PDF(Pubmed)
Abstract：
UNASSIGNED: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the degeneration of motor neurons in the brain and spinal cord with a poor prognosis. Previous studies have observed cognitive decline and changes in brain morphometry in ALS patients. However, it remains unclear whether the brain structural alterations contribute to the risk of ALS. In this study, we conducted a bidirectional two-sample Mendelian randomization (MR) and colocalization analysis to investigate this causal relationship.
UNASSIGNED: Summary data of genome-wide association study were obtained for ALS and the brain structures, including surface area (SA), thickness and volume of subcortical structures. Inverse-variance weighted (IVW) method was used as the main estimate approach. Sensitivity analysis was conducted detect heterogeneity and pleiotropy. Colocalization analysis was performed to calculate the posterior probability of causal variation and identify the common genes.
UNASSIGNED: In the forward MR analysis, we found positive associations between the SA in four cortical regions (lingual, parahippocampal, pericalcarine, and middle temporal) and the risk of ALS. Additionally, decreased thickness in nine cortical regions (caudal anterior cingulate, frontal pole, fusiform, inferior temporal, lateral occipital, lateral orbitofrontal, pars orbitalis, pars triangularis, and pericalcarine) was significantly associated with a higher risk of ALS. In the reverse MR analysis, genetically predicted ALS was associated with reduced thickness in the bankssts and increased thickness in the caudal middle frontal, inferior parietal, medial orbitofrontal, and superior temporal regions. Colocalization analysis revealed the presence of shared causal variants between the two traits.
UNASSIGNED: Our results suggest that altered brain morphometry in individuals with high ALS risk may be genetically mediated. The causal associations of widespread multifocal extra-motor atrophy in frontal and temporal lobes with ALS risk support the notion of a continuum between ALS and frontotemporal dementia. These findings enhance our understanding of the cortical structural patterns in ALS and shed light on potentially viable therapeutic targets.
UNASSIGNED: Summary data of genome-wide association study were obtained for ALS and the brain structures, including surface area (SA), thickness and volume of subcortical structures. Inverse-variance weighted (IVW) method was used as the main estimate approach. Sensitivity analysis was conducted detect heterogeneity and pleiotropy. Colocalization analysis was performed to calculate the posterior probability of causal variation and identify the common genes.
UNASSIGNED: In the forward MR analysis, we found positive associations between the SA in four cortical regions (lingual, parahippocampal, pericalcarine, and middle temporal) and the risk of ALS. Additionally, decreased thickness in nine cortical regions (caudal anterior cingulate, frontal pole, fusiform, inferior temporal, lateral occipital, lateral orbitofrontal, pars orbitalis, pars triangularis, and pericalcarine) was significantly associated with a higher risk of ALS. In the reverse MR analysis, genetically predicted ALS was associated with reduced thickness in the bankssts and increased thickness in the caudal middle frontal, inferior parietal, medial orbitofrontal, and superior temporal regions. Colocalization analysis revealed the presence of shared causal variants between the two traits.
UNASSIGNED: Our results suggest that altered brain morphometry in individuals with high ALS risk may be genetically mediated. The causal associations of widespread multifocal extra-motor atrophy in frontal and temporal lobes with ALS risk support the notion of a continuum between ALS and frontotemporal dementia. These findings enhance our understanding of the cortical structural patterns in ALS and shed light on potentially viable therapeutic targets.
摘要：
■肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，其特征是脑和脊髓中运动神经元的变性，预后不良。先前的研究已经观察到ALS患者的认知能力下降和大脑形态测量的变化。然而,目前尚不清楚大脑结构改变是否会导致ALS的风险。在这项研究中,我们进行了双向双样本孟德尔随机化(MR)和共定位分析,以调查这种因果关系.
■获得了ALS和大脑结构的全基因组关联研究的摘要数据，包括表面积（SA），皮层下结构的厚度和体积。采用逆方差加权(IVW)方法作为主要的估计方法。敏感性分析检测异质性和多效性。进行共定位分析以计算因果变异的后验概率并识别常见基因。
■在正向MR分析中，我们发现四个皮质区域的SA之间存在正相关(语言，海马旁,pericalcarine,和中颞叶）和ALS的风险。此外,九个皮质区域的厚度减少(尾前扣带回，额叶极点,梭形,颞下，枕骨外侧,外侧眶额，轨道，三角条,和pericalcarine）与较高的ALS风险显着相关。在反向MR分析中，遗传预测的ALS与堤岸厚度减少和尾中部额叶厚度增加有关，下顶叶，内侧眶额，和优越的时间区域。共定位分析揭示了两个性状之间存在共同的因果变异。
■我们的研究结果表明，ALS高危个体的大脑形态改变可能是遗传介导的。额叶和颞叶中广泛的多灶性运动外萎缩与ALS风险的因果关系支持ALS和额颞叶痴呆之间的连续性概念。这些发现增强了我们对ALS皮质结构模式的理解，并揭示了潜在可行的治疗靶点。
■获得了ALS和大脑结构的全基因组关联研究的摘要数据，包括表面积（SA），皮层下结构的厚度和体积。采用逆方差加权(IVW)方法作为主要的估计方法。敏感性分析检测异质性和多效性。进行共定位分析以计算因果变异的后验概率并识别常见基因。
■在正向MR分析中，我们发现四个皮质区域的SA之间存在正相关(语言，海马旁,pericalcarine,和中颞叶）和ALS的风险。此外,九个皮质区域的厚度减少(尾前扣带回，额叶极点,梭形,颞下，枕骨外侧,外侧眶额，轨道，三角条,和pericalcarine）与较高的ALS风险显着相关。在反向MR分析中，遗传预测的ALS与堤岸厚度减少和尾中部额叶厚度增加有关，下顶叶，内侧眶额，和优越的时间区域。共定位分析揭示了两个性状之间存在共同的因果变异。
■我们的研究结果表明，ALS高危个体的大脑形态改变可能是遗传介导的。额叶和颞叶中广泛的多灶性运动外萎缩与ALS风险的因果关系支持ALS和额颞叶痴呆之间的连续性概念。这些发现增强了我们对ALS皮质结构模式的理解，并揭示了潜在可行的治疗靶点。
