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

CM O'Seaghdha; HS Wu; Q Yang; K Kapur; I Guessous; AM Zuber; A Kottgen; C Stoudmann; A Teumer; Z Kutalik; M Mangino; Abbas Dehghan; WH Zhang; G Eiriksdottir; G (Guo) Li; T Tanaka; L Portas; LM Lopez; C Hayward; K Lohman; K Matsuda; S Padmanabhan; D Firsov; R Sorice; S Ulivi; AC Brockhaus; ME Kleber; A Mahajan; FD Ernst; V Gudnason; LJ (Lenore) Launer; A Mace; E Boerwinckle; DE Arking; C Tanikawa; Y Nakamura; MJ Brown; JM Gaspoz; JM Theler; DS Siscovick; BM Psaty; S Bergmann; P Vollenweider; V Vitart; AF Wright; T Zemunik; M Boban; I Kolcic; P Navarro; EM Brown; Karol Estrada Gil; JZ (Jing Zhong) Ding; TB Harris; S Bandinelli; D Hernandez; AB Singleton; G Girotto; D Ruggiero; AP d'Adamo; A Robino; T Meitinger; C Meisinger; G Davies; JM Starr; JC Chambers; BO Boehm; BR Winkelmann; J Huang; F Murgia; SH Wild; H Campbell; AP Morris; OH Franco Duran; Bert Hofman; André Uitterlinden; Fernando Rivadeneira; U Volker; A Hannemann; R Biffar; W Hoffmann; SY Shin; P Lescuyer; H Henry; C Schurmann; PB Munroe; P Gasparini; N Pirastu; M Ciullo; C Gieger; W Marz; L Lind; TD Spector; AV Smith; I Rudan; JF Wilson; O Polasek; IJ Deary; M Pirastu; L Ferrucci; YM Liu; B Kestenbaum; JS Kooner; JCM Witteman; M Nauck; WHL Kao; H Wallaschofski; O Bonny; CS Fox; M Bochud

doi:10.1371/journal.pgen.1003796

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

CM O'Seaghdha, HS Wu, Q Yang, K Kapur, I Guessous, AM Zuber, A Kottgen, C Stoudmann, A Teumer, Z Kutalik, M Mangino, Abbas Dehghan, WH Zhang, G Eiriksdottir, G (Guo) Li, T Tanaka, L Portas, LM Lopez, C Hayward, K LohmanK Matsuda, S Padmanabhan, D Firsov, R Sorice, S Ulivi, AC Brockhaus, ME Kleber, A Mahajan, FD Ernst, V Gudnason, LJ (Lenore) Launer, A Mace, E Boerwinckle, DE Arking, C Tanikawa, Y Nakamura, MJ Brown, JM Gaspoz, JM Theler, DS Siscovick, BM Psaty, S Bergmann, P Vollenweider, V Vitart, AF Wright, T Zemunik, M Boban, I Kolcic, P Navarro, EM Brown, Karol Estrada Gil, JZ (Jing Zhong) Ding, TB Harris, S Bandinelli, D Hernandez, AB Singleton, G Girotto, D Ruggiero, AP d'Adamo, A Robino, T Meitinger, C Meisinger, G Davies, JM Starr, JC Chambers, BO Boehm, BR Winkelmann, J Huang, F Murgia, SH Wild, H Campbell, AP Morris, OH Franco Duran, Bert Hofman, André Uitterlinden, Fernando Rivadeneira, U Volker, A Hannemann, R Biffar, W Hoffmann, SY Shin, P Lescuyer, H Henry, C Schurmann, PB Munroe, P Gasparini, N Pirastu, M Ciullo, C Gieger, W Marz, L Lind, TD Spector, AV Smith, I Rudan, JF Wilson, O Polasek, IJ Deary, M Pirastu, L Ferrucci, YM Liu, B Kestenbaum, JS Kooner, JCM Witteman, M Nauck, WHL Kao, H Wallaschofski, O Bonny, CS Fox, M Bochud

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Abstract

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.

