Genome-wide Association Study of 24-Hour Urinary Excretion of Calcium, Magnesium, and Uric Acid

Abstract

Objectives: The urinary excretion of organic and inorganic substances and their concentrations have attracted extensive attention for their role in the pathogenesis of urinary stone disease. The urinary excretion of specific factors associates with sex and age and seems to have a hereditary component, but the precise genomic determinants remain ill-defined.

Methods: Genome-wide association studies previously conducted in 3 cohorts (Genetic Epidemiology Network of Arteriopathy study, January 1, 2006, through December 31, 2012; the combined Nurses' Health Study (NHS), NHS II, and Health Professionals Follow-up Study, January 1, 1994, through December 31, 2003; and the Prevention of Renal and Vascular End-stage Disease study, January 1, 1997, through December 31, 1998) were combined into meta-analyses to evaluate genetic associations with available urinary phenotypes relevant to stone pathogenesis (calcium, magnesium, and uric acid excretion; total urine volume).

Results: One region on chromosome 9q21.13 showed strong evidence of an association with urinary magnesium excretion. The strongest signal in this region was near TRPM6, whose protein product mediates magnesium transport in the colon and kidney, and C9orf40, C9orf41, NMRK1, and OSTF1 (rs1176815; P=1.70×10^-14, with each copy of the A allele corresponding to a daily 5.29-mg decrease in magnesium excretion). The single nucleotide polymorphism (SNP) that achieved genome-wide significance for calcium excretion (rs17216707 on chromosome 20; P=1.12×10^-8) was previously associated with fibroblast growth factor 23 levels, which regulate phosphorus and vitamin D metabolism. Urine volume and uric acid excretion did not have any genome-wide significant SNPs.

Conclusion: Common variants near genes important for magnesium metabolism and bone health associate with urinary magnesium and calcium excretion.

Keywords: BMI, body mass index; CKD, chronic kidney disease; FGF23, fibroblast growth factor 23; GDUL, Genetic Determinants of Urinary Lithogenicity; GENOA, Genetic Epidemiology Network of Arteriopathy; GWAS, Genome-wide association study; HPFS, Health Professionals Follow-up Study; NHS, Nurses’ Health Study; PREVEND, Prevention of Renal and Vascular End-stage Disease; QQ, quantile-quantile; SNP, single nucleotide polymorphism.

Figure 1

Quantile-quantile plots for meta-analysis of urine traits: calcium (A), urine volume (B), uric acid (C), and magnesium (D). Fixed effects, inverse variance–weighted meta-analyses were performed on summary statistics, corrected for study-specific genomic control lambda. Meta-analysis λ values were as follows: λ=0.9967 (A); λ=0.9977 (B); λ=0.9884 (C); λ=1.0019 (D).

Figure 2

Manhattan plots for meta-analysis of urine excretion traits: calcium (A), urine volume (B), uric acid (C), and magnesium (D). Fixed effects, inverse variance–weighted meta-analyses performed on summary statistics, corrected for study-specific genomic control lambda. Top line (red) represents genome-wide significant finding (P<5×10^–8), and bottom line (blue) represents genome-wide suggestive finding (P<1×10^–6).

Figure 3

Regional plot for genome-wide significant results on chromosome 9 (chr9) for the magnesium excretion meta-analysis. The left y-axis shows –log10(P) from the association between single nucleotide polymorphisms (SNPs) and magnesium excretion; right y-axis, the SNP recombination rate based on the 1000 Genomes 2012 Europe reference panel (hg19); x-axis, chromosomal location and gene regions; and r² color code, degree of linkage disequilibrium (correlation) with the most strongly associated SNP (purple diamond).