Genetic variants predisposing to an increased risk of kidney stone disease.

Summary

This multi-method human genetics study mapped 79 signals at 71 loci for kidney stone disease and used Mendelian randomization and colocalization to implicate DGKD, SLC34A1, and CYP24A1 in causal calcium/phosphate pathways. Drug-target MR suggested large relative risk reductions by modulating CASR/DGKD/CYP24A1/SLC34A1, and in vitro experiments showed cinacalcet rescues DGKD-variant CaSR signaling.

Key Findings

• Identified 79 independent KSD-associated signals at 71 loci.
• MR implicated increased serum calcium and decreased serum phosphate as causal risk factors from three genomic regions.
• Colocalization pinpointed putative causal noncoding variants near DGKD, SLC34A1, and CYP24A1 explaining 11%–19% of KSD cases.
• Drug-target MR suggested up to ~90% relative risk reduction by reducing calcium via CASR/DGKD/CYP24A1 or increasing phosphate via SLC34A1.
• DGKD missense variants impaired CaSR signaling in vitro, rescued by the calcimimetic cinacalcet.

Clinical Implications

Genotyping could stratify kidney stone risk and guide pathway-specific interventions (e.g., calcimimetics for impaired CaSR/DGKD signaling or modulation of phosphate handling via SLC34A1). Prospective trials should test genotype-informed prevention.

Limitations

• Ancestry composition and cohort-specific details are not provided in the abstract, limiting assessment of generalizability.
• MR relies on instrumental variable assumptions; clinical efficacy of pathway modulation remains to be proven in prospective trials.

Future Directions

Conduct ancestry-diverse validations, pragmatic genotype-guided prevention trials (e.g., calcimimetic use in high-risk genotypes), and mechanistic studies in human tissues to refine targets.