Yao Yu, Gao Feng, Wu Yanni, Zhang Xin, Xu Jun, Du Haiyang, Wang Xintao
Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Front Neurol. 2022 Sep 15;13:993150. doi: 10.3389/fneur.2022.993150. eCollection 2022.
Multiple sclerosis (MS) is a neurodegenerative disorder and an autoimmune disease. Until now, observational studies have indicated the association of bone mineral density (BMD) and fracture with the risk of MS. However, these studies indicated inconsistent findings. Until now, genome-wide association studies (GWAS) have been conducted in BMD, fracture, and MS, which provide large-scale datasets to investigate the causal association of BMD and fracture with the risk of MS using the Mendelian randomization (MR) study. Here, we performed an MR study to clarify the causal association between BMD/fracture and the risk of MS using large-scale publicly available GWAS datasets from BMD, fracture, and MS. We first evaluated the bidirectional causal effects of BMD and MS. The main analysis method inverse-variance weighted (IVW) showed no significant causal effect of BMD on the risk of MS (β = 0.058, and = 1.98E-01), and MS on the risk of BMD (β = -0.001, and = 7.83E-01). We then evaluated the bidirectional causal effects of fracture and MS. However, we only identified a significant causal effect of fracture on the risk of MS using IVW (β = -0.375, = 0.002), but no significant causal effect of MS on the risk of the fracture using IVW (β = 0.011, = 2.39E-01). Therefore, our main analysis method IVW only found a significant causal effect of fracture on MS using the threshold for the statistically significant association < 0.05/4 = 0.0125. Meanwhile, multivariable MR analyses showed that the causal effect of fracture on MS was independent of smoking, drinking, and obesity, but dependent on BMD. In summary, our MR analysis demonstrates that genetically increased fracture may reduce the risk of MS. Our findings should be further verified and the underlying mechanisms should be further evaluated by future studies.
多发性硬化症（MS）是一种神经退行性疾病和自身免疫性疾病。到目前为止，观察性研究表明骨矿物质密度（BMD）和骨折与MS风险之间存在关联。然而，这些研究结果并不一致。到目前为止，已经针对BMD、骨折和MS开展了全基因组关联研究（GWAS），这些研究提供了大规模数据集，以便使用孟德尔随机化（MR）研究来探究BMD和骨折与MS风险之间的因果关联。在此，我们使用来自BMD、骨折和MS的大规模公开可用GWAS数据集进行了一项MR研究，以阐明BMD/骨折与MS风险之间的因果关联。我们首先评估了BMD和MS的双向因果效应。主要分析方法逆方差加权（IVW）显示，BMD对MS风险没有显著因果效应（β = 0.058，P = 1.98E-01），MS对BMD风险也没有显著因果效应（β = -0.001，P = 7.83E-01）。然后我们评估了骨折和MS的双向因果效应。然而，我们仅使用IVW确定了骨折对MS风险有显著因果效应（β = -0.375，P = 0.002），但使用IVW未发现MS对骨折风险有显著因果效应（β = 0.011，P = 2.39E-01）。因此，我们的主要分析方法IVW仅在统计学显著关联的阈值P < 0.05/4 = 0.0125时发现骨折对MS有显著因果效应。同时，多变量MR分析表明，骨折对MS的因果效应独立于吸烟、饮酒和肥胖，但依赖于BMD。总之，我们的MR分析表明，遗传因素导致的骨折增加可能会降低MS风险。我们的研究结果应进一步验证，其潜在机制应由未来的研究进一步评估。
