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

Area of Science:

• Genetics
• Genomics
• Epidemiology

Background:

• Kidney stone disease (KSD) is multifactorial with a poorly understood genetic basis in East Asian populations.
• Elucidating genetic factors is crucial for understanding KSD pathogenesis in this demographic.

Purpose of the Study:

• To comprehensively identify genetic factors associated with KSD in Taiwanese Han Chinese individuals.
• To validate findings using national health data and assess the predictive utility of a polygenic risk score (PRS).

Main Methods:

• Genome-wide association study (GWAS) on 108,483 participants (7,635 with KSD).
• Phenome-wide association study (PheWAS) using the National Health Insurance Research Database.
• Polygenic risk score (PRS) development and evaluation.

Main Results:

• Significant KSD associations found at rs1481012 (chromosome 4) and rs12872074 (chromosome 13).
• Identified genes include ABCG2, DGKH, and the novel locus PKD2.
• PheWAS confirmed variant associations with kidney calculus and related phenotypes; PRS achieved an AUC of 0.97.

Conclusions:

• This study reveals significant genetic contributors to KSD in an East Asian population.
• National health databases aid in validating findings and uncovering novel disease correlations, suggesting immune dysregulation's role.
• PRS demonstrates potential for clinical application in KSD risk prediction, pending further validation.