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

Kapur K, Johnson T, Beckmann ND, Sehmi J, Tanaka T, Kutalik Z, Styrkarsdottir U, Zhang W, Marek D, Gudbjartsson DF, Milaneschi Y, Holm H, Diiorio A, Waterworth D, Li Y, Singleton AB, Bjornsdottir US, Sigurdsson G, Hernandez DG, Desilva R, Elliott P, Eyjolfsson GI, Guralnik JM, Scott J, Thorsteinsdottir U, Bandinelli S, Chambers J, Stefansson K, Waeber G, Ferrucci L, Kooner JS, Mooser V, Vollenweider P, Beckmann JS, Bochud M, Bergmann S - PLoS Genet. (2010)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.

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.

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Related in: MedlinePlus

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.
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pgen-1001035-g002: 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.

Mentions: Genome-wide association scans were performed first independently for each cohort using linear regression and then the effect sizes from each cohort were meta-analyzed (see Materials and Methods). Due to the possibility of population substructure obscuring effects of genetic variants, meta-analysis was performed separately for (i) combined European and Indian Asian cohorts (N = 12,865) and restricted to cohorts of (ii) European (N = 8,919), and (iii) Indian Asian descent (N = 3,947). The meta-analyses yielded 100 SNPs from the combined cohorts, 70 SNPs when restricting to European cohorts and 22 SNPs restricting to Indian Asian cohorts that exceeded the genome-wide significance threshold of 5×10-8 (Figure 1A–1C) (the full list is provided in Table S2A, S2B, S2C). All SNPs reaching statistical significance clustered around the CASR locus at 3q13. The most significant SNP in the (i) combined and (ii) European meta-analyses was rs1801725 (p = 6.29×10-37, p = 2.58×10-18, respectively) and in the (iii) Indian Asian meta-analysis was rs17251221 (p = 1.07×10-21). These two SNPs are less than 11 kb apart and are in high linkage disequilibrium with each other (r2 = 0.946, 0.494, 1.0, 1.0 in HapMap CEU, CHB, JPT, YRI, respectively), and therefore most likely derive from the same association signal. We find that rs1801725 explains 1.26% of the variance in serum calcium, with the effect sizes and standard errors of the serum calcium increasing T allele in individual cohorts shown in Figure 2 and Table S3. According to our additive model, each rs1801725 T allele increases log10 serum calcium (in units mmol/L) by 3.61×10-3, equivalent to a multiplicative effect of 1.008 on serum calcium (see also Table S2). At an average serum calcium level of 2.25 mmol/L, each rs1801725 T allele yields an increase of 0.01874 mmol/L, or 21% of one standard deviation of serum calcium levels in a normal population. The regional pattern of association of SNPs around the CASR locus, and their linkage disequilibrium with rs1801725, are shown in Figure 3. Of note, rs1042636, which has been associated with decreased serum calcium [23], also achieved genome-wide significance with the G minor allele associated with decreased serum calcuim (p = 4.96×10-9). However, conditional on the rs1801725 locus, located 12 bps upstream, the rs1042636 p-value became 3.32×10−4, indicating that the two loci share contributions to serum calcium levels.


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

Kapur K, Johnson T, Beckmann ND, Sehmi J, Tanaka T, Kutalik Z, Styrkarsdottir U, Zhang W, Marek D, Gudbjartsson DF, Milaneschi Y, Holm H, Diiorio A, Waterworth D, Li Y, Singleton AB, Bjornsdottir US, Sigurdsson G, Hernandez DG, Desilva R, Elliott P, Eyjolfsson GI, Guralnik JM, Scott J, Thorsteinsdottir U, Bandinelli S, Chambers J, Stefansson K, Waeber G, Ferrucci L, Kooner JS, Mooser V, Vollenweider P, Beckmann JS, Bochud M, Bergmann S - PLoS Genet. (2010)

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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2908705&req=5

pgen-1001035-g002: 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.
Mentions: Genome-wide association scans were performed first independently for each cohort using linear regression and then the effect sizes from each cohort were meta-analyzed (see Materials and Methods). Due to the possibility of population substructure obscuring effects of genetic variants, meta-analysis was performed separately for (i) combined European and Indian Asian cohorts (N = 12,865) and restricted to cohorts of (ii) European (N = 8,919), and (iii) Indian Asian descent (N = 3,947). The meta-analyses yielded 100 SNPs from the combined cohorts, 70 SNPs when restricting to European cohorts and 22 SNPs restricting to Indian Asian cohorts that exceeded the genome-wide significance threshold of 5×10-8 (Figure 1A–1C) (the full list is provided in Table S2A, S2B, S2C). All SNPs reaching statistical significance clustered around the CASR locus at 3q13. The most significant SNP in the (i) combined and (ii) European meta-analyses was rs1801725 (p = 6.29×10-37, p = 2.58×10-18, respectively) and in the (iii) Indian Asian meta-analysis was rs17251221 (p = 1.07×10-21). These two SNPs are less than 11 kb apart and are in high linkage disequilibrium with each other (r2 = 0.946, 0.494, 1.0, 1.0 in HapMap CEU, CHB, JPT, YRI, respectively), and therefore most likely derive from the same association signal. We find that rs1801725 explains 1.26% of the variance in serum calcium, with the effect sizes and standard errors of the serum calcium increasing T allele in individual cohorts shown in Figure 2 and Table S3. According to our additive model, each rs1801725 T allele increases log10 serum calcium (in units mmol/L) by 3.61×10-3, equivalent to a multiplicative effect of 1.008 on serum calcium (see also Table S2). At an average serum calcium level of 2.25 mmol/L, each rs1801725 T allele yields an increase of 0.01874 mmol/L, or 21% of one standard deviation of serum calcium levels in a normal population. The regional pattern of association of SNPs around the CASR locus, and their linkage disequilibrium with rs1801725, are shown in Figure 3. Of note, rs1042636, which has been associated with decreased serum calcium [23], also achieved genome-wide significance with the G minor allele associated with decreased serum calcuim (p = 4.96×10-9). However, conditional on the rs1801725 locus, located 12 bps upstream, the rs1042636 p-value became 3.32×10−4, indicating that the two loci share contributions to serum calcium levels.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.

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.

Show MeSH
Related in: MedlinePlus