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 whom 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, 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.