Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations.
O'Seaghdha CM., Wu H., Yang Q., Kapur K., Guessous I., Zuber AM., Köttgen A., Stoudmann C., Teumer A., Kutalik Z., Mangino M., Dehghan A., Zhang W., Eiriksdottir G., Li G., Tanaka T., Portas L., Lopez LM., Hayward C., Lohman K., Matsuda K., Padmanabhan S., Firsov D., Sorice R., Ulivi S., Brockhaus AC., Kleber ME., Mahajan A., Ernst FD., Gudnason V., Launer LJ., Mace A., Boerwinckle E., Arking DE., Tanikawa C., Nakamura Y., Brown MJ., Gaspoz J-M., Theler J-M., Siscovick DS., Psaty BM., Bergmann S., Vollenweider P., Vitart V., Wright AF., Zemunik T., Boban M., Kolcic I., Navarro P., Brown EM., Estrada K., Ding J., Harris TB., Bandinelli S., Hernandez D., Singleton AB., Girotto G., Ruggiero D., d'Adamo AP., Robino A., Meitinger T., Meisinger C., Davies G., Starr JM., Chambers JC., Boehm BO., Winkelmann BR., Huang J., Murgia F., Wild SH., Campbell H., Morris AP., Franco OH., Hofman A., Uitterlinden AG., Rivadeneira F., Völker U., Hannemann A., Biffar R., Hoffmann W., Shin S-Y., Lescuyer P., Henry H., Schurmann C., SUNLIGHT Consortium None., GEFOS Consortium None., Munroe PB., Gasparini P., Pirastu N., Ciullo M., Gieger C., März W., Lind L., Spector TD., Smith AV., Rudan I., Wilson JF., Polasek O., Deary IJ., Pirastu M., Ferrucci L., Liu Y., Kestenbaum B., Kooner JS., Witteman JCM., Nauck M., Kao WHL., Wallaschofski H., Bonny O., Fox CS., Bochud M.
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.