Pei Yu-Fang, Hu Wen-Zhu, Hai Rong, Wang Xiu-Yan, Ran Shu, Lin Yong, Shen Hui, Tian Qing, Lei Shu-Feng, Zhang Yong-Hong, Papasian Christopher J, Deng Hong-Wen, Zhang Lei
Department of Epidemiology and Health Statistics, School of Public Health, Medical College of Soochow University, Jiangsu, PR China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Jiangsu, PR China.
Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Jiangsu, PR China; Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Jiangsu, PR China.
Bone. 2016 Oct;91:1-10. doi: 10.1016/j.bone.2016.07.004. Epub 2016 Jul 7.
Aiming to identify genomic variants associated with osteoporosis, we performed a genome-wide association meta-analysis of bone mineral density (BMD) at Ward's triangle of the hip in 7175 subjects from 6 samples. We performed in silico replications with femoral neck, trochanter, and inter-trochanter BMDs in 6912 subjects from the Framingham heart study (FHS), and with forearm, femoral neck and lumbar spine BMDs in 32965 subjects from the GEFOS summary results. Combining the evidence from all samples, we identified 2 novel loci for areal BMD: 1q43 (rs1414660, discovery p=1.20×10(-8), FHS p=0.05 for trochanter BMD; rs9287237, discovery p=3.55×10(-7), FHS p=9.20×10(-3) for trochanter BMD, GEFOS p=0.02 for forearm BMD, nearest gene FMN2) and 2q32.2 (rs56346965, discovery p=7.48×10(-7), FHS p=0.10 for inter-trochanter BMD, GEFOS p=0.02 for spine BMD, nearest gene NAB1). The two lead SNPs rs1414660 and rs56346965 are eQTL sites for the genes GREM2 and NAB1 respectively. Functional annotation of GREM2 and NAB1 illustrated their involvement in BMP signaling pathway and in bone development. We also replicated three previously reported loci: 5q14.3 (rs10037512, discovery p=3.09×10(-6), FHS p=8.50×10(-3), GEFOS p=1.23×10(-24) for femoral neck BMD, nearest gene MEF2C), 6q25.1 (rs3020340, discovery p=1.64×10(-6), GEFOS p=1.69×10(-3) for SPN-BMD, nearest gene ESR1) and 7q21.3 (rs13310130, discovery p=8.79×10(-7), GEFOS p=2.61×10(-7) for spine BMD, nearest gene SHFM1). Our findings provide additional insights that further enhance our understanding of bone development, osteoporosis, and fracture pathogenesis.
为了确定与骨质疏松症相关的基因组变异，我们对来自6个样本的7175名受试者髋部沃德三角区的骨密度（BMD）进行了全基因组关联荟萃分析。我们利用弗雷明汉心脏研究（FHS）中6912名受试者的股骨颈、转子和转子间骨密度进行了电子复制，并利用GEFOS汇总结果中32965名受试者的前臂、股骨颈和腰椎骨密度进行了电子复制。综合所有样本的证据，我们确定了两个新的骨面积密度位点：1q43（rs1414660，发现p = 1.20×10(-8)，FHS中转子骨密度p = 0.05；rs9287237，发现p = 3.55×10(-7)，FHS中转子骨密度p = 9.20×10(-3)，GEFOS中前臂骨密度p = 0.02，最近的基因是FMN2）和2q32.2（rs56346965，发现p = 7.48×10(-7)，FHS中转子间骨密度p = 0.10，GEFOS中脊柱骨密度p = 0.02，最近的基因是NAB1）。两个主要单核苷酸多态性（SNP）rs1414660和rs56346965分别是基因GREM2和NAB1的表达数量性状位点（eQTL）。GREM2和NAB1的功能注释表明它们参与骨形态发生蛋白（BMP）信号通路和骨骼发育。我们还复制了三个先前报道的位点：5q14.3（rs10037512，发现p = 3.09×10(-6)，FHS中股骨颈骨密度p = 8.50×10(-3)，GEFOS中股骨颈骨密度p = 1.23×10(-24)，最近的基因是MEF2C）、6q25.1（rs3020340，发现p = 1.64×10(-6)，GEFOS中SPN骨密度p = 1.69×10(-3)，最近的基因是ESR1）和7q21.3（rs13310130，发现p = 8.79×10(-7)，GEFOS中脊柱骨密度p = 2.61×10(-7)，最近的基因是SHFM1）。我们的研究结果提供了更多见解，进一步加深了我们对骨骼发育、骨质疏松症和骨折发病机制的理解。
