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 & 89 others 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 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

Research output: Contribution to journalArticle

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 languageEnglish (US)
Article numbere1003796
JournalPLoS Genetics
Volume9
Issue number9
DOIs
StatePublished - Sep 2013

Fingerprint

Genome-Wide Association Study
meta-analysis
Meta-Analysis
serum
genome
calcium
Calcium
loci
bone
Serum
Diacylglycerol Kinase
gene
Gene Expression
Bone and Bones
Dietary Calcium
diacylglycerol kinase
bones
gene expression
Bone Density
Genes

ASJC Scopus subject areas

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

Cite this

O'Seaghdha, C. M., Wu, H., Yang, Q., Kapur, K., Guessous, I., Zuber, A. M., ... Bochud, M. (2013). Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations. PLoS Genetics, 9(9), [e1003796]. https://doi.org/10.1371/journal.pgen.1003796

Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations. / 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; 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; Kestenbaum, Bryan; Kooner, Jaspal S.; Witteman, Jacqueline C M; Nauck, Matthias; Kao, W. H Linda; Wallaschofski, Henri; Bonny, Olivier; Fox, Caroline S.; Bochud, Murielle.

In: PLoS Genetics, Vol. 9, No. 9, e1003796, 09.2013.

Research output: Contribution to journalArticle

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, D, 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
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 ; 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 ; Kestenbaum, Bryan ; Kooner, Jaspal S. ; Witteman, Jacqueline C M ; Nauck, Matthias ; Kao, W. H Linda ; Wallaschofski, Henri ; Bonny, Olivier ; Fox, Caroline S. ; Bochud, Murielle. / Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations. In: PLoS Genetics. 2013 ; Vol. 9, No. 9.
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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.",
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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

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

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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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