Genetic variation influences glutamate concentrations in brains of patients with multiple sclerosis
| العنوان: | Genetic variation influences glutamate concentrations in brains of patients with multiple sclerosis |
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| المؤلفون: | Paul M. Matthews, Pouya Khankhanian, Darin T. Okuda, Sergio E. Baranzini, Radhika Srinivasan, Stephen L. Hauser, Sarah J. Nelson, Daniel Pelletier, Jorge R. Oksenberg |
| المصدر: | Brain. 133:2603-2611 |
| بيانات النشر: | Oxford University Press (OUP), 2010. |
| سنة النشر: | 2010 |
| مصطلحات موضوعية: | Adult, Male, Magnetic Resonance Spectroscopy, Multiple Sclerosis, Genotype, Statistics as Topic, Glutamic Acid, Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Glutamatergic, Gene Frequency, medicine, Humans, Computer Simulation, Oxidoreductases Acting on Sulfur Group Donors, Genetic association, Genetics, Aspartic Acid, Models, Genetic, Multiple sclerosis, Neurodegeneration, Glutamate receptor, Brain, Genetic Variation, Original Articles, Glutamic acid, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Female, Neurology (clinical), Sulfatases, Follow-Up Studies, Genome-Wide Association Study |
| الوصف: | 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 × 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. |
| تدمد: | 1460-2156 0006-8950 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5ea5ec1a40a0c27d2e7813fd373b6525Test https://doi.org/10.1093/brain/awq192Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....5ea5ec1a40a0c27d2e7813fd373b6525 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602156 00068950 |
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