predominant roles in oxidative stress and inflammation, and enrichment in FoxO, TNF, apoptosis, and IL-17/Th17 pathways. PPI analysis identified 11 hub genes linked to oxidative stress and inflammation. Conclusion: Oxidative stress-related genes, particularly CREM and MAPT, are potential modulators of kidney and ureteral calculi risk, warranting further mechanistic and translational investigation.