Genome-wide meta-analysis for serum calcium identifies significantly associated SNPs near the calcium-sensing receptor (CASR) gene

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 x 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 x 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 x 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.

Figure 1. Genome-wide association results.

Manhattan plots showing significance of association of all SNPs in the meta-analysis for (A) combined European and Indian Asian cohorts, (B) European cohorts only and (C) Indian Asian cohorts only. SNPs are plotted on the x-axis according to their position on each chromosome against association with serum calcium concentrations on the y-axis (shown as −log₁₀ p-values).

Figure 2. Comparison of rs1801725 significance across cohorts.

The effect size and 95% confidence intervals of the serum calcium increasing T allele of SNP rs1801725 are shown separately for each cohort (CoLaus, LOLIPOP_EWA, LOLIPOP_EWP, LOLIPOP_IAA, LOLIPOP_IAI, LOLIPOP_IAP, BLSA, InCHIANTI) and for the replication cohort deCODE. European cohorts are shown in blue and Indian Asian cohorts are drawn in green. The size of the box is proportional to the precision 1/se² and the meta-analysis estimate and 95% confidence interval across all cohorts is given by a diamond.

Figure 3. Regional association plot of the CASR locus.

Plots show genomic position on the x-axis and −log₁₀ p-values on the y-axis for SNPs in the CASR locus on chromosome 3. The sentinel hit is shown as a red square. Patterns of linkage disequilibrium between the sentinel SNP and all other SNPs are color-coded. Red circles indicate high correlation (r²>0.8), green circles indicate moderate correlation (r²>0.5), blue circles indicate low correlation (r²>0.2) and black circles indicate no correlation (r²<0.2). The fine-scale recombination rates from – are plotted in light blue.