Genetic analyses in a sample of individuals with high or low BMD shows association with multiple Wnt pathway genes
Genetic analyses in a sample of individuals with high or low BMD shows association with multiple Wnt pathway genes
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在骨密度（BMD）高或低的个体样本中进行的基因分析显示与多个Wnt信号通路基因相关。
DOI：
10.1359/jbmr.071113
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发表时间：
2008-04-01
影响因子：
6.2
通讯作者：
Brown, Matthew A.
中科院分区：
文献类型：
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作者：
Sims, Anne-Marie;Shephard, Neil;Brown, Matthew A.
使用一个中等规模的队列选择极端BMD（n = 344;绝对值BMD，1.5-4.0），显着关联的几个成员的Wnt信号通路与骨密度测量。这证实了极端截断选择是一个强大的设计骨phenotypes.Introduction的数量性状关联研究：虽然骨密度变化的高遗传力早已建立，很少有基因已被最终证明影响骨密度的变化在一般人群中。在数量性状关联研究中，极端截短选择被认为是一种比随机队列设计更有效的选择。我们试图在骨密度测定法测量BMD、BMC和股骨颈面积的研究中检验这些理论预测，方法是在一个中等规模的极端截断选择队列中，调查它们与Wnt通路成员的相关性，其中一些先前已被证明与更大队列中的BMD相关（绝对值BMD Z分数= 1.5-4.0; n = 344）。选取13个Wnt信号通路基因的96个标签单核苷酸多态性（tag-single nucleotide polymorphism，SNPs）标记常见遗传变异（次要等位基因频率[MAF] > 5%，r（2）> 0.8）在13个Wnt信号通路基因的所有外显子的5 kb内。研究的基因包括LRP 1、LRP 5、LRP 6、Wnt 3a、Wnt 7 b、Wnt 10 b、SFRP 1、SFRP 2、DKK 1、DKK 2、FZD 7、WISP 3和SOST。采用Illumina Goldengate微阵列SNP基因分型方法对344例高或低BNID患者进行基因分型。相关性进行了测试，无论是由Cochrane-Armitage测试的二分变量或线性回归的quantitativetrauls.Results：强关联显示与LRP 5，多态性，其中以前已被证明会影响全髋关节BMD（最小p = 0.0006）。此外，Wnt拮抗剂SFRP 1的多态性与BMD和BMC显著相关（最小p = 0.00042）。先前报道的LRP 1、LRP 6和SOST与BMD的相关性得到证实。另外两个Wnt通路基因，Wnt 3a和DKK 2，也表现出名义关联与BMD.Conclusions：这项研究表明，Wnt通路的多个成员的多态性与BMD的变化。此外，这项研究表明，在一个实际的试验中，研究设计涉及极端截断选择和中等样本量可以鲁棒地确定相关的影响大小的基因参与在一般人群中的BMD变化。这对将来设计与骨质疏松症相关的定量骨表型的全基因组研究具有意义。
Using a moderate-sized cohort selected with extreme BMD (n = 344; absolute value BMD, 1.5-4.0), significant association of several members of the Wnt signaling pathway with bone densitometry measures was shown. This confirms that extreme truncate selection is a powerful design for quantitative trait association studies of bone phenotypes.Introduction: Although the high heritability of BMD variation has long been established, few genes have been conclusively shown to affect the variation of BMD in the general population. Extreme truncate selection has been proposed as a more powerful alternative to unselected cohort designs in quantitative trait association studies. We sought to test these theoretical predictions in studies of the bone densitometry measures BMD, BMC, and femoral neck area, by investigating their association with members of the Wnt pathway, some of which have previously been shown to be associated with BMD in much larger cohorts, in a moderate-sized extreme truncate selected cohort (absolute value BMD Z-scores = 1.5-4.0; n = 344).Materials and Methods: Ninety-six tag-single nucleotide polymorphism (SNPs) lying in 13 Wnt signaling pathway genes were selected to tag common genetic variation (minor allele frequency [MAF] > 5% with an r(2) > 0.8) within 5 kb of all exons of 13 Wnt signaling pathway genes. The genes studied included LRP1, LRP5, LRP6, Wnt3a, Wnt7b, Wnt10b, SFRP1, SFRP2, DKK1, DKK2, FZD7, WISP3, and SOST. Three hundred forty-four cases with either high or low BNID were genotyped by Illumina Goldengate microarray SNP genotyping methods. Association was tested either by Cochrane-Armitage test for dichotomous variables or by linear regression for quantitative traits.Results: Strong association was shown with LRP5, polymorphisms of which have previously been shown to influence total hip BMD (minimum p = 0.0006). In addition, polymorphisms of the Wnt antagonist, SFRP1, were significantly associated with BMD and BMC (minimum p = 0.00042). Previously reported associations of LRP1, LRP6, and SOST with BMD were confirmed. Two other Wnt pathway genes, Wnt3a and DKK2, also showed nominal association with BMD.Conclusions: This study shows that polymorphisms of multiple members of the Wnt pathway are associated with BMD variation. Furthermore, this study shows in a practical trial that study designs involving extreme truncate selection and moderate sample sizes can robustly identify genes of relevant effect sizes involved in BMD variation in the general population. This has implications for the design of future genome-wide studies of quantitative bone phenotypes relevant to osteoporosis.