Jeong Sohyun, Tsai Ming-Ju, Shen Changbing, Hsu Yi-Hsiang
Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston 02131, MA.
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston 02215, MA.
medRxiv. 2023 Sep 13:2023.09.12.23295444. doi: 10.1101/2023.09.12.23295444.
Musculoskeletal disorders were commonly reported in patients with multiple sclerosis. However, the underlying etiology linking Multiple Sclerosis (MS) and musculoskeletal disorders is not well studied. With large-scale Genome-Wide Association Studies (GWAS) publicly available, we conducted genetic correlation analysis to identify shared pleiotropic genetic effects between MS and musculoskeletal traits. We also conducted Mendelian Randomization (MR) to estimate the causal relation between MS and increased risks of musculoskeletal disorders.
Linkage Disequilibrium Score Regression (LDSR) analysis was performed to estimate heritability and genetic correlation. Univariable, multivariable, and bidirectional MR analyses were conducted to estimate the causal relation. These analyses were done by utilizing the recent GWAS summary statistics of MS, fracture, frailty, falls, and several musculoskeletal risk factors, including bone mineral density, lean mass, grip strengths, and vitamin D.
LDSR analysis showed a moderate genetic correlation of MS with falls (RG=0.10, =) but not with fracture and frailty. Genetic variants (rs13191659) in gene which is associated with iron status biomarkers was found to be associated with both MS and falls. In MR analyses after excluding outlier SNPs with potential pleiotropic effects and correcting for multiple testing, MS presented no causal association with fracture and frailty but a minimal association with falls. Falls showed causally increased risks of fracture and frailty.
Our study suggests a potential genetic correlation with shared pleiotropic genetic effects between MS and falls. However, we didn't find evidence to support the causal relation between MS and increased risks of falls, fracture, and frailty.
多发性硬化症患者中常报告有肌肉骨骼疾病。然而，将多发性硬化症（MS）与肌肉骨骼疾病联系起来的潜在病因尚未得到充分研究。由于有公开可用的大规模全基因组关联研究（GWAS），我们进行了遗传相关性分析，以确定MS与肌肉骨骼特征之间共享的多效性遗传效应。我们还进行了孟德尔随机化（MR）分析，以估计MS与肌肉骨骼疾病风险增加之间的因果关系。
进行连锁不平衡评分回归（LDSR）分析以估计遗传力和遗传相关性。进行单变量、多变量和双向MR分析以估计因果关系。这些分析是通过利用MS、骨折、衰弱、跌倒以及包括骨密度、瘦体重、握力和维生素D在内的几种肌肉骨骼危险因素的最新GWAS汇总统计数据来完成的。
LDSR分析显示MS与跌倒之间存在中等程度的遗传相关性（RG = 0.10，=），但与骨折和衰弱无关。发现与铁状态生物标志物相关的基因中的遗传变异（rs13191659）与MS和跌倒均相关。在排除具有潜在多效性影响的异常单核苷酸多态性（SNP）并校正多重检验后的MR分析中，MS与骨折和衰弱无因果关联，但与跌倒有最小关联。跌倒显示出骨折和衰弱的因果风险增加。
我们的研究表明MS与跌倒之间可能存在共享多效性遗传效应的潜在遗传相关性。然而，我们没有找到证据支持MS与跌倒、骨折和衰弱风险增加之间的因果关系。
