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

Conall M. O'Seaghdha; Hongsheng Wu; Qiong Yang; Karen Kapur; Idris Guessous; Annie Mercier Zuber; Anna Köttgen; Candice Stoudmann; Alexander Teumer; Zoltán Kutalik; Massimo Mangino; Abbas Dehghan; Weihua Zhang; Gudny Eiriksdottir; Guo Li; Toshiko Tanaka; Laura Portas; Lorna M. Lopez; Caroline Hayward; Kurt Lohman; Koichi Matsuda; Sandosh Padmanabhan; Dmitri Firsov; Rossella Sorice; Sheila Ulivi; A. Catharina Brockhaus; Marcus E. Kleber; Anubha Mahajan; Florian D. Ernst; Vilmundur Gudnason; Lenore J. Launer; Aurelien Mace; Eric Boerwinckle; Dan E. Arking; Chizu Tanikawa; Yusuke Nakamura; Morris J. Brown; Jean Michel Gaspoz; Jean Marc Theler; David S. Siscovick; Bruce M. Psaty; Sven Bergmann; Peter Vollenweider; Veronique Vitart; Alan F. Wright; Tatijana Zemunik; Mladen Boban; Ivana Kolcic; Pau Navarro; Edward M. Brown; Karol Estrada; Jingzhong Ding; Tamara B. Harris; Stefania Bandinelli; Dena Hernandez; Andrew B. Singleton; Giorgia Girotto; Daniela Ruggiero; Adamo Pio d'Adamo; Antonietta Robino; Thomas Meitinger; Christa Meisinger; Gail Davies; John M. Starr; John C. Chambers; Bernhard O. Boehm; Bernhard R. Winkelmann; Jie Huang; Federico Murgia; Sarah H. Wild; Harry Campbell; Andrew P. Morris; Oscar H. Franco; Albert Hofman; Andre G. Uitterlinden; Fernando Rivadeneira; Uwe Völker; Anke Hannemann; Reiner Biffar; Wolfgang Hoffmann; So Youn Shin; Pierre Lescuyer; Hughes Henry; Claudia Schurmann; Patricia B. Munroe; Paolo Gasparini; Nicola Pirastu; Marina Ciullo; Christian Gieger; Winfried März; Lars Lind; Tim D. Spector; Albert V. Smith; Igor Rudan; James F. Wilson; Ozren Polasek; Ian J. Deary; Mario Pirastu; Luigi Ferrucci; Yongmei Liu; Bryan Kestenbaum; Jaspal S. Kooner; Jacqueline C.M. Witteman; Matthias Nauck; W. H.Linda Kao; Henri Wallaschofski; Olivier Bonny; Caroline S. Fox; Murielle Bochud

doi:10.1371/journal.pgen.1003796

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

Conall M. O'Seaghdha, Hongsheng Wu, Qiong Yang, Karen Kapur, Idris Guessous, Annie Mercier Zuber, Anna Köttgen, Candice Stoudmann, Alexander Teumer, Zoltán Kutalik, Massimo Mangino, Abbas Dehghan, Weihua Zhang, Gudny Eiriksdottir, Guo Li, Toshiko Tanaka, Laura Portas, Lorna M. Lopez, Caroline Hayward, Kurt LohmanKoichi Matsuda, Sandosh Padmanabhan, Dmitri Firsov, Rossella Sorice, Sheila Ulivi, A. Catharina Brockhaus, Marcus E. Kleber, Anubha Mahajan, Florian D. Ernst, Vilmundur Gudnason, Lenore J. Launer, Aurelien Mace, Eric Boerwinckle, Dan E. Arking, Chizu Tanikawa, Yusuke Nakamura, Morris J. Brown, Jean Michel Gaspoz, Jean Marc Theler, David S. Siscovick, Bruce M. Psaty, Sven Bergmann, Peter Vollenweider, Veronique Vitart, Alan F. Wright, Tatijana Zemunik, Mladen Boban, Ivana Kolcic, Pau Navarro, Edward M. Brown, Karol Estrada, Jingzhong Ding, Tamara B. Harris, Stefania Bandinelli, Dena Hernandez, Andrew B. Singleton, Giorgia Girotto, Daniela Ruggiero, Adamo Pio d'Adamo, Antonietta Robino, Thomas Meitinger, Christa Meisinger, Gail Davies, John M. Starr, John C. Chambers, Bernhard O. Boehm, Bernhard R. Winkelmann, Jie Huang, Federico Murgia, Sarah H. Wild, Harry Campbell, Andrew P. Morris, Oscar H. Franco, Albert Hofman, Andre G. Uitterlinden, Fernando Rivadeneira, Uwe Völker, Anke Hannemann, Reiner Biffar, Wolfgang Hoffmann, So Youn Shin, Pierre Lescuyer, Hughes Henry, Claudia Schurmann, Patricia B. Munroe, Paolo Gasparini, Nicola Pirastu, Marina Ciullo, Christian Gieger, Winfried März, Lars Lind, Tim D. Spector, Albert V. Smith, Igor Rudan, James F. Wilson, Ozren Polasek, Ian J. Deary, Mario Pirastu, Luigi Ferrucci, Yongmei Liu, Bryan Kestenbaum, Jaspal S. Kooner, Jacqueline C.M. Witteman, Matthias Nauck, W. H.Linda Kao, Henri Wallaschofski, Olivier Bonny, Caroline S. Fox, Murielle Bochud

