Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels.

Journal Article (Journal Article)

Serum calcium levels are tightly regulated. We performed genome-wide association studies (GWAS) in population-based studies participating in the CHARGE Consortium to uncover common genetic variations associated with total serum calcium levels. GWAS of serum calcium concentrations was performed in 20 611 individuals of European ancestry for ∼2.5 million genotyped and imputed single-nucleotide polymorphisms (SNPs). The SNP with the lowest P-value was rs17251221 (P = 2.4 * 10(-22), minor allele frequency 14%) in the calcium-sensing receptor gene (CASR). This lead SNP was associated with higher serum calcium levels [0.06 mg/dl (0.015 mmol/l) per copy of the minor G allele] and accounted for 0.54% of the variance in serum calcium concentrations. The identification of variation in CASR that influences serum calcium concentration confirms the results of earlier candidate gene studies. The G allele of rs17251221 was also associated with higher serum magnesium levels (P = 1.2 * 10(-3)), lower serum phosphate levels (P = 2.8 * 10(-7)) and lower bone mineral density at the lumbar spine (P = 0.038), but not the femoral neck. No additional genomic loci contained SNPs associated at genome-wide significance (P < 5 * 10(-8)). These associations resemble clinical characteristics of patients with familial hypocalciuric hypercalcemia, an autosomal-dominant disease arising from rare inactivating mutations in the CASR gene. We conclude that common genetic variation in the CASR gene is associated with similar but milder features in the general population.

Full Text

Duke Authors

Cited Authors

  • O'Seaghdha, CM; Yang, Q; Glazer, NL; Leak, TS; Dehghan, A; Smith, AV; Kao, WHL; Lohman, K; Hwang, S-J; Johnson, AD; Hofman, A; Uitterlinden, AG; Chen, Y-DI; GEFOS Consortium, ; Brown, EM; Siscovick, DS; Harris, TB; Psaty, BM; Coresh, J; Gudnason, V; Witteman, JC; Liu, YM; Kestenbaum, BR; Fox, CS; Köttgen, A

Published Date

  • November 1, 2010

Published In

Volume / Issue

  • 19 / 21

Start / End Page

  • 4296 - 4303

PubMed ID

  • 20705733

Pubmed Central ID

  • PMC2951868

Electronic International Standard Serial Number (EISSN)

  • 1460-2083

Digital Object Identifier (DOI)

  • 10.1093/hmg/ddq342


  • eng

Conference Location

  • England