TY - JOUR
T1 - Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six loci influencing serum magnesium levels
AU - Meyer, Tamra E.
AU - Verwoert, Germaine C.
AU - Hwang, Shih Jen
AU - Glazer, Nicole L.
AU - Smith, Albert V.
AU - van Rooij, Frank J.A.
AU - Ehret, Georg B.
AU - Boerwinkle, Eric
AU - Felix, Janine F.
AU - Leak, Tennille S.
AU - Harris, Tamara B.
AU - Yang, Qiong
AU - Dehghan, Abbas
AU - Aspelund, Thor
AU - Katz, Ronit
AU - Homuth, Georg
AU - Kocher, Thomas
AU - Rettig, Rainer
AU - Ried, Janina S.
AU - Gieger, Christian
AU - Prucha, Hanna
AU - Pfeufer, Arne
AU - Meitinger, Thomas
AU - Coresh, Josef
AU - Hofman, Albert
AU - Sarnak, Mark J.
AU - Chen, Yii Der Ida
AU - Uitterlinden, Andrë G.
AU - Chakravarti, Aravinda
AU - Psaty, Bruce M.
AU - van Duijn, Cornelia M.
AU - Linda-Kao, W. H.
AU - Witteman, Jacqueline C.M.
AU - Gudnason, Vilmundur
AU - Siscovick, David S.
AU - Fox, Caroline S.
AU - Köttgen, Anna
N1 - Funding Information:
FHS: This research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center.
PY - 2010/8
Y1 - 2010/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77957345374&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1001045
DO - 10.1371/journal.pgen.1001045
M3 - Article
C2 - 20700443
AN - SCOPUS:77957345374
SN - 1553-7390
VL - 6
JO - PLoS Genetics
JF - PLoS Genetics
IS - 8
ER -
