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

Author

Listed:
  • 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
  • The SUNLIGHT consortium
  • The GEFOS consortium
  • 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

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 Summary: Calcium is vital to many biological processes and its serum concentration is tightly regulated. Family studies have shown that serum calcium is under strong genetic control. 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. We identified seven loci (six new regions) as being robustly associated with serum calcium. Three loci implicate regions involved in rare monogenic diseases including disturbances of serum calcium levels. Several of the newly identified loci harbor genes linked to the hormonal control of serum calcium. In mice experiments, we characterized the expression of these genes in gut, kidney, and bone, and explored the influence of dietary calcium intake on the expression of these genes in these organs. Our results shed new light on the genetics of calcium homeostasis and suggest a role for dietary calcium intake in bone-specific gene expression.

Suggested Citation

  • 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 De, 2013. "Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations," PLOS Genetics, Public Library of Science, vol. 9(9), pages 1-13, September.
    • Handle: RePEc:plo:pgen00:1003796
    DOI: 10.1371/journal.pgen.1003796
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    as
    1. Karen Kapur & Toby Johnson & Noam D Beckmann & Joban Sehmi & Toshiko Tanaka & Zoltán Kutalik & Unnur Styrkarsdottir & Weihua Zhang & Diana Marek & Daniel F Gudbjartsson & Yuri Milaneschi & Hilma Holm , 2010. "Genome-Wide Meta-Analysis for Serum Calcium Identifies Significantly Associated SNPs near the Calcium-Sensing Receptor (CASR) Gene," PLOS Genetics, Public Library of Science, vol. 6(7), pages 1-12, July.
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