School of Medicine

Research output: Contribution to journal › Article › peer-review

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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 (US)
Article number	e1003796
Journal	PLoS genetics
Volume	9
Issue number	9
DOIs	https://doi.org/10.1371/journal.pgen.1003796
State	Published - Sep 2013

ASJC Scopus subject areas

Ecology, Evolution, Behavior and Systematics
Molecular Biology
Genetics
Genetics(clinical)
Cancer Research

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

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, 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, 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, SY, Lescuyer, P, Henry, H, Schurmann, C, 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 2013, 'Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations', PLoS genetics, vol. 9, no. 9, e1003796. https://doi.org/10.1371/journal.pgen.1003796

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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 = "O'Seaghdha, {Conall M.} and Hongsheng Wu and Qiong Yang and Karen Kapur and Idris Guessous and Zuber, {Annie Mercier} and Anna K{\"o}ttgen and Candice Stoudmann and Alexander Teumer and Zolt{\'a}n Kutalik and Massimo Mangino and Abbas Dehghan and Weihua Zhang and Gudny Eiriksdottir and Guo Li and Toshiko Tanaka and Laura Portas and Lopez, {Lorna M.} and Caroline Hayward and Kurt Lohman and Koichi Matsuda and Sandosh Padmanabhan and Dmitri Firsov and Rossella Sorice and Sheila Ulivi and Brockhaus, {A. Catharina} and Kleber, {Marcus E.} and Anubha Mahajan and Ernst, {Florian D.} and Vilmundur Gudnason and Launer, {Lenore J.} and Aurelien Mace and Eric Boerwinckle and Arking, {Dan E.} and Chizu Tanikawa and Yusuke Nakamura and Brown, {Morris J.} and Gaspoz, {Jean Michel} and Theler, {Jean Marc} and Siscovick, {David S.} and Psaty, {Bruce M.} and Sven Bergmann and Peter Vollenweider and Veronique Vitart and Wright, {Alan F.} and Tatijana Zemunik and Mladen Boban and Ivana Kolcic and Pau Navarro and Brown, {Edward M.} and Karol Estrada and Jingzhong Ding and Harris, {Tamara B.} and Stefania Bandinelli and Dena Hernandez and Singleton, {Andrew B.} and Giorgia Girotto and Daniela Ruggiero and d'Adamo, {Adamo Pio} and Antonietta Robino and Thomas Meitinger and Christa Meisinger and Gail Davies and Starr, {John M.} and Chambers, {John C.} and Boehm, {Bernhard O.} and Winkelmann, {Bernhard R.} and Jie Huang and Federico Murgia and Wild, {Sarah H.} and Harry Campbell and Morris, {Andrew P.} and Franco, {Oscar H.} and Albert Hofman and Uitterlinden, {Andre G.} and Fernando Rivadeneira and Uwe V{\"o}lker and Anke Hannemann and Reiner Biffar and Wolfgang Hoffmann and Shin, {So Youn} and Pierre Lescuyer and Hughes Henry and Claudia Schurmann and Munroe, {Patricia B.} and Paolo Gasparini and Nicola Pirastu and Marina Ciullo and Christian Gieger and Winfried M{\"a}rz and Lars Lind and Spector, {Tim D.} and Smith, {Albert V.} and Igor Rudan and Wilson, {James F.} and Ozren Polasek and Deary, {Ian J.} and Mario Pirastu and Luigi Ferrucci and Yongmei Liu and Bryan Kestenbaum and Kooner, {Jaspal S.} and Witteman, {Jacqueline C.M.} and Matthias Nauck and Kao, {W. H.Linda} and Henri Wallaschofski and Olivier Bonny and Fox, {Caroline S.} and Murielle Bochud",

year = "2013",

month = sep,

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

language = "English (US)",

volume = "9",

journal = "PLoS genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "9",

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TY - JOUR

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

AU - O'Seaghdha, Conall M.

