以前,有32个与骨质疏松症和骨折相关的基因区域一直没有被确定,现在已被一个大型的、世界性研究协会所确定。这些区域中的DNA序列变化要么赋予骨弱化疾病的风险,要么预防骨弱化疾病。很多但不是所有区域编码那些蛋白质,该蛋白质参与涉及骨骼健康的已知途径。
该研究不仅表明骨质疏松源自于数十个基因的综合影响,也指出许多开发抗骨质疏松药物的新方法。它所用的meta分析法包括了17个全基因组相关性研究,180个研究人员和10多万参与者,也鉴定出了与股骨骨折或下背骨折风险密切相关的6个区域。但是,该研究的个人预测力相对较低。
该研究掩盖了全基因组关联研究(GWAS,一种快速扫描与疾病发生相关的全基因组细微区别的方法)能力辜负早期宣传的挫折。当GWAS在2005年首次被介绍时,许多研究人员就预言它将很快确定许多疾病的决定性突变。对于诸如骨质疏松、II型糖尿症和肥胖之类的复杂疾病,这种乐观评价证明是没有根据的,这些疾病可能涉及许多基因和环境成分的综合影响。这表明,大多数GWAS中参与者数量可能需要大大扩大才能提供有用的数据。
为此,世界各地的研究小组综合了来自17个全基因组关联研究的数据,对来自北美、欧洲、东亚和澳大利亚的近33000名参与者的骨矿物密度进行集中研究。这样综合研究的结果让研究人员甚至能确定任何一个研究可能已经失之交臂的弱关联。
为了深入研究,研究小组鉴定了基因组的87个区域,然后在另外34个骨矿物密度研究中分析这些区域,其中总参与人数近51000。为了观察那些影响骨矿物密度与骨折真实发生率的变异之间的关联,研究人员比较了这些区域的序列或拼写在31000名骨折患者与100000多名未患骨折的人的不同。最后,发现6个变异与骨折风险显著相关,还发现许多先前涉及骨形成与健康的基因:Wnt信号通路成员、涉及间质细胞分化重要通路的几个基因、哺乳动物骨骼形成期间涉及软骨内成骨的其他几个基因。(生物谷bioon.com)
doi:10.1038/ng.2249
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Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture
Karol Estrada, Unnur Styrkarsdottir, Evangelos Evangelou, Yi-Hsiang Hsu, Emma L Duncan,Evangelia E Ntzani, Ling Oei, Omar M E Albagha, Najaf Amin, John P Kemp, Daniel L Koller, Guo Li,Ching-Ti Liu, Ryan L Minster, Alireza Moayyeri, Liesbeth Vandenput, Dana Willner, Su-Mei Xiao,Laura M Yerges-Armstrong, Hou-Feng Zheng, Nerea Alonso, Joel Eriksson,Candace M Kammerer,Stephen K Kaptoge, Paul J Leo et al.
Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10?8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10?4, Bonferroni corrected), of which six reached P < 5 × 10?8, including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.