Integrating GWAS and Co-expression Network Data Identifies Bone Mineral Density Genes SPTBN1 and MARK3 and an Osteoblast Functional Module.
Integrating GWAS and Co-expression Network Data Identifies Bone Mineral Density Genes SPTBN1 and MARK3 and an Osteoblast Functional Module.
复制标题
集成GWAS和共表达网络数据标识骨矿物质密度基因SPTBN1和MARK3以及成骨细胞功能模块。
DOI：
10.1016/j.cels.2016.10.014
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发表时间：
2017-01-25
期刊：
影响因子：
9.3
通讯作者：
Farber CR
中科院分区：
文献类型：
--
作者：
Calabrese GM;Mesner LD;Stains JP;Tommasini SM;Horowitz MC;Rosen CJ;Farber CR
骨矿物质密度（BMD）是骨质疏松性骨折的高度遗传性预测因子。 BMD 的全基因组关联研究 (GWAS) 已确定了数十种关联；然而，负责大多数关联的基因仍然难以捉摸。在这里，我们使用骨共表达网络来预测 BMD GWAS 位点的因果基因，前提是疾病背后的基因通常在功能上相关，并且功能相关的基因通常是共表达的。通过将 BMD GWAS 涉及的基因映射到骨共表达网络上，我们预测并推断了 64 个 GWAS 位点中的 30 个因果基因的功能。我们通过实验证实，预测为因果关系的两个基因 SPTBN1 和 MARK3 可能分别导致 GWAS 位点对染色体 2p16.2 和 14q32.32 的影响。这种方法为剖析其他 BMD GWAS 关联提供了路线图。此外，它应该适用于多种疾病的 GWAS 数据。
Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. Genome-wide association studies (GWAS) for BMD have identified dozens of associations; yet, the genes responsible for most associations remain elusive. Here, we used a bone co-expression network to predict causal genes at BMD GWAS loci based on the premise that genes underlying a disease are often functionally related and functionally related genes are often co-expressed. By mapping genes implicated by BMD GWAS onto a bone co-expression network, we predicted and inferred the function of causal genes for 30 of 64 GWAS loci. We experimentally confirmed that two of the genes predicted to be causal, SPTBN1 and MARK3, are potentially responsible for the effects of GWAS loci on Chromosomes 2p16.2 and 14q32.32, respectively. This approach provides a roadmap for the dissection of additional BMD GWAS associations. Furthermore, it should be applicable to GWAS data for a wide range of diseases.