title: 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 approximately 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 x 10(-8)) or suggestive associations (p<4 x 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 x 10(-7). Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels.
authors.affiliation: Human Genetics Center and Division of Epidemiology, The University of Texas Health Science Center at Houston, School of Public Health, Houston, Texas, USA.
authors.forename: Tamra E
authors.initials: TE
authors.lastname: Meyer
authors.forename: Germaine C
authors.initials: GC
authors.lastname: Verwoert
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Hwang
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Glazer
authors.forename: Albert V
authors.initials: AV
authors.lastname: Smith
authors.forename: Frank J A
authors.initials: FJ
authors.lastname: van Rooij
authors.forename: Georg B
authors.initials: GB
authors.lastname: Ehret
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Janine F
authors.initials: JF
authors.lastname: Felix
authors.forename: Tennille S
authors.initials: TS
authors.lastname: Leak
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yang
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
authors.forename: Thor
authors.initials: T
authors.lastname: Aspelund
authors.forename: Ronit
authors.initials: R
authors.lastname: Katz
authors.forename: Georg
authors.initials: G
authors.lastname: Homuth
authors.forename: Thomas
authors.initials: T
authors.lastname: Kocher
authors.forename: Rainer
authors.initials: R
authors.lastname: Rettig
authors.forename: Janina S
authors.initials: JS
authors.lastname: Ried
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: Hanna
authors.initials: H
authors.lastname: Prucha
authors.forename: Arne
authors.initials: A
authors.lastname: Pfeufer
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Josef
authors.initials: J
authors.lastname: Coresh
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Sarnak
authors.forename: Yii-Der Ida
authors.initials: YD
authors.lastname: Chen
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: W H Linda
authors.initials: WH
authors.lastname: Kao
authors.forename: Jacqueline C M
authors.initials: JC
authors.lastname: Witteman
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
authors.forename: David S
authors.initials: DS
authors.lastname: Siscovick
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.forename: Anna
authors.initials: A
authors.lastname: Köttgen
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008274:Magnesium / Q000097:blood*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011188:Potassium / Q000097:blood*; D012964:Sodium / Q000097:blood*; D044465:White People / Q000235:genetics*
chemical_list: D012964:Sodium; D008274:Magnesium; D011188:Potassium