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The nature and importance of genetic factors regulating the differential handling of Ca²⁺ and Mg²⁺ by the renal tubule in the general population are poorly defined. We conducted a genome-wide meta-analysis of urinary magnesium-to-calcium ratio to identify associated common genetic variants. We included 9320 adults of European descent from four genetic isolates and three urban cohorts. Urinary magnesium and calcium concentrations were measured centrally in spot urine, and each study conducted linear regression analysis of urinary magnesium-to-calcium ratio on ~2.5 million single-nucleotide polymorphisms (SNPs) using an additive model. We investigated, in mouse, the renal expression profile of the top candidate gene and its variation upon changes in dietary magnesium. The genome-wide analysis evidenced a top locus (rs172639, p = 1.7 × 10⁻¹²), encompassing CLDN14, the gene …