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Meta-Analysis
. 2013 Mar;28(3):547-58.
doi: 10.1002/jbmr.1796.

Meta-analysis of genome-wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women

Daniel L Koller  1 , Hou-Feng Zheng, David Karasik, Laura Yerges-Armstrong, Ching-Ti Liu, Fiona McGuigan, John P Kemp, Sylvie Giroux, Dongbing Lai, Howard J Edenberg, Munro Peacock, Stefan A Czerwinski, Audrey C Choh, George McMahon, Beate St Pourcain, Nicholas J Timpson, Debbie A Lawlor, David M Evans, Bradford Towne, John Blangero, Melanie A Carless, Candace Kammerer, David Goltzman, Christopher S Kovacs, Jerilynn C Prior, Tim D Spector, Francois Rousseau, Jon H Tobias, Kristina Akesson, Michael J Econs, Braxton D Mitchell, J Brent Richards, Douglas P Kiel, Tatiana Foroud
Affiliations
Meta-Analysis

Meta-analysis of genome-wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women

Daniel L Koller et al. J Bone Miner Res. 2013 Mar.

Abstract

Previous genome-wide association studies (GWAS) have identified common variants in genes associated with variation in bone mineral density (BMD), although most have been carried out in combined samples of older women and men. Meta-analyses of these results have identified numerous single-nucleotide polymorphisms (SNPs) of modest effect at genome-wide significance levels in genes involved in both bone formation and resorption, as well as other pathways. We performed a meta-analysis restricted to premenopausal white women from four cohorts (n = 4061 women, aged 20 to 45 years) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. After imputation, age- and weight-adjusted bone-mineral density (BMD) values were tested for association with each SNP. Association of an SNP in the WNT16 gene (rs3801387; p = 1.7 × 10(-9) ) and multiple SNPs in the ESR1/C6orf97 region (rs4870044; p = 1.3 × 10(-8) ) achieved genome-wide significance levels for lumbar spine BMD. These SNPs, along with others demonstrating suggestive evidence of association, were then tested for association in seven replication cohorts that included premenopausal women of European, Hispanic-American, and African-American descent (combined n = 5597 for femoral neck; n = 4744 for lumbar spine). When the data from the discovery and replication cohorts were analyzed jointly, the evidence was more significant (WNT16 joint p = 1.3 × 10(-11) ; ESR1/C6orf97 joint p = 1.4 × 10(-10) ). Multiple independent association signals were observed with spine BMD at the ESR1 region after conditioning on the primary signal. Analyses of femoral neck BMD also supported association with SNPs in WNT16 and ESR1/C6orf97 (p < 1 × 10(-5) ). Our results confirm that several of the genes contributing to BMD variation across a broad age range in both sexes have effects of similar magnitude on BMD of the spine in premenopausal women. These data support the hypothesis that variants in these genes of known skeletal function also affect BMD during the premenopausal period.

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Conflict of interest statement

DISCLOSURE PAGE

All authors state that they have no conflicts of interest.

