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

Conall M. O'Seaghdha, Qiong Yang, Nicole L. Glazer, Tennille S. Leak, Abbas Dehghan, Albert V. Smith, W. H Linda Kao, Kurt Lohman, Shih Jen Hwang, Andrew D. Johnson, Albert Hofman, Andre G. Uitterlinden, Yii der Ida Chen, Edward M. Brown, David S. Siscovick, Tamara B. Harris, Bruce M. Psaty, Josef Coresh, Vilmundur Gudnason, Jacqueline C. Witteman & 4 others Yong Mei Liu, Bryan R. Kestenbaum, Caroline S. Fox, Anna K̈ttgen

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article numberddq342
Pages (from-to)4296-4303
Number of pages8
JournalHuman Molecular Genetics
Volume19
Issue number21
DOIs
StatePublished - Aug 12 2010

Fingerprint

Calcium-Sensing Receptors
Calcium
Serum
Genes
Single Nucleotide Polymorphism
Genome-Wide Association Study
Alleles
Femur Neck
Rare Diseases
Gene Frequency
Bone Density
Magnesium
Population
Spine
Phosphates
Genome
Mutation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

O'Seaghdha, C. M., Yang, Q., Glazer, N. L., Leak, T. S., Dehghan, A., Smith, A. V., ... K̈ttgen, A. (2010). Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels. Human Molecular Genetics, 19(21), 4296-4303. [ddq342]. https://doi.org/10.1093/hmg/ddq342

Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels. / O'Seaghdha, Conall M.; Yang, Qiong; Glazer, Nicole L.; Leak, Tennille S.; Dehghan, Abbas; Smith, Albert V.; Kao, W. H Linda; Lohman, Kurt; Hwang, Shih Jen; Johnson, Andrew D.; Hofman, Albert; Uitterlinden, Andre G.; Chen, Yii der Ida; Brown, Edward M.; Siscovick, David S.; Harris, Tamara B.; Psaty, Bruce M.; Coresh, Josef; Gudnason, Vilmundur; Witteman, Jacqueline C.; Liu, Yong Mei; Kestenbaum, Bryan R.; Fox, Caroline S.; K̈ttgen, Anna.

In: Human Molecular Genetics, Vol. 19, No. 21, ddq342, 12.08.2010, p. 4296-4303.

Research output: Contribution to journalArticle

O'Seaghdha, CM, Yang, Q, Glazer, NL, Leak, TS, Dehghan, A, Smith, AV, Kao, WHL, Lohman, K, Hwang, SJ, Johnson, AD, Hofman, A, Uitterlinden, AG, Chen, YDI, Brown, EM, Siscovick, DS, Harris, TB, Psaty, BM, Coresh, J, Gudnason, V, Witteman, JC, Liu, YM, Kestenbaum, BR, Fox, CS & K̈ttgen, A 2010, 'Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels', Human Molecular Genetics, vol. 19, no. 21, ddq342, pp. 4296-4303. https://doi.org/10.1093/hmg/ddq342
O'Seaghdha CM, Yang Q, Glazer NL, Leak TS, Dehghan A, Smith AV et al. Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels. Human Molecular Genetics. 2010 Aug 12;19(21):4296-4303. ddq342. https://doi.org/10.1093/hmg/ddq342
O'Seaghdha, Conall M. ; Yang, Qiong ; Glazer, Nicole L. ; Leak, Tennille S. ; Dehghan, Abbas ; Smith, Albert V. ; Kao, W. H Linda ; Lohman, Kurt ; Hwang, Shih Jen ; Johnson, Andrew D. ; Hofman, Albert ; Uitterlinden, Andre G. ; Chen, Yii der Ida ; Brown, Edward M. ; Siscovick, David S. ; Harris, Tamara B. ; Psaty, Bruce M. ; Coresh, Josef ; Gudnason, Vilmundur ; Witteman, Jacqueline C. ; Liu, Yong Mei ; Kestenbaum, Bryan R. ; Fox, Caroline S. ; K̈ttgen, Anna. / Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels. In: Human Molecular Genetics. 2010 ; Vol. 19, No. 21. pp. 4296-4303.
@article{84a01e79c6924ec8a5b37b04ee727e2b,
title = "Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels",
abstract = "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.",
author = "O'Seaghdha, {Conall M.} and Qiong Yang and Glazer, {Nicole L.} and Leak, {Tennille S.} and Abbas Dehghan and Smith, {Albert V.} and Kao, {W. H Linda} and Kurt Lohman and Hwang, {Shih Jen} and Johnson, {Andrew D.} and Albert Hofman and Uitterlinden, {Andre G.} and Chen, {Yii der Ida} and Brown, {Edward M.} and Siscovick, {David S.} and Harris, {Tamara B.} and Psaty, {Bruce M.} and Josef Coresh and Vilmundur Gudnason and Witteman, {Jacqueline C.} and Liu, {Yong Mei} and Kestenbaum, {Bryan R.} and Fox, {Caroline S.} and Anna K̈ttgen",
year = "2010",
month = "8",
day = "12",
doi = "10.1093/hmg/ddq342",
language = "English (US)",
volume = "19",
pages = "4296--4303",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "21",

}

TY - JOUR

T1 - Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels

AU - O'Seaghdha, Conall M.

AU - Yang, Qiong

AU - Glazer, Nicole L.

AU - Leak, Tennille S.

AU - Dehghan, Abbas

AU - Smith, Albert V.

AU - Kao, W. H Linda

AU - Lohman, Kurt

AU - Hwang, Shih Jen

AU - Johnson, Andrew D.

AU - Hofman, Albert

AU - Uitterlinden, Andre G.

AU - Chen, Yii der Ida

AU - Brown, Edward M.

AU - Siscovick, David S.

AU - Harris, Tamara B.

AU - Psaty, Bruce M.

AU - Coresh, Josef

AU - Gudnason, Vilmundur

AU - Witteman, Jacqueline C.

AU - Liu, Yong Mei

AU - Kestenbaum, Bryan R.

AU - Fox, Caroline S.

AU - K̈ttgen, Anna

PY - 2010/8/12

Y1 - 2010/8/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77957870933&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77957870933&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddq342

DO - 10.1093/hmg/ddq342

M3 - Article

VL - 19

SP - 4296

EP - 4303

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 21

M1 - ddq342

ER -