title: Common genetic variants associate with serum phosphorus concentration.
abstract: Phosphorus is an essential mineral that maintains cellular energy and mineralizes the skeleton. Because complex actions of ion transporters and regulatory hormones regulate serum phosphorus concentrations, genetic variation may determine interindividual variation in phosphorus metabolism. Here, we report a comprehensive genome-wide association study of serum phosphorus concentration. We evaluated 16,264 participants of European ancestry from the Cardiovascular Heath Study, Atherosclerosis Risk in Communities Study, Framingham Offspring Study, and the Rotterdam Study. We excluded participants with an estimated GFR <45 ml/min per 1.73 m(2) to focus on phosphorus metabolism under normal conditions. We imputed genotypes to approximately 2.5 million single-nucleotide polymorphisms in the HapMap and combined study-specific findings using meta-analysis. We tested top polymorphisms from discovery cohorts in a 5444-person replication sample. Polymorphisms in seven loci with minor allele frequencies 0.08 to 0.49 associate with serum phosphorus concentration (P = 3.5 x 10(-16) to 3.6 x 10(-7)). Three loci were near genes encoding the kidney-specific type IIa sodium phosphate co-transporter (SLC34A1), the calcium-sensing receptor (CASR), and fibroblast growth factor 23 (FGF23), proteins that contribute to phosphorus metabolism. We also identified genes encoding phosphatases, kinases, and phosphodiesterases that have yet-undetermined roles in phosphorus homeostasis. In the replication sample, five of seven top polymorphisms associate with serum phosphorous concentrations (P < 0.05 for each). In conclusion, common genetic variants associate with serum phosphorus in the general population. Further study of the loci identified in this study may help elucidate mechanisms of phosphorus regulation.
authors.affiliation: Division of Nephrology, Department of Medicine, University of Washington, Kidney Research Institute, Seattle, Washington 98104-2499, USA. brk@u.washington.edu
authors.forename: Bryan
authors.initials: B
authors.lastname: Kestenbaum
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Glazer
authors.forename: Anna
authors.initials: A
authors.lastname: Köttgen
authors.forename: Janine F
authors.initials: JF
authors.lastname: Felix
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Hwang
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Liu
authors.forename: Kurt
authors.initials: K
authors.lastname: Lohman
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Kritchevsky
authors.forename: Dorothy B
authors.initials: DB
authors.lastname: Hausman
authors.forename: Ann-Kristin
authors.initials: AK
authors.lastname: Petersen
authors.forename: Christian
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authors.lastname: Gieger
authors.forename: Janina S
authors.initials: JS
authors.lastname: Ried
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: H Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.forename: Igor
authors.initials: I
authors.lastname: Rudan
authors.forename: Ian H
authors.initials: IH
authors.lastname: de Boer
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Rice
authors.forename: Yii-Der Ida
authors.initials: YD
authors.lastname: Chen
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.forename: Dan E
authors.initials: DE
authors.lastname: Arking
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Josef
authors.initials: J
authors.lastname: Coresh
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yang
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.forename: Frank J A
authors.initials: FJ
authors.lastname: van Rooij
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Michael G
authors.initials: MG
authors.lastname: Shlipak
authors.forename: W H Linda
authors.initials: WH
authors.lastname: Kao
authors.forename: Jacqueline C M
authors.initials: JC
authors.lastname: Witteman
authors.forename: David S
authors.initials: DS
authors.lastname: Siscovick
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D007668:Kidney / Q000502:physiology; D008297:Male; D008875:Middle Aged; D010758:Phosphorus / Q000097:blood*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D044169:Receptors, Calcium-Sensing / Q000235:genetics; D012737:Sex Factors; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000235:genetics; D044465:White People
chemical_list: C095550:CASR protein, human; C000717427:FGF23 protein, human; D044169:Receptors, Calcium-Sensing; C493554:SLC34A1 protein, human; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D010758:Phosphorus; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23