Figures

Figure 1
Figure 1. Genome-wide results from the meta-analysis of the Discovery Sample
A. Lumbar Spine BMD. B. Femoral Neck BMD. The X axis indicates the chromosomal position of each SNP while the Y axis denotes the evidence of association shown as -log(p-value).
Figure 1
Figure 1. Genome-wide results from the meta-analysis of the Discovery Sample
A. Lumbar Spine BMD. B. Femoral Neck BMD. The X axis indicates the chromosomal position of each SNP while the Y axis denotes the evidence of association shown as -log(p-value).
Figure 2
Figure 2. Evidence of association with lumbar spine BMD in WNT16/FAM3C and ESR1/C6orf97 chromosomal regions
X axis is the physical position on the chromosome (Mb); Y-axis denotes the association test result as -log(p-value), with colored shading reflected degree of linkage disequilibrium with the top SNP in the region (white diamond symbol). A. SNP rs3801387 in the WNT16 region; B. SNP rs4870044 in the ESR1/C6orf97 region.
Figure 2
Figure 2. Evidence of association with lumbar spine BMD in WNT16/FAM3C and ESR1/C6orf97 chromosomal regions
X axis is the physical position on the chromosome (Mb); Y-axis denotes the association test result as -log(p-value), with colored shading reflected degree of linkage disequilibrium with the top SNP in the region (white diamond symbol). A. SNP rs3801387 in the WNT16 region; B. SNP rs4870044 in the ESR1/C6orf97 region.
Figure 3
Figure 3. Effect sizes for all studies contributing to the meta-analysis for lumbar spine BMD
Effect sizes in standardized units (mean BMD=0, standard deviation=1) are shown along with their 95% confidence intervals for each individual study. The overall effect size estimate from the Joint meta-analysis is indicated in the bottom bar. Results are shown for SNPs: A. rs3801387 in WNT16; B. rs487004, rs6930633; and rs2982575 in the C6orf97/ESR1 region. In panel B, effect sizes are shown as positive quantities for ease of comparison.
Figure 3
Figure 3. Effect sizes for all studies contributing to the meta-analysis for lumbar spine BMD
Effect sizes in standardized units (mean BMD=0, standard deviation=1) are shown along with their 95% confidence intervals for each individual study. The overall effect size estimate from the Joint meta-analysis is indicated in the bottom bar. Results are shown for SNPs: A. rs3801387 in WNT16; B. rs487004, rs6930633; and rs2982575 in the C6orf97/ESR1 region. In panel B, effect sizes are shown as positive quantities for ease of comparison.
Figure 4
Figure 4. Results from conditional analysis of lumbar spine BMD with GWAS SNPs in the WNT16 and ESR1/C6orf97 regions
−log(p-value) is shown for SNPs in these regions. Degree of linkage disequilibrium with the SNP with highest remaining −log(p-value) after conditioning (indicated by white diamond symbol) is shown according to the color scale at top left or top right. A) SNPs in WNT16 region conditioned on SNP rs3801387 (compare to Figure 2A). B–D) SNPs in ESR1/C6orf97 region conditioned on SNPs rs487004, rs6930633; and rs2982575 respectively (compare to Figure 2B).
Figure 4
Figure 4. Results from conditional analysis of lumbar spine BMD with GWAS SNPs in the WNT16 and ESR1/C6orf97 regions
−log(p-value) is shown for SNPs in these regions. Degree of linkage disequilibrium with the SNP with highest remaining −log(p-value) after conditioning (indicated by white diamond symbol) is shown according to the color scale at top left or top right. A) SNPs in WNT16 region conditioned on SNP rs3801387 (compare to Figure 2A). B–D) SNPs in ESR1/C6orf97 region conditioned on SNPs rs487004, rs6930633; and rs2982575 respectively (compare to Figure 2B).
Figure 4
Figure 4. Results from conditional analysis of lumbar spine BMD with GWAS SNPs in the WNT16 and ESR1/C6orf97 regions
−log(p-value) is shown for SNPs in these regions. Degree of linkage disequilibrium with the SNP with highest remaining −log(p-value) after conditioning (indicated by white diamond symbol) is shown according to the color scale at top left or top right. A) SNPs in WNT16 region conditioned on SNP rs3801387 (compare to Figure 2A). B–D) SNPs in ESR1/C6orf97 region conditioned on SNPs rs487004, rs6930633; and rs2982575 respectively (compare to Figure 2B).
Figure 4
Figure 4. Results from conditional analysis of lumbar spine BMD with GWAS SNPs in the WNT16 and ESR1/C6orf97 regions
−log(p-value) is shown for SNPs in these regions. Degree of linkage disequilibrium with the SNP with highest remaining −log(p-value) after conditioning (indicated by white diamond symbol) is shown according to the color scale at top left or top right. A) SNPs in WNT16 region conditioned on SNP rs3801387 (compare to Figure 2A). B–D) SNPs in ESR1/C6orf97 region conditioned on SNPs rs487004, rs6930633; and rs2982575 respectively (compare to Figure 2B).
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