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; Edward M Brown; John C Chambers; So-Youn Shin; James F Wilson; SUNLIGHT Consortium

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, Edward M Brown, John C Chambers, So-Youn Shin, James F Wilson, SUNLIGHT Consortium

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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
Pages (from-to)	e1003796
Journal	PLoS Genetics
Volume	9
Issue number	9
DOIs	https://doi.org/10.1371/journal.pgen.1003796
Publication status	Published - 2013

Keywords

Animals
Bone Density
Bone and Bones
Calcium
European Continental Ancestry Group
Gene Expression Regulation
Genome-Wide Association Study
Homeostasis
Humans
Kidney
Mice
Polymorphism, Single Nucleotide

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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., ... SUNLIGHT Consortium (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

@article{5d740441c4b54c7d87d318997fd753b2,

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.",

keywords = "Animals, Bone Density, Bone and Bones, Calcium, European Continental Ancestry Group, Gene Expression Regulation, Genome-Wide Association Study, Homeostasis, Humans, Kidney, Mice, Polymorphism, Single Nucleotide",

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 Jean-Michel Gaspoz and Jean-Marc Theler 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 Brown, {Edward M} and Chambers, {John C} and So-Youn Shin and Wilson, {James F} and {SUNLIGHT Consortium}",

year = "2013",

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

language = "English",

volume = "9",

pages = "e1003796",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "9",

}

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, Brown, EM, Chambers, JC, Shin, S-Y, Wilson, JF & SUNLIGHT Consortium 2013, 'Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations', PLoS Genetics, vol. 9, no. 9, pp. 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, 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 - Brown, Edward M

AU - Chambers, John C

AU - Shin, So-Youn

AU - Wilson, James F

AU - SUNLIGHT Consortium

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.

KW - Animals

KW - Bone Density

KW - Bone and Bones

KW - Calcium

KW - European Continental Ancestry Group

KW - Gene Expression Regulation

KW - Genome-Wide Association Study

KW - Homeostasis

KW - Humans

KW - Kidney

KW - Mice

KW - Polymorphism, Single Nucleotide

U2 - 10.1371/journal.pgen.1003796

DO - 10.1371/journal.pgen.1003796

M3 - Article (Academic Journal)

C2 - 24068962

SN - 1553-7390

VL - 9

SP - e1003796

JO - PLoS Genetics

JF - PLoS Genetics

IS - 9

ER -

Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations

Abstract

Keywords

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