Pleiotropic Genetic Effects between Multiple Sclerosis and Musculoskeletal Traits.
Pleiotropic Genetic Effects between Multiple Sclerosis and Musculoskeletal Traits.
复制标题
多发性硬化症和肌肉骨骼特征之间的多效性遗传效应。
DOI：
10.1101/2023.09.12.23295444
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Hsu,Yi-Hsiang
中科院分区：
文献类型：
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作者：
Jeong,Sohyun;Tsai,Ming-Ju;Shen,Changbing;Hsu,Yi-Hsiang
背景多发性硬化症患者常报告肌肉骨骼疾病。然而，联系多发性硬化症（MS）和肌肉骨骼疾病的潜在病因尚未得到很好的研究。随着大规模全基因组关联研究（GWAS）的公开，我们进行了遗传相关性分析，以确定MS和肌肉骨骼性状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），以估计MS和肌肉骨骼疾病风险增加之间的因果关系。方法采用连锁不平衡计分回归分析方法估计遗传力和遗传相关。进行单变量、多变量和双向MR分析以估计因果关系。这些分析是利用最近GWAS对MS、骨折、虚弱、福尔斯和几个肌肉骨骼风险因素（包括骨矿物质密度、瘦体重、握力和维生素D）的汇总统计进行的。结果LDSR分析显示MS与福尔斯有中度遗传相关性（RG=0.10，p=0.01），但与骨折和虚弱无相关性。与铁状态生物标志物相关的LINC00240基因中的遗传变异（rs13191659）被发现与MS和福尔斯都相关。在排除具有潜在多效性效应的离群SNP并校正多重检验后的MR分析中，MS与骨折和虚弱无因果关系，但与福尔斯的相关性极小。福尔斯显示骨折和虚弱的风险增加。结论MS与福尔斯之间存在潜在的遗传相关性，具有共同的多效遗传效应。然而，我们没有发现证据支持MS与福尔斯、骨折和虚弱风险增加之间的因果关系。
Background 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. Methods 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. Results LDSR analysis showed a moderate genetic correlation of MS with falls (RG=0.10, p=0.01) but not with fracture and frailty. Genetic variants (rs13191659) in LINC00240 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. Conclusion 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.