Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China.
Center for Bioinformatics and Genomics, School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana.
J Clin Endocrinol Metab. 2018 Jan 1;103(1):125-138. doi: 10.1210/jc.2017-01531.
Genome-wide association studies (GWASs) have been successful in identifying loci associated with osteoporosis and obesity. However, the findings explain only a small fraction of the total genetic variance.
The aim of this study was to identify novel pleiotropic genes important in osteoporosis and obesity.
A pleiotropic conditional false discovery rate method was applied to three independent GWAS summary statistics of femoral neck bone mineral density, body mass index, and waist-to-hip ratio. Next, differential expression analysis was performed for the potentially pleiotropic genes, and weighted genes coexpression network analysis (WGCNA) was conducted to identify functional connections between the suggested pleiotropic genes and known osteoporosis/obesity genes using transcriptomic expression data sets in osteoporosis/obesity-related cells.
We identified seven potentially pleiotropic loci-rs3759579 (MARK3), rs2178950 (TRPS1), rs1473 (PUM1), rs9825174 (XXYLT1), rs2047937 (ZNF423), rs17277372 (DNM3), and rs335170 (PRDM6)-associated with osteoporosis and obesity. Of these loci, the PUM1 gene was differentially expressed in osteoporosis-related cells (B lymphocytes) and obesity-related cells (adipocytes). WGCNA showed that PUM1 positively interacted with several known osteoporosis genes (AKAP11, JAG1, and SPTBN1). ZNF423 was the highly connected intramodular hub gene and interconnected with 21 known osteoporosis-related genes, including JAG1, EN1, and FAM3C.
Our study identified seven potentially pleiotropic genes associated with osteoporosis and obesity. The findings may provide new insights into a potential genetic determination and codetermination mechanism of osteoporosis and obesity.
全基因组关联研究(GWAS)已成功鉴定出与骨质疏松症和肥胖相关的基因座。然而,这些发现仅解释了总遗传变异的一小部分。
本研究旨在鉴定与骨质疏松症和肥胖症相关的新的多效性基因。
应用多效性条件假发现率方法对三个独立的股骨颈骨密度、体重指数和腰臀比 GWAS 汇总统计数据进行分析。接下来,对潜在的多效性基因进行差异表达分析,并使用骨质疏松症/肥胖症相关细胞中的转录组表达数据集,对提示的多效性基因与已知的骨质疏松症/肥胖症基因之间的功能连接进行加权基因共表达网络分析(WGCNA)。
我们确定了七个潜在的多效性位点 rs3759579(MARK3)、rs2178950(TRPS1)、rs1473(PUM1)、rs9825174(XXYLT1)、rs2047937(ZNF423)、rs17277372(DNM3)和 rs335170(PRDM6)与骨质疏松症和肥胖症相关。在这些位点中,PUM1 基因在骨质疏松症相关细胞(B 淋巴细胞)和肥胖症相关细胞(脂肪细胞)中差异表达。WGCNA 显示 PUM1 与几个已知的骨质疏松症基因(AKAP11、JAG1 和 SPTBN1)呈正相互作用。ZNF423 是高度连接的模块内枢纽基因,与包括 JAG1、EN1 和 FAM3C 在内的 21 个已知的骨质疏松症相关基因相互连接。
我们的研究确定了七个与骨质疏松症和肥胖症相关的潜在多效性基因。这些发现可能为骨质疏松症和肥胖症的潜在遗传决定和共同决定机制提供新的见解。