Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six loci influencing serum magnesium levels

Abstract

Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using ∼2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p<5×10−8) or suggestive associations (p<4×10−7) were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding p<4×10−7. Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels.

Author Summary

Magnesium, potassium, and sodium are involved in important physiological processes. To better understand how common genetic variation may contribute to inter-individual differences in serum concentrations of these electrolytes, we evaluated single nucleotide polymorphisms (SNPs) across the genome in association with serum magnesium, potassium, and sodium levels in 15,366 participants of European descent from the CHARGE Consortium. We then verified the associations in an additional 8,463 study participants. Six different genomic regions contain variants that are reproducibly associated with serum magnesium levels, and only one of the regions had been previously known to influence serum magnesium concentrations in humans. The identified SNPs also show association with clinically defined hypomagnesemia, and some of them with traits that have been linked to serum magnesium levels, including kidney function, fasting glucose, and bone mineral density. We further provide evidence for a physiological role of magnesium transporters in humans which have previously only been studied in model systems. None of the SNPs evaluated in our study are significantly associated with serum levels of sodium or potassium. Additional studies are needed to investigate the underlying molecular mechanisms in order to help us understand the contribution of these newly identified regions to magnesium homeostasis.