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.

Membrane Topology and Intracellular Processing of Cyclin M2 (CNNM2)

“…Although their physiological role is still poorly understood, all members are likely involved in electrolyte homeostasis. CNNM1 has been identified as a cytosolic copper chaperone, CNNM2 was shown to mediate Mg 2ϩ -sensitive Na ϩ currents in HEK293 cells, and Cnnm2, Cnnm3, and Cnnm4 have been linked with serum Mg 2ϩ levels (3,21,22). Furthermore, Cnnm2 has been associated with coronary artery disease and hypertension (23)(24)(25).…”

Genetic factors related to gastric cancer susceptibility identified using a genome‐wide association study

“…(58) However, it was demonstrated using the GWAS that hypomagnesaemia was correlated with the G allele of rs4072037, the protective allele for GC development. (57) As no correlation was observed between MUC1 and IGC in the present study ( 13 and Hiromi Sakamoto, Teruhiko Yoshida Fig. 3.…”

“…From a different viewpoint, MUC1 was identified as associating with the serum magnesium level using GWAS. (57) Because a correlation between a low serum magnesium level and GC was suggested, it is possible that MUC1 affects GC susceptibility by playing a role in magnesium homeostasis. (58) However, it was demonstrated using the GWAS that hypomagnesaemia was correlated with the G allele of rs4072037, the protective allele for GC development.…”

A novel mutation and variable phenotypic expression in a large consanguineous pedigree with Jalili syndrome

“…7 The protein encoded by CNNM4 is a member of the ancient conserved domain protein family and is possibly involved in the metal ion transport, particularly magnesium, which is necessary for accurate function of the photoreceptors, and homeostasis in the retina. 14,15 CNNM4 expression has been demonstrated in the enamel and dentin-forming cells, suggesting that disturbance of the Mg 2+ transport leads to mineral deficiency observed in dental enamel of AI patients. 5,7 Various kinds of mutations including missense, nonsense, deletion, and single base duplication have been identified in CNNM4 in Jalili syndrome.…”