Zhang Lei, Choi Hyung Jin, Estrada Karol, Leo Paul J, Li Jian, Pei Yu-Fang, Zhang Yinping, Lin Yong, Shen Hui, Liu Yao-Zhong, Liu Yongjun, Zhao Yingchun, Zhang Ji-Gang, Tian Qing, Wang Yu-ping, Han Yingying, Ran Shu, Hai Rong, Zhu Xue-Zhen, Wu Shuyan, Yan Han, Liu Xiaogang, Yang Tie-Lin, Guo Yan, Zhang Feng, Guo Yan-fang, Chen Yuan, Chen Xiangding, Tan Lijun, Zhang Lishu, Deng Fei-Yan, Deng Hongyi, Rivadeneira Fernando, Duncan Emma L, Lee Jong Young, Han Bok Ghee, Cho Nam H, Nicholson Geoffrey C, McCloskey Eugene, Eastell Richard, Prince Richard L, Eisman John A, Jones Graeme, Reid Ian R, Sambrook Philip N, Dennison Elaine M, Danoy Patrick, Yerges-Armstrong Laura M, Streeten Elizabeth A, Hu Tian, Xiang Shuanglin, Papasian Christopher J, Brown Matthew A, Shin Chan Soo, Uitterlinden André G, Deng Hong-Wen
Center of System Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai, China.
Hum Mol Genet. 2014 Apr 1;23(7):1923-33. doi: 10.1093/hmg/ddt575. Epub 2013 Nov 17.
Aiming to identify novel genetic variants and to confirm previously identified genetic variants associated with bone mineral density (BMD), we conducted a three-stage genome-wide association (GWA) meta-analysis in 27 061 study subjects. Stage 1 meta-analyzed seven GWA samples and 11 140 subjects for BMDs at the lumbar spine, hip and femoral neck, followed by a Stage 2 in silico replication of 33 SNPs in 9258 subjects, and by a Stage 3 de novo validation of three SNPs in 6663 subjects. Combining evidence from all the stages, we have identified two novel loci that have not been reported previously at the genome-wide significance (GWS; 5.0 × 10(-8)) level: 14q24.2 (rs227425, P-value 3.98 × 10(-13), SMOC1) in the combined sample of males and females and 21q22.13 (rs170183, P-value 4.15 × 10(-9), CLDN14) in the female-specific sample. The two newly identified SNPs were also significant in the GEnetic Factors for OSteoporosis consortium (GEFOS, n = 32 960) summary results. We have also independently confirmed 13 previously reported loci at the GWS level: 1p36.12 (ZBTB40), 1p31.3 (GPR177), 4p16.3 (FGFRL1), 4q22.1 (MEPE), 5q14.3 (MEF2C), 6q25.1 (C6orf97, ESR1), 7q21.3 (FLJ42280, SHFM1), 7q31.31 (FAM3C, WNT16), 8q24.12 (TNFRSF11B), 11p15.3 (SOX6), 11q13.4 (LRP5), 13q14.11 (AKAP11) and 16q24 (FOXL1). Gene expression analysis in osteogenic cells implied potential functional association of the two candidate genes (SMOC1 and CLDN14) in bone metabolism. Our findings independently confirm previously identified biological pathways underlying bone metabolism and contribute to the discovery of novel pathways, thus providing valuable insights into the intervention and treatment of osteoporosis.
为了识别新的基因变异并确认先前已鉴定出的与骨密度（BMD）相关的基因变异，我们对27061名研究对象进行了一项三阶段全基因组关联（GWA）荟萃分析。第一阶段对7个GWA样本和11140名研究对象的腰椎、髋部和股骨颈骨密度进行荟萃分析，随后在第二阶段对9258名研究对象中的33个单核苷酸多态性（SNP）进行电子复制，在第三阶段对6663名研究对象中的3个SNP进行从头验证。综合所有阶段的证据，我们发现了两个此前未在全基因组显著性（GWS；5.0×10⁻⁸）水平报道过的新位点：在男性和女性合并样本中的14q24.2（rs227425，P值3.98×10⁻¹³，SMOC1）以及女性特异性样本中的21q22.13（rs170183，P值4.15×10⁻⁹，CLDN14）。这两个新鉴定出的SNP在骨质疏松症遗传因素（GEFOS，n = 32960）汇总结果中也具有显著性。我们还在GWS水平独立确认了13个先前报道过的位点：1p36.12（ZBTB40）、1p31.3（GPR177）、4p16.3（FGFRL1）、4q22.1（MEPE）、5q14.3（MEF2C）、6q25.1（C6orf97，ESR1）、7q21.3（FLJ42280，SHFM1）、7q31.31（FAM3C，WNT16）、8q24.12（TNFRSF11B）、11p15.3（SOX6）、11q13.4（LRP5）、13q14.11（AKAP11）和16q24（FOXL1）。成骨细胞中的基因表达分析表明这两个候选基因（SMOC1和CLDN14）在骨代谢中可能存在潜在的功能关联。我们的研究结果独立确认了先前已确定的骨代谢潜在生物学途径，并有助于发现新的途径，从而为骨质疏松症的干预和治疗提供有价值的见解。
