Bone mineral density (BMD) and whole-body lean mass (WBLM) are two important phenotypes of osteoporosis and sarcopenia. Previous studies have shown that BMD and lean mass were phenotypically and genetically correlated. To identify the novel common genetic factors shared between BMD and WBLM, we performed the conditional false discovery rate (cFDR) analysis using summary data of the genome-wide association study of femoral neck BMD (n = 53,236) and WBLM (n = 38,292) from the Genetic Factors for Osteoporosis Consortium (GEFOS). We identified eight pleiotropic Single Nucleotide Polymorphism (SNPs) (PLCL1 rs11684176 and rs2880389, JAZF1 rs198, ADAMTSL3 rs10906982, RFTN2/MARS2 rs7340470, SH3GL3 rs1896797, ST7L rs10776755, ANKRD44/SF3B1 rs11888760) significantly associated with femoral neck BMD and WBLM (ccFDR < 0.05). Bayesian fine-mapping analysis showed that rs11888760, rs198, and rs1896797 were the possible functional variants in the ANKRD44/SF3B1, JAZF1i, and SH3GL3 loci, respectively. Functional annotation suggested that rs11888760 was likely to comprise a DNA regulatory element and linked to the expression of RFTN2 and PLCL1. PLCL1 showed differential expression in laryngeal posterior cricoarytenoid muscle between rats of 6 months and 30 months of age. Our findings, together with PLCL1’s potential functional relevance to bone and skeletal muscle function, suggested that rs11888760 was the possible pleiotropic functional variants appearing to coregulate both bone and muscle metabolism through regulating the expression of PLCL1. The findings enhanced our knowledge of genetic associations between BMD and lean mass and provide a rationale for subsequent functional studies of the implicated genes in the pathophysiology of diseases, such as osteoporosis and sarcopenia.

中文翻译：

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使用 cFDR 方法鉴定骨矿物质密度和瘦体重的新型多效性基因

骨矿物质密度 (BMD) 和全身瘦体重 (WBLM) 是骨质疏松症和肌肉减少症的两种重要表型。以前的研究表明，BMD 和瘦体重在表型和遗传上是相关的。为了确定 BMD 和 WBLM 之间共享的新的共同遗传因素，我们使用股骨颈 BMD ( n  = 53,236) 和 WBLM ( n  = 38,292)的全基因组关联研究的汇总数据进行了条件错误发现率 (cFDR) 分析来自骨质疏松症遗传因素联盟 (GEFOS)。我们鉴定了八个多效性单核苷酸多态性 (SNP)（PLCL1 rs11684176 和 rs2880389、JAZF1 rs198、ADAMTSL3 rs10906982、RFTN2/MARS2rs7340470、SH3GL3 rs1896797、ST7L rs10776755、ANKRD44/SF3B1 rs11888760）与股骨颈 BMD 和 WBLM 显着相关（ccFDR < 0.05）。贝叶斯精细定位分析表明，rs11888760、rs198 和 rs1896797 分别是ANKRD44/SF3B1、JAZF1i和SH3GL3基因座中可能的功能变异。功能注释表明 rs11888760 可能包含一个 DNA 调节元件，并与RFTN2和PLCL1的表达相关联。可编程逻辑控制器1在 6 个月和 30 个月大的大鼠之间在喉后环杓肌中表现出差异表达。我们的发现，连同 PLCL1与骨骼和骨骼肌功能的潜在功能相关性，表明 rs11888760 是可能的多效性功能变体，似乎通过调节PLCL1的表达来调节骨骼和肌肉代谢。这些发现增强了我们对 BMD 和瘦体重之间遗传关联的了解，并为随后对疾病病理生理学中相关基因的功能研究提供了理论依据，例如骨质疏松症和肌肉减少症。