Cross-Species Comparison between Mouse Kidney Multi-Omics and Human Genome-Wide Association Studies Highlights Molecular Features Associated with Oxalate Nephropathy

Urolithiasis, a recurrent and increasingly prevalent disease globally, has a complex pathophysiology that impedes comprehensive understanding. This study sought to identify new pathogenetic molecules linked to urolithiasis through multi-omics analysis of a urolithiasis mouse model's kidneys and human genome-wide association analysis (GWAS). In the multi-omics analysis of urolithiasis mouse kidneys using RNA-seq, whole cell proteome, and phosphoproteome, we identified 1,173 genes, 342 proteins, and 516 phosphorylated peptides which were differentially expressed (DE) when comparing model with control mice. We employed large-scale urolithiasis GWAS resources from BioBank Japan, UK Biobank, and FinnGen through a meta-analysis, which provided 343 urolithiasis-related genes by gene enrichment analysis. Integrating the results of mouse and human analyses, we identified 46 urolithiasis-associated candidate molecules shared across species. We then further validated relevance of these 46 molecules in human urolithiasis. DE analysis comparing gene expression of the human renal papilla with and without stones found upregulation of CRYAB and SHROOM3, which are specifically expressed in collecting duct principal cells. Colocalization analysis between urolithiasis GWAS and expression quantitative trait loci (eQTL) data of human renal tubules revealed colocalization for GLUD1, UMOD, SLC34A1, and TCEA3. Colocalization analysis between the urolithiasis GWAS and 51 urolithiasis-related human phenotype GWAS found that SNX17 and UMOD showed prominent genetic pleiotropy. This study not only highlights novel urolithiasis-related molecules such as CRYAB, SHROOM3, TCEA3, and SNX17 but also elucidates cell types harboring the effects of known urolithiasis-related molecules. Consequently, successful mapping of renal effectuating molecules in urolithiasis has been achieved.