Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations

Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based coh...

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Vydané v:	PLoS genetics Ročník 9; číslo 9; s. e1003796
Hlavní autori:	O'Seaghdha, Conall M., Wu, Hongsheng, Yang, Qiong, Kapur, Karen, Guessous, Idris, Zuber, Annie Mercier, Köttgen, Anna, Stoudmann, Candice, Teumer, Alexander, Kutalik, Zoltán, Mangino, Massimo, Dehghan, Abbas, Zhang, Weihua, Eiriksdottir, Gudny, Li, Guo, Tanaka, Toshiko, Portas, Laura, Lopez, Lorna M., Hayward, Caroline, Lohman, Kurt, Matsuda, Koichi, Padmanabhan, Sandosh, Firsov, Dmitri, Sorice, Rossella, Ulivi, Sheila, Brockhaus, A. Catharina, Kleber, Marcus E., Mahajan, Anubha, Ernst, Florian D., Gudnason, Vilmundur, Launer, Lenore J., Mace, Aurelien, Boerwinckle, Eric, Arking, Dan E., Tanikawa, Chizu, Nakamura, Yusuke, Brown, Morris J., Gaspoz, Jean-Michel, Theler, Jean-Marc, Siscovick, David S., Psaty, Bruce M., Bergmann, Sven, Vollenweider, Peter, Vitart, Veronique, Wright, Alan F., Zemunik, Tatijana, Boban, Mladen, Kolcic, Ivana, Navarro, Pau, Brown, Edward M., Estrada, Karol, Ding, Jingzhong, Harris, Tamara B., Bandinelli, Stefania, Hernandez, Dena, Singleton, Andrew B., Girotto, Giorgia, Ruggiero, Daniela, d'Adamo, Adamo Pio, Robino, Antonietta, Meitinger, Thomas, Meisinger, Christa, Davies, Gail, Starr, John M., Chambers, John C., Boehm, Bernhard O., Winkelmann, Bernhard R., Huang, Jie, Murgia, Federico, Wild, Sarah H., Campbell, Harry, Morris, Andrew P., Franco, Oscar H., Hofman, Albert, Uitterlinden, Andre G., Rivadeneira, Fernando, Völker, Uwe, Hannemann, Anke, Biffar, Reiner, Hoffmann, Wolfgang, Shin, So–Youn, Lescuyer, Pierre, Henry, Hughes, Schurmann, Claudia, Munroe, Patricia B., Gasparini, Paolo, Pirastu, Nicola, Ciullo, Marina, Gieger, Christian, März, Winfried, Lind, Lars, Spector, Tim D., Smith, Albert V., Rudan, Igor, Wilson, James F., Polasek, Ozren, Deary, Ian J., Pirastu, Mario, Ferrucci, Luigi, Liu, Yongmei
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Public Library of Science 01.09.2013 Public Library of Science (PLoS)
Predmet:	Animals Bone and Bones - metabolism Bone density Bone Density - genetics Calcium Calcium - blood Calcium, Dietary Experiments Gene expression Gene Expression Regulation Genetic aspects Genome-wide association studies Genome-Wide Association Study Genomes Homeostasis Homeostasis - genetics Humans Kidney - metabolism Kinases Meta-analysis Mice Ontology Physiological aspects Polymorphism, Single Nucleotide Population White People - genetics United States
ISSN:	1553-7404, 1553-7390, 1553-7404
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Shrnutí:	Calcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Writing group. The authors have declared that no competing interests exist. Conceived and designed the experiments: CMOS HWu QY KK WHLK HWa OB CSF MBoc. Performed the experiments: CMOS HWu QY KK IG AMZ AK CSt ZK TH GE LJL VG DEA LF DSS BMP OHF AHo AGU JCMW IJD JMS MP EMB PV SBe CH VV SBa IR OP JW HC JSK JCC AHa CSc MN RB UV PBM MJB JMT JMG TDS WH APM LL WM BOB BRW CG CM WHLK HWa OB CSF MBoc. Analyzed the data: CMOS HWu QY KK IG AMZ AK AT ZK YL TH JD KL AVS GE LJL VG TT GL AD FR LML LP FM JH AMac SBe CH VV JFW WZ AHo AGU FR KE SP MM FDE AMah WH APM MEK ACB CG WHLK HWa OB CSF MBoc. Contributed reagents/materials/analysis tools: IG YL VG EB DH AS DSS BMP AGU FR IJD JMS MP PV GD VV CH JSK JCC PBM MM SYS APM MEK TM WHLK HWa CSF MBoc. Wrote the paper: CMOS IG AK HWa OB CSF MBoc. Revising and reviewing the manuscript for important intellectual content: CMOS HWu QY KK IG AMZ AK CSto AT ZK MM AD WZ GE GL TT LP LML CH KL KM SP DF RS SU ACB MEK AMah FDE VG LJL AMac EB DEA CT YN MJB JMG JMT DSS BMP SBe PV VV AFW TZ MBob IK PN EMB KE JD TBH SBa DH ABS GG DR APA AR TM CM GD JMS JCC BOB BRW JH FM SHW HC APM OHF AHo AGU FR UV AHa RB WH SYS PL HH CSc PBM PG NP MC CG WM LL TDS AVS IR JFW OP IJD MP LF YL BK JSK JCMW MN WHLK HWa OB CSF MBoc.
ISSN:	1553-7404 1553-7390 1553-7404
DOI:	10.1371/journal.pgen.1003796