Original language	English
Article number	e1003796
Journal	PLoS Genetics (print)
Volume	9
Issue number	9
DOIs	https://doi.org/10.1371/journal.pgen.1003796
Publication status	Published - 2013

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EMC MM-01-39-09-A
EMC NIHES-01-64-01

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O'Seaghdha, CM., Wu, HS., Yang, Q., Kapur, K., Guessous, I., Zuber, AM., Kottgen, A., Stoudmann, C., Teumer, A., Kutalik, Z., Mangino, M., Dehghan, A., Zhang, WH., Eiriksdottir, G., Li, G., Tanaka, T., Portas, L., Lopez, LM., Hayward, C., ... Bochud, M. (2013). Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations. PLoS Genetics (print), 9(9), Article e1003796. https://doi.org/10.1371/journal.pgen.1003796

@article{2b07c268eb0344eb8f4c6f77bb64afa2,

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

abstract = "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.",

author = "CM O'Seaghdha and HS Wu and Q Yang and K Kapur and I Guessous and AM Zuber and A Kottgen and C Stoudmann and A Teumer and Z Kutalik and M Mangino and Abbas Dehghan and WH Zhang and G Eiriksdottir and Li, \{G (Guo)\} and T Tanaka and L Portas and LM Lopez and C Hayward and K Lohman and K Matsuda and S Padmanabhan and D Firsov and R Sorice and S Ulivi and AC Brockhaus and ME Kleber and A Mahajan and FD Ernst and V Gudnason and Launer, \{LJ (Lenore)\} and A Mace and E Boerwinckle and DE Arking and C Tanikawa and Y Nakamura and MJ Brown and JM Gaspoz and JM Theler and DS Siscovick and BM Psaty and S Bergmann and P Vollenweider and V Vitart and AF Wright and T Zemunik and M Boban and I Kolcic and P Navarro and EM Brown and \{Estrada Gil\}, Karol and Ding, \{JZ (Jing Zhong)\} and TB Harris and S Bandinelli and D Hernandez and AB Singleton and G Girotto and D Ruggiero and AP d'Adamo and A Robino and T Meitinger and C Meisinger and G Davies and JM Starr and JC Chambers and BO Boehm and BR Winkelmann and J Huang and F Murgia and SH Wild and H Campbell and AP Morris and \{Franco Duran\}, OH and Bert Hofman and Andr{\'e} Uitterlinden and Fernando Rivadeneira and U Volker and A Hannemann and R Biffar and W Hoffmann and SY Shin and P Lescuyer and H Henry and C Schurmann and PB Munroe and P Gasparini and N Pirastu and M Ciullo and C Gieger and W Marz and L Lind and TD Spector and AV Smith and I Rudan and JF Wilson and O Polasek and IJ Deary and M Pirastu and L Ferrucci and YM Liu and B Kestenbaum and JS Kooner and JCM Witteman and M Nauck and WHL Kao and H Wallaschofski and O Bonny and CS Fox and M Bochud",

year = "2013",

doi = "10.1371/journal.pgen.1003796",

language = "English",

volume = "9",

journal = "PLoS Genetics (print)",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "9",

}

O'Seaghdha, CM, Wu, HS, Yang, Q, Kapur, K, Guessous, I, Zuber, AM, Kottgen, A, Stoudmann, C, Teumer, A, Kutalik, Z, Mangino, M, Dehghan, A, Zhang, WH, 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, JM, Theler, JM, Siscovick, DS, Psaty, BM, Bergmann, S, Vollenweider, P, Vitart, V, Wright, AF, Zemunik, T, Boban, M, Kolcic, I, Navarro, P, Brown, EM, Estrada Gil, K, Ding, JZ, 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 Duran, OH, Hofman, B, Uitterlinden, A, Rivadeneira, F, Volker, U, Hannemann, A, Biffar, R, Hoffmann, W, Shin, SY, Lescuyer, P, Henry, H, Schurmann, C, Munroe, PB, Gasparini, P, Pirastu, N, Ciullo, M, Gieger, C, Marz, W, Lind, L, Spector, TD, Smith, AV, Rudan, I, Wilson, JF, Polasek, O, Deary, IJ, Pirastu, M, Ferrucci, L, Liu, YM, Kestenbaum, B, Kooner, JS, Witteman, JCM, Nauck, M, Kao, WHL, Wallaschofski, H, Bonny, O, Fox, CS & Bochud, M 2013, 'Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations', PLoS Genetics (print), vol. 9, no. 9, e1003796. https://doi.org/10.1371/journal.pgen.1003796

