Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, School of Public Health, Health Science Center, Xi'an Jiaotong University, No.76 Yan Ta West Road, Xi'an, 710061, People's Republic of China.
Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, People's Republic of China.
Osteoporos Int. 2019 Jul;30(7):1521-1528. doi: 10.1007/s00198-019-04958-z. Epub 2019 Apr 15.
To scan novel candidate genes associated with osteoporosis, a two-stage transcriptome-wide association study (TWAS) of bone mineral density (BMD) was conducted. The BMD-associated genes identified by TWAS were then compared with the gene expression profiling of BMD in bone cells, B cells, and mesenchymal stem cells. We identified multiple candidate genes and gene ontology (GO) terms associated with BMD.
Osteoporosis (OP) is a metabolic bone disease characterized by decrease in BMD. Our objective is to scan novel candidate genes associated with OP.
A transcriptome-wide association study (TWAS) was performed by integrating the genome-wide association study (GWAS) summary of bone mineral density (BMD) with two pre-computed mRNA expression weights of peripheral blood and muscle skeleton. Then, another independent GWAS data of BMD was used to verify the discovery results. The BMD-associated genes identified between discovery and replicate TWAS were further subjected to gene ontology (GO) analysis implemented by DAVID. Finally, the BMD-associated genes and GO terms were further compared with the mRNA expression profiling results of BMD to detect the common genes and GO terms shared by both DNA-level TWAS and mRNA expression profile analysis.
TWAS identified 95 common genes with permutation P value < 0.05 for peripheral blood and muscle skeleton, such as TMTC4 in muscle skeleton and DDX17 in peripheral blood. Further comparing the genes detected by discovery-replicate TWAS with the differentially expressed genes identified by mRNA expression profiling of OP patients found 18 overlapped genes, such as MUL1 in muscle skeleton and SPTBN1 in peripheral blood. GO analysis of the genes identified by discovery-replicate TWAS detected 12 BMD-associated GO terms, such as negative regulation of cell growth and regulation of glycogen catabolic process. Further comparing the GO results of discovery-replicate TWAS and mRNA expression profiles found 6 overlapped GO terms, such as membrane and cell adhesion.
Our study identified multiple candidate genes and GO terms for BMD, providing novel clues for understanding the genetic mechanism of OP.
为了扫描与骨质疏松症相关的新候选基因，我们进行了两阶段全转录组关联研究（TWAS）以研究骨密度（BMD）。然后，将通过 TWAS 鉴定的与 BMD 相关的基因与骨细胞、B 细胞和间充质干细胞中 BMD 的基因表达谱进行比较。我们确定了多个与 BMD 相关的候选基因和基因本体论（GO）术语。
骨质疏松症（OP）是一种以 BMD 降低为特征的代谢性骨病。我们的目标是扫描与 OP 相关的新候选基因。
通过整合全基因组关联研究（GWAS）骨密度（BMD）的汇总数据与外周血和肌肉骨骼的两个预先计算的 mRNA 表达权重，进行全转录组关联研究（TWAS）。然后，使用另一个独立的 BMD GWAS 数据来验证发现结果。在发现和复制 TWAS 之间鉴定的与 BMD 相关的基因进一步进行基因本体论（GO）分析，该分析由 DAVID 实施。最后，将与 BMD 相关的基因和 GO 术语与 BMD 的 mRNA 表达谱分析结果进一步比较，以检测 DNA 水平 TWAS 和 mRNA 表达谱分析共有的基因和 GO 术语。
TWAS 确定了 95 个与肌肉骨骼中的 TMTC4 和外周血中的 DDX17 等组织的外周血和肌肉骨骼的 mRNA 表达权重相关的常见基因，其置换 P 值<0.05。进一步比较发现 TWAS 检测到的基因与 OP 患者 mRNA 表达谱鉴定的差异表达基因之间有 18 个重叠基因，如肌肉骨骼中的 MUL1 和外周血中的 SPTBN1。对发现-复制 TWAS 鉴定的基因进行 GO 分析，检测到 12 个与 BMD 相关的 GO 术语，如细胞生长的负调节和糖原分解代谢过程的调节。进一步比较发现 TWAS 的 GO 结果与 mRNA 表达谱之间有 6 个重叠的 GO 术语，如膜和细胞粘附。
我们的研究确定了多个与 BMD 相关的候选基因和 GO 术语，为理解 OP 的遗传机制提供了新的线索。
