Meta-analysis of genome-wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women.
Meta-analysis of genome-wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women.
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DOI：
10.1002/jbmr.1796
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发表时间：
2013-03
影响因子：
6.2
通讯作者：
Foroud, Tatiana
中科院分区：
文献类型：
--
作者：
Koller, Daniel L.;Zheng, Hou-Feng;Karasik, David;Yerges-Armstrong, Laura;Liu, Ching-Ti;McGuigan, Fiona;Kemp, John P.;Giroux, Sylvie;Lai, Dongbing;Edenberg, Howard J.;Peacock, Munro;Czerwinski, Stefan A.;Choh, Audrey C.;McMahon, George;St Pourcain, Beate;Timpson, Nicholas J.;Lawlor, Debbie A.;Evans, David M.;Towne, Bradford;Blangero, John;Carless, Melanie A.;Kammerer, Candace;Goltzman, David;Kovacs, Christopher S.;Prior, Jerilynn C.;Spector, Tim D.;Rousseau, Francois;Tobias, Jon H.;Akesson, Kristina;Econs, Michael J.;Mitchell, Braxton D.;Richards, J. Brent;Kiel, Douglas P.;Foroud, Tatiana
以前的全基因组关联研究（GWAS）已经确定了与骨矿物质密度（BMD）变化相关的基因中的常见变异，尽管大多数是在老年女性和男性的合并样本中进行的。这些结果的荟萃分析已经确定了许多SNP在参与骨形成和再吸收以及其他途径的基因中在全基因组显著性水平上具有适度影响。我们进行了一项荟萃分析，仅限于绝经前白色妇女从四个队列（n= 4,061妇女，年龄20至45岁），以确定基因影响峰值骨量在腰椎和股骨颈。插补后，年龄和体重调整的BMD值与每个SNP的关联进行了测试。WNT 16基因中的一个SNP（rs3801387; p=1.7 × 10−9）和ESR 1/C6 orf 97中的多个SNP（rs 4870044; p=1.3 × 10−8）的关联达到了腰椎BMD的全基因组显著性水平。这些SNPs，连同沿着其他显示出关联性证据的SNPs，然后在7个复制队列中进行关联性测试，其中包括欧洲、西班牙裔美国人和非洲裔美国人血统的绝经前妇女（股骨颈合并n= 5，597;腰椎合并n = 4，744）。当联合分析来自发现和复制队列的数据时，证据更加显著（WNT 16联合p=1.3 × 10−11; ESR 1/C6 orf 97联合p= 1.4 × 10−10）。在对主要信号进行调节后，在ESR 1区域观察到脊柱BMD的多个独立关联信号。对股骨颈BMD的分析也支持WNT 16和ESR 1/C6 orf 97中SNP的相关性（p< 1 × 10−5）。我们的研究结果证实，在广泛的年龄范围内，在两种性别的BMD变异的几个基因对绝经前妇女的脊柱BMD的影响相似的幅度。这些数据支持这样的假设，即这些已知骨骼功能的基因的变异也会影响绝经前时期的BMD。
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 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= 4,061 women, ages 20 to 45) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. Following imputation, age- and weight-adjusted BMD values were tested for association with each SNP. Association of a SNP in the WNT16 gene (rs3801387; p=1.7 × 10−9) and multiple SNPs in the ESR1/C6orf97 (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=5,597 for femoral neck; 4,744 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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影响因子：
30.8
作者：
Styrkarsdottir, Unnur;Halldorsson, Bjarni V.;Stefansson, Kari
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