AU - Wu, Hongsheng

AU - Yang, Qiong

AU - Kapur, Karen

AU - Guessous, Idris

AU - Zuber, Annie Mercier

AU - Köttgen, Anna

AU - Stoudmann, Candice

AU - Teumer, Alexander

AU - Kutalik, Zoltán

AU - Mangino, Massimo

AU - Dehghan, Abbas

AU - Zhang, Weihua

AU - Eiriksdottir, Gudny

AU - Li, Guo

AU - Tanaka, Toshiko

AU - Portas, Laura

AU - Lopez, Lorna M.

AU - Hayward, Caroline

AU - Lohman, Kurt

AU - Matsuda, Koichi

AU - Padmanabhan, Sandosh

AU - Firsov, Dmitri

AU - Sorice, Rossella

AU - Ulivi, Sheila

AU - Brockhaus, A. Catharina

AU - Kleber, Marcus E.

AU - Mahajan, Anubha

AU - Ernst, Florian D.

AU - Gudnason, Vilmundur

AU - Launer, Lenore J.

AU - Mace, Aurelien

AU - Boerwinckle, Eric

AU - Arking, Dan E.

AU - Tanikawa, Chizu

AU - Nakamura, Yusuke

AU - Brown, Morris J.

AU - Gaspoz, Jean Michel

AU - Theler, Jean Marc

AU - Siscovick, David S.

AU - Psaty, Bruce M.

AU - Bergmann, Sven

AU - Vollenweider, Peter

AU - Vitart, Veronique

AU - Wright, Alan F.

AU - Zemunik, Tatijana

AU - Boban, Mladen

AU - Kolcic, Ivana

AU - Navarro, Pau

AU - Brown, Edward M.

AU - Estrada, Karol

AU - Ding, Jingzhong

AU - Harris, Tamara B.

AU - Bandinelli, Stefania

AU - Hernandez, Dena

AU - Singleton, Andrew B.

AU - Girotto, Giorgia

AU - Ruggiero, Daniela

AU - d'Adamo, Adamo Pio

AU - Robino, Antonietta

AU - Meitinger, Thomas

AU - Meisinger, Christa

AU - Davies, Gail

AU - Starr, John M.

AU - Chambers, John C.

AU - Boehm, Bernhard O.

AU - Winkelmann, Bernhard R.

AU - Huang, Jie

AU - Murgia, Federico

AU - Wild, Sarah H.

AU - Campbell, Harry

AU - Morris, Andrew P.

AU - Franco, Oscar H.

AU - Hofman, Albert

AU - Uitterlinden, Andre G.

AU - Rivadeneira, Fernando

AU - Völker, Uwe

AU - Hannemann, Anke

AU - Biffar, Reiner

AU - Hoffmann, Wolfgang

AU - Shin, So Youn

AU - Lescuyer, Pierre

AU - Henry, Hughes

AU - Schurmann, Claudia

AU - Munroe, Patricia B.

AU - Gasparini, Paolo

AU - Pirastu, Nicola

AU - Ciullo, Marina

AU - Gieger, Christian

AU - März, Winfried

AU - Lind, Lars

AU - Spector, Tim D.

AU - Smith, Albert V.

AU - Rudan, Igor

AU - Wilson, James F.

AU - Polasek, Ozren

AU - Deary, Ian J.

AU - Pirastu, Mario

AU - Ferrucci, Luigi

AU - Liu, Yongmei

AU - Kestenbaum, Bryan

AU - Kooner, Jaspal S.

AU - Witteman, Jacqueline C.M.

AU - Nauck, Matthias

AU - Kao, W. H.Linda

AU - Wallaschofski, Henri

AU - Bonny, Olivier

AU - Fox, Caroline S.

AU - Bochud, Murielle

PY - 2013/9

Y1 - 2013/9

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.

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DO - 10.1371/journal.pgen.1003796

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JF - PLoS genetics

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ER -

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

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