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

Tamra E. Meyer, Germaine C. Verwoert, Shih Jen Hwang, Nicole L. Glazer, Albert V. Smith, Frank J.A. van Rooij, Georg B. Ehret, Eric Boerwinkle, Janine F. Felix, Tennille S. Leak, Tamara B. Harris, Qiong Yang, Abbas Dehghan, Thor Aspelund, Ronit Katz, Georg Homuth, Thomas Kocher, Rainer Rettig, Janina S. Ried, Christian GiegerHanna Prucha, Arne Pfeufer, Thomas Meitinger, Josef Coresh, Albert Hofman, Mark J. Sarnak, Yii Der Ida Chen, Andrë G. Uitterlinden, Aravinda Chakravarti, Bruce M. Psaty, Cornelia M. van Duijn, W. H. Linda-Kao, Jacqueline C.M. Witteman, Vilmundur Gudnason, David S. Siscovick, Caroline S. Fox, Anna Köttgen

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalPLoS genetics
Volume6
Issue number8
DOIs
StatePublished - Aug 2010

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    Meyer, T. E., Verwoert, G. C., Hwang, S. J., Glazer, N. L., Smith, A. V., van Rooij, F. J. A., Ehret, G. B., Boerwinkle, E., Felix, J. F., Leak, T. S., Harris, T. B., Yang, Q., Dehghan, A., Aspelund, T., Katz, R., Homuth, G., Kocher, T., Rettig, R., Ried, J. S., ... Köttgen, A. (2010). Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six loci influencing serum magnesium levels. PLoS genetics, 6(8). https://doi.org/10.1371/journal.pgen.1001045