TY - JOUR

T1 - Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations

AU - O'Seaghdha, CM

AU - Wu, HS

AU - Yang, Q

AU - Kapur, K

AU - Guessous, I

AU - Zuber, AM

AU - Kottgen, A

AU - Stoudmann, C

AU - Teumer, A

AU - Kutalik, Z

AU - Mangino, M

AU - Dehghan, Abbas

AU - Zhang, WH

AU - Eiriksdottir, G

AU - Li, G (Guo)

AU - Tanaka, T

AU - Portas, L

AU - Lopez, LM

AU - Hayward, C

AU - Lohman, K

AU - Matsuda, K

AU - Padmanabhan, S

AU - Firsov, D

AU - Sorice, R

AU - Ulivi, S

AU - Brockhaus, AC

AU - Kleber, ME

AU - Mahajan, A

AU - Ernst, FD

AU - Gudnason, V

AU - Launer, LJ (Lenore)

AU - Mace, A

AU - Boerwinckle, E

AU - Arking, DE

AU - Tanikawa, C

AU - Nakamura, Y

AU - Brown, MJ

AU - Gaspoz, JM

AU - Theler, JM

AU - Siscovick, DS

AU - Psaty, BM

AU - Bergmann, S

AU - Vollenweider, P

AU - Vitart, V

AU - Wright, AF

AU - Zemunik, T

AU - Boban, M

AU - Kolcic, I

AU - Navarro, P

AU - Brown, EM

AU - Estrada Gil, Karol

AU - Ding, JZ (Jing Zhong)

AU - Harris, TB

AU - Bandinelli, S

AU - Hernandez, D

AU - Singleton, AB

AU - Girotto, G

AU - Ruggiero, D

AU - d'Adamo, AP

AU - Robino, A

AU - Meitinger, T

AU - Meisinger, C

AU - Davies, G

AU - Starr, JM

AU - Chambers, JC

AU - Boehm, BO

AU - Winkelmann, BR

AU - Huang, J

AU - Murgia, F

AU - Wild, SH

AU - Campbell, H

AU - Morris, AP

AU - Franco Duran, OH

AU - Hofman, Bert

AU - Uitterlinden, André

AU - Rivadeneira, Fernando

AU - Volker, U

AU - Hannemann, A

AU - Biffar, R

AU - Hoffmann, W

AU - Shin, SY

AU - Lescuyer, P

AU - Henry, H

AU - Schurmann, C

AU - Munroe, PB

AU - Gasparini, P

AU - Pirastu, N

AU - Ciullo, M

AU - Gieger, C

AU - Marz, W

AU - Lind, L

AU - Spector, TD

AU - Smith, AV

AU - Rudan, I

AU - Wilson, JF

AU - Polasek, O

AU - Deary, IJ

AU - Pirastu, M

AU - Ferrucci, L

AU - Liu, YM

AU - Kestenbaum, B

AU - Kooner, JS

AU - Witteman, JCM

AU - Nauck, M

AU - Kao, WHL

AU - Wallaschofski, H

AU - Bonny, O

AU - Fox, CS

AU - Bochud, M

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pgen.1003796

DO - 10.1371/journal.pgen.1003796

M3 - Article

C2 - 24068962

SN - 1553-7390

VL - 9

JO - PLoS Genetics (print)

JF - PLoS Genetics (print)

IS - 9

M1 - e1003796

ER -

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

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