Genetic variation influences glutamate concentrations in brains of patients with multiple sclerosis
Genetic variation influences glutamate concentrations in brains of patients with multiple sclerosis
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DOI：
10.1093/brain/awq192
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发表时间：
2010-09-01
期刊：
影响因子：
14.5
通讯作者：
Pelletier, Daniel
中科院分区：
文献类型：
--
作者：
Baranzini, Sergio E.;Srinivasan, Radhika;Pelletier, Daniel
谷氨酸是哺乳动物大脑中主要的兴奋性神经递质。整个大脑都需要通过谷氨酸突触进行神经冲动的适当传输，并构成包括学习和记忆在内的许多过程的基础。然而，异常高水平的细胞外脑谷氨酸可导致神经轴突细胞死亡。我们之前曾报道过多发性硬化症患者大脑中谷氨酸水平升高。这里使用了两种互补分析来评估基因组对谷氨酸水平的控制程度。首先，使用脑谷氨酸浓度作为数量特征，对 382 名多发性硬化症患者进行了全基因组关联分析。在第二种方法中，使用蛋白质相互作用网络来寻找同一途径内的相关基因。最相关的标记是 rs794185 (P < 6.44 x 10(-7))，这是硫酸酯酶修饰因子 1 基因内的非编码单核苷酸多态性。我们的途径方法鉴定了由 70 个与谷氨酸生物学高度相关的基因组成的模块。携带该模块基因中相关等位基因数量较多的个体表现出最高水平的谷氨酸。在一年的随访中，这些人的 N-乙酰天冬氨酸和脑容量也出现了更大的下降。然后根据每年脑容量损失量对患者进行分层，并在“高”（n = 250）和“低”（n = 132）神经退行性变组中采用相同的方法。与 rs794185 的关联在高度神经退行性变的组中非常显着。此外，即使在分层之后，基于网络的路径分析的结果也基本保持不变。这些分析的结果表明，与神经变性有关的神经化学途径活性的差异至少部分是由常见遗传多态性的遗传来解释的。基于光谱的成像为遗传关联研究提供了一种新的定量内表型，旨在识别导致多发性硬化症临床表达异质性的新因素。
Glutamate is the main excitatory neurotransmitter in the mammalian brain. Appropriate transmission of nerve impulses through glutamatergic synapses is required throughout the brain and forms the basis of many processes including learning and memory. However, abnormally high levels of extracellular brain glutamate can lead to neuroaxonal cell death. We have previously reported elevated glutamate levels in the brains of patients suffering from multiple sclerosis. Here two complementary analyses to assess the extent of genomic control over glutamate levels were used. First, a genome-wide association analysis in 382 patients with multiple sclerosis using brain glutamate concentration as a quantitative trait was conducted. In a second approach, a protein interaction network was used to find associated genes within the same pathway. The top associated marker was rs794185 (P < 6.44 x 10(-7)), a non-coding single nucleotide polymorphism within the gene sulphatase modifying factor 1. Our pathway approach identified a module composed of 70 genes with high relevance to glutamate biology. Individuals carrying a higher number of associated alleles from genes in this module showed the highest levels of glutamate. These individuals also showed greater decreases in N-acetylaspartate and in brain volume over 1 year of follow-up. Patients were then stratified by the amount of annual brain volume loss and the same approach was performed in the 'high' (n = 250) and 'low' (n = 132) neurodegeneration groups. The association with rs794185 was highly significant in the group with high neurodegeneration. Further, results from the network-based pathway analysis remained largely unchanged even after stratification. Results from these analyses indicated that variance in the activity of neurochemical pathways implicated in neurodegeneration is explained, at least in part, by the inheritance of common genetic polymorphisms. Spectroscopy-based imaging provides a novel quantitative endophenotype for genetic association studies directed towards identifying new factors that contribute to the heterogeneity of clinical expression of multiple sclerosis.