Common variants in the calcium-sensing receptor gene are associated with total serum calcium levels.
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.
O'Seaghdha
Conall M
CM
Division of Nephrology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Yang
Qiong
Q
Glazer
Nicole L
NL
Leak
Tennille S
TS
Dehghan
Abbas
A
Smith
Albert V
AV
Kao
W H Linda
WH
Lohman
Kurt
K
Hwang
Shih-Jen
SJ
Johnson
Andrew D
AD
Hofman
Albert
A
Uitterlinden
Andre G
AG
Chen
Yii-Der Ida
YD
Brown
Edward M
EM
Siscovick
David S
DS
Harris
Tamara B
TB
Psaty
Bruce M
BM
Coresh
Josef
J
Gudnason
Vilmundur
V
Witteman
Jacqueline C
JC
Liu
Yong Mei
YM
Kestenbaum
Bryan R
BR
Fox
Caroline S
CS
Köttgen
Anna
A
D000328:Adult; D002118:Calcium / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D044169:Receptors, Calcium-Sensing / Q000235:genetics*
D044169:Receptors, Calcium-Sensing; D002118:Calcium