Genetic Susceptibility to Nephrolithiasis: A Genome-Phenome Approach with Polygenic Risk Score Analysis

Introduction Kidney stone disease (KSD) is multifactorial, and the genetic basis is poorly understood among the East Asian population. This study aims to elucidate comprehensive genetic factors associated with KSD. Methods We conducted a genome-wide association study (GWAS) on Taiwanese Han Chinese individuals from the Taiwan Biobank to investigate genetic predispositions to KSD. A total of 108,483 participants were included, of which 7,635 reported having KSD. A phenome-wide association study (PheWAS) leveraging the National Health Insurance Research Database was used to verify GWAS findings and explore disease associations. We also assessed individual genetic risk for KSD using a polygenic risk score (PRS). Results Our analysis identified significant associations with KSD at single-nucleotide polymorphisms rs1481012 (odds ratio = 1.13, P=5.5310-11) and rs12872074 (odds ratio = 1.16, P=4.7710-17) on chromosomes 4 and 13, respectively. We pinpointed ABCG2, DGKH and a novel locus PKD2. Biological pathways including protein dimerization and CD4+ T cells regulation were identified in gene-set analysis. PheWAS confirmed the association of these lead variants with calculus of kidney and various phenotypes. PRS reached an area under the receiver operating characteristic curve of 0.97 on the discovery sample. Conclusion This comprehensive study highlights the significant genetic contributors to KSD in an East Asian population. Our findings underscore the potential of using a national health database to validate our analyses and reveal novel disease correlations, which supported immune dysregulation in disease pathogenesis. PRS highlights the contribution of genetic variants to KSD risk and suggests potential for future clinical application, although validation in independent populations will be required to determine its predictive utility.