Background Amyotrophic lateral sclerosis (ALS) is a disease of the motor network associated with brain structure and functional connectivity alterations that are implicated in disease progression. Whether such changes have a causal role in ALS, fitting with a postulated influence of premorbid cerebral architecture on the phenotypes associated with neurodegenerative disorders is not known. Methods This study considered causal effects and shared genetic risk of 2240 structural and functional MRI brain scan imaging-derived phenotypes (IDPs) on ALS using two sample Mendelian randomisation, with putative associations further examined with extensive sensitivity analysis. Shared genetic predisposition between IDPs and ALS was explored using genetic correlation analysis. Results Increased white matter volume in the cerebral hemispheres was causally associated with ALS. Weaker causal associations were observed for brain stem grey matter volume, parieto-occipital white matter surface and volume of the left thalamic ventral anterior nucleus. Genetic correlation was observed between ALS and intracellular volume fraction and isotropic free water volume fraction within the posterior limb of the internal capsule. Conclusions This study provides evidence that premorbid brain structure, in particular white matter volume, contributes to the risk of ALS.

中文翻译：

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病前大脑结构影响肌萎缩侧索硬化症的风险

背景肌萎缩侧索硬化症（ALS）是一种与大脑结构和功能连接改变相关的运动网络疾病，而大脑结构和功能连接改变与疾病进展有关。这些变化是否在 ALS 中具有因果作用，是否符合病前大脑结构对神经退行性疾病相关表型的假设影响，目前尚不清楚。方法本研究使用两个样本孟德尔随机化，考虑了 2240 个结构和功能 MRI 脑扫描成像衍生表型 (IDP) 对 ALS 的因果影响和共同遗传风险，并通过广泛的敏感性分析进一步检查了假定的关联。使用遗传相关分析探讨了国内流离失所者和 ALS 之间的共同遗传倾向。结果 大脑半球白质体积增加与 ALS 存在因果关系。脑干灰质体积、顶枕白质表面和左侧丘脑腹侧前核体积之间的因果关系较弱。观察到 ALS 与内囊后肢内细胞内体积分数和各向同性自由水体积分数之间的遗传相关性。结论 这项研究提供的证据表明，病前大脑结构，特别是白质体积，会导致 ALS 风险。