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Identifying Suitable Targets for Alzheimer's Disease and Other Eight Common Neurological Disorders Using the Human Plasma Proteome: A Mendelian Randomization Study

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机构: [1]Capital Med Univ, Xuanwu Hosp, Dept Neurol & Innovat Ctr Neurol Disorders, Natl Ctr Neurol Disorders, Beijing, Peoples R China [2]Guangzhou Med