Integrating Epigenomic Elements and GWASs Identifies BDNF Gene Affecting Bone Mineral Density and Osteoporotic Fracture Risk.
Integrating Epigenomic Elements and GWASs Identifies BDNF Gene Affecting Bone Mineral Density and Osteoporotic Fracture Risk.
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整合表观基因组元素和 GWAS 识别影响骨矿物质密度和骨质疏松性骨折风险的 BDNF 基因
DOI：
10.1038/srep30558
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发表时间：
2016-07-28
影响因子：
4.6
通讯作者：
Yang TL
中科院分区：
文献类型：
--
作者：
Guo Y;Dong SS;Chen XF;Jing YA;Yang M;Yan H;Shen H;Chen XD;Tan LJ;Tian Q;Deng HW;Yang TL
为了确定骨质疏松症的易感基因，我们进行了一项综合分析，结合表观基因组元素和以前的全基因组关联研究(GWASs)数据，然后在群体和功能水平上进行验证，这可以识别共同的调控元件，并预测对骨质疏松症具有生物学意义的新的易感基因。通过这种方法，我们发现了一组明显富含或缺失骨质疏松相关基因启动子的表观基因组元件，包括4个转录因子结合位点、27个组蛋白标记和21种染色质状态分段类型。利用这些表观基因组标记，我们进行了反向预测分析，以优先发现新的候选基因。对所有优先基因的功能丰富分析揭示了几个与骨质疏松相关的关键途径，包括Wnt信号转导。使用可用的GWASs数据集进一步验证具有高优先级的基因。有3个基因与脊柱骨密度显著相关，包括BDNF、PDE4D和SATB2，它们都与骨代谢密切相关。最重要的基因BDNF也与骨质疏松性骨折有关。RNA干扰显示BDNF基因敲除可抑制成骨细胞的分化。我们的结果表明，表观基因组数据可以用来指示共同的表观基因组标记，以发现与骨质疏松症具有生物学功能的额外基因座。
To identify susceptibility genes for osteoporosis, we conducted an integrative analysis that combined epigenomic elements and previous genome-wide association studies (GWASs) data, followed by validation at population and functional levels, which could identify common regulatory elements and predict new susceptibility genes that are biologically meaningful to osteoporosis. By this approach, we found a set of distinct epigenomic elements significantly enriched or depleted in the promoters of osteoporosis-associated genes, including 4 transcription factor binding sites, 27 histone marks, and 21 chromatin states segmentation types. Using these epigenomic marks, we performed reverse prediction analysis to prioritize the discovery of new candidate genes. Functional enrichment analysis of all the prioritized genes revealed several key osteoporosis related pathways, including Wnt signaling. Genes with high priority were further subjected to validation using available GWASs datasets. Three genes were significantly associated with spine bone mineral density, including BDNF, PDE4D, and SATB2, which all closely related to bone metabolism. The most significant gene BDNF was also associated with osteoporotic fractures. RNA interference revealed that BDNF knockdown can suppress osteoblast differentiation. Our results demonstrated that epigenomic data could be used to indicate common epigenomic marks to discover additional loci with biological functions for osteoporosis.