Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass
Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass
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DOI：
10.1359/jbmr.060806
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发表时间：
2007-02-01
影响因子：
6.2
通讯作者：
Ralston, Stuart H.
中科院分区：
文献类型：
--
作者：
Ioannidis, John P. A.;Ng, Mandy Y.;Ralston, Stuart H.
骨密度是一种遗传性状，是骨质疏松性骨折风险的重要预测因子。已经进行了几次全基因组扫描，试图检测调节骨密度的位点，但研究之间的连锁峰的复制有限。为了解决这些不一致，我们对全基因组连锁扫描进行了协作荟萃分析，其中研究了股骨颈骨密度（FN-BMD）或腰椎骨密度（LS-BMD）。材料和方法：数据来自9个全基因组扫描，涉及11,842名受试者。对LS-BMD、FN-BMD和性别数据分别进行分析。对于每项研究，定义30 cM的基因组箱，并根据其所含的最大LOD评分进行排序。虽然在不同的研究中使用了不同的密度计，但我们使用的排序方法意味着结果不会因为使用了不同的测量设备而混淆。通过蒙特卡罗检验获得高平均秩和异质性的显著性。结果：对于LS-BMD，最显著的数量性状位点（QTL）在染色体1p13.3-q23.3上（p = 0.004），但异质性较高，且对女性有特异性影响。其他重要的LS-BMD qtl位于染色体12q24.31-qter、3p25.3-p22.1、11p12-q13.3和1q32-q42.3上，包括18p11-q12.3上的一个未被单独研究检测到的qtl。FN-BMD最强QTL位于9q31.1 ~ q33.3染色体上（p = 0.002）。在染色体17p12-q21.33、14q1 .3.1-q24.1、9q21.32-q31.1和5q1.4.3-q23.2上发现了其他显著qtl。在男性和女性之间，箱子的平均排列没有相关性，而且调节男性和女性骨密度的基因座在不同的位置有很大的不同。结论：这项大规模荟萃分析为先前研究中发现的几个QTL的复制提供了证据，并在染色体18p11-q12.3上发现了一个单个研究未发现的QTL。然而，尽管样本量很大，但所鉴定的单个位点都没有达到全基因组意义。
Introduction: BMD is a heritable trait and an important predictor of osteoporotic fracture risk. Several genome-wide scans have been performed in an attempt to detect loci that regulate BMD, but there has been limited replication of linkage peaks between studies. In an attempt to resolve these inconsistencies, we conducted a collaborative meta-analysis of genome-wide linkage scans in which femoral neck BMD (FN-BMD) or lumbar spine BMD (LS-BMD) had been studied.Materials and Methods: Data were accumulated from nine genome-wide scans involving 11,842 subjects. Data were analyzed separately for LS-BMD and FN-BMD and by sex. For each study, genomic bins of 30 cM were defined and ranked according to the maximum LOD score they contained. While various densitometers were used in different studies, the ranking approach that we used means that the results are not confounded by the fact that different measurement devices were used. Significance for high average rank and heterogeneity was obtained through Monte Carlo testing.Results: For LS-BMD, the quantitative trait locus (QTL) with greatest significance was on chromosome 1p13.3-q23.3 (p = 0.004), but this exhibited high heterogeneity and the effect was specific for women. Other significant LS-BMD QTLs were on chromosomes 12q24.31-qter, 3p25.3-p22.1, 11p12-q13.3, and 1q32-q42.3, including one on 18p11-q12.3 that had not been detected by individual studies. For FN-BMD, the strongest QTL was on chromosome 9q31.1-q33.3 (p = 0.002). Other significant QTLs were identified on chromosomes 17p12-q21.33, 14ql.3.1-q24.1, 9q21.32-q31.1, and 5q1.4.3-q23.2. There was no correlation in average ranks of bins between men and women and the loci that regulated BMD in men and women and at different sites were largely distinct.Conclusions: This large-scale meta-analysis provided evidence for replication of several QTLs identified in previous studies and also identified a QTL on chromosome 18p11-q12.3, which had not been detected by individual studies. However, despite the large sample size, none of the individual loci identified reached genome-wide significance.