Nat Genetics：科学家发现新的易感性骨折和骨质疏松症基因群

一项汇集澳大利亚、东亚、欧洲和北美共50多个研究的国际联合项目发现一批骨质疏松基因，使人类认知的骨质疏松基因数增加了一倍，这也是人类首次大规模发现遗传变异与骨折风险的关系。这项研究成果发表在近期出版的《自然遗传学》Nature Genetics杂志上。澳大利亚昆士兰大学的科学家在这项研究中发挥了重要作用。
    
骨质疏松症是一种无声，但频繁和致命性的老年疾病。在澳大利亚，髋部骨折女性患者12个月内死亡率占25％，男性患者甚至更高。对65岁以上的女性威胁比乳腺癌还大。长期以来，虽然人们普遍认为质疏松症是由基因决定的，但具体是由哪些基因造成的仍是一个谜。

目前，双能X射线骨密度仪被广泛用于测量骨密度，诊断骨质疏松和评估骨折风险。一般来说，骨密度越高，骨折风险越小。这项研究共计扫描8万多人，研究骨折病例3万多例、无骨折病例10万多例，是迄今为止最大规模的骨质疏松症遗传研究。新的研究发现，基因组有56个区域的变种影响人们的骨密度，其中有14种会增大骨折的风险。

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.