Hinda and Arthur Marcus Institution for Aging Research, Hebrew SeniorLife, Boston, MA, 02131, USA.
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA.
J Bone Miner Metab. 2024 May;42(3):335-343. doi: 10.1007/s00774-024-01504-8. Epub 2024 May 27.
Patients with multiple sclerosis (MS) commonly present musculoskeletal disorders characterized by lower bone mineral density (BMD) and muscle weakness. However, the underlying etiology remains unclear. Our objective is to identify shared pleiotropic genetic effects and estimate the causal relationship between MS and musculoskeletal disorders.
We conducted linkage disequilibrium score regression (LDSR), colocalization, and Mendelian randomization (MR) analyses using summary statistics from recent large-scale genome-wide association studies (GWAS), encompassing MS, falls, fractures, and frailty. Additional MR analyses explored the causal relationship with musculoskeletal risk factors, such as BMD, lean mass, grip strength, and vitamin D.
We observed a moderate genetic correlation between MS and falls (RG = 0.10, P-value = 0.01) but not between MS with fracture or frailty in the LDSR analyses. MR revealed MS had no causal association with fracture and frailty but a moderate association with falls (OR: 1.004, FDR q-value = 0.018). We further performed colocalization analyses using nine SNPs that exhibited significant associations with both MS and falls in MR. Two SNPs (rs7731626 on ANKRD55 and rs701006 on OS9 gene) showed higher posterior probability of colocalization (PP.H4 = 0.927), suggesting potential pleiotropic effects between MS and falls. The nine genes are associated with central nervous system development and inflammation signaling pathways.
We found potential pleiotropic genetic effects between MS and falls. However, our analysis did not reveal a causal relationship between MS and increased risks of falls, fractures, or frailty. This suggests that the musculoskeletal disorders frequently reported in MS patients in clinical studies are more likely attributed to secondary factors associated with disease progression and treatment, rather than being directly caused by MS itself.
多发性硬化症（MS）患者常出现骨骼肌肉疾病，表现为骨密度（BMD）降低和肌肉无力。然而，其潜在病因尚不清楚。本研究旨在确定多发性硬化症和骨骼肌肉疾病之间存在共享的多效遗传效应，并评估两者之间的因果关系。
我们利用来自最近大规模全基因组关联研究（GWAS）的汇总统计数据，进行连锁不平衡得分回归（LDSR）、共定位和孟德尔随机化（MR）分析，这些 GWAS 涵盖了多发性硬化症、跌倒、骨折和虚弱。另外的 MR 分析探讨了与骨骼肌肉风险因素（如 BMD、瘦体重、握力和维生素 D）之间的因果关系。
在 LDSR 分析中，我们观察到多发性硬化症与跌倒之间存在中度遗传相关性（RG=0.10，P 值=0.01），但多发性硬化症与骨折或虚弱之间没有相关性。MR 结果显示，多发性硬化症与骨折和虚弱之间没有因果关系，但与跌倒之间存在中度关联（OR：1.004，FDR q 值=0.018）。我们进一步使用在 MR 中与多发性硬化症和跌倒均具有显著关联的 9 个 SNP 进行共定位分析。两个 SNP（位于 ANKRD55 上的 rs7731626 和位于 OS9 基因上的 rs701006）显示出更高的共定位后验概率（PP.H4=0.927），表明多发性硬化症和跌倒之间可能存在多效性效应。这 9 个基因与中枢神经系统发育和炎症信号通路有关。
我们发现多发性硬化症和跌倒之间存在潜在的多效遗传效应。然而，我们的分析并未发现多发性硬化症与跌倒、骨折或虚弱风险增加之间存在因果关系。这表明，在临床研究中经常报告的多发性硬化症患者的骨骼肌肉疾病更可能归因于与疾病进展和治疗相关的次要因素，而不是直接由多发性硬化症本身引起。
