Abstract
BACKGROUND: Taiwan has the highest prevalence of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) globally, making them major public health concerns with significant morbidity, mortality, and healthcare burden. While genetic risk factors for kidney disease have been identified in previous studies, the contribution of rare genetic variants remains unclear. METHODS: This study utilized whole-exome sequencing (WES) to investigate the role of missense rare variants in CKD and ESKD susceptibility. Genomic data from 500 Taiwanese individuals at Taipei Medical University Hospital were included based on strict clinical diagnostic criteria, comprising 200 CKD cases, 200 ESKD cases, and 100 healthy controls. Independent validation was performed using ESKD Asian cohorts from the All of Us Research Program (AoU) (N = 222) and the Tohoku Medical Megabank Organization (ToMMo) (N = 140). RESULTS: We identified rare pathogenic variants in known monogenic kidney disease genes, including PKD1 and COL4A4, confirming their role in disease susceptibility. We replicated GWAS-reported genes such as SPI1, RIN3, FTO, SIPA1L3, and EEF1E1, highlighting their contribution through both common and rare variants. Beyond previously reported genes, we identified novel rare pathogenic variants in PEX1, GANAB, DYNC2H1, and PROKR2. Pathway enrichment analysis suggested that ciliopathies, inflammation, and metabolic dysfunction may contribute to kidney disease progression. Furthermore, the polygenic score (PGS) for ESKD demonstrated strong predictive utility for kidney function, with high genetic risk having a greater influence than comorbidities such as diabetes and overweight. The prediction power of ESKD PGS was further confirmed in the AoU Asian population. CONCLUSIONS: This study provides novel insights into the genetic architecture of CKD and ESKD in the Taiwanese population, utilizing a hospital-based cohort with strict clinical diagnostic criteria to ensure precise phenotype classification. We propose that individuals with high genetic risk may benefit from earlier interventions, while those with lower PGS may be better managed through lifestyle modifications targeting comorbidities. The findings highlight the importance of preventive strategies and precision medicine in kidney disease management.