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Genome-Wide Meta-Analysis for Serum Calcium Identifies Significantly Associated SNPs near the Calcium-Sensing Receptor (CASR) Gene

Author

Listed:
  • 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
  • Angelo DiIorio
  • Dawn Waterworth
  • Yun Li
  • Andrew B Singleton
  • Unnur S Bjornsdottir
  • Gunnar Sigurdsson
  • Dena G Hernandez
  • Ranil DeSilva
  • Paul Elliott
  • Gudmundur I Eyjolfsson
  • Jack M Guralnik
  • James Scott
  • Unnur Thorsteinsdottir
  • Stefania Bandinelli
  • John Chambers
  • Kari Stefansson
  • Gérard Waeber
  • Luigi Ferrucci
  • Jaspal S Kooner
  • Vincent Mooser
  • Peter Vollenweider
  • Jacques S Beckmann
  • Murielle Bochud
  • Sven Bergmann

Abstract

Calcium has a pivotal role in biological functions, and serum calcium levels have been associated with numerous disorders of bone and mineral metabolism, as well as with cardiovascular mortality. Here we report results from a genome-wide association study of serum calcium, integrating data from four independent cohorts including a total of 12,865 individuals of European and Indian Asian descent. Our meta-analysis shows that serum calcium is associated with SNPs in or near the calcium-sensing receptor (CASR) gene on 3q13. The top hit with a p-value of 6.3×10-37 is rs1801725, a missense variant, explaining 1.26% of the variance in serum calcium. This SNP had the strongest association in individuals of European descent, while for individuals of Indian Asian descent the top hit was rs17251221 (p = 1.1×10-21), a SNP in strong linkage disequilibrium with rs1801725. The strongest locus in CASR was shown to replicate in an independent Icelandic cohort of 4,126 individuals (p = 1.02×10-4). This genome-wide meta-analysis shows that common CASR variants modulate serum calcium levels in the adult general population, which confirms previous results in some candidate gene studies of the CASR locus. This study highlights the key role of CASR in calcium regulation.Author Summary: Calcium levels in blood serum play an important role in many biological processes. The regulation of serum calcium is under strong genetic control. This study describes the first meta-analysis of a genome-wide association study from four cohorts totaling 12,865 participants of European and Indian Asian descent. Confirming previous results in some candidate gene studies, we find that common polymorphisms at the calcium-sensing receptor (CASR) gene locus are associated with serum calcium concentrations. We show that CASR variants give rise to the strongest signals associated with serum calcium levels in both European and Indian Asian populations, while no other locus reaches genome-wide significance. Our results show that CASR is a key player in genetic regulation of serum calcium in the adult general population.

Suggested Citation

  • 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.
    • Handle: RePEc:plo:pgen00:1001035
    DOI: 10.1371/journal.pgen.1001035
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    References listed on IDEAS

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    1. Brendan Maher, 2008. "Personal genomes: The case of the missing heritability," Nature, Nature, vol. 456(7218), pages 18-21, November.
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    1. 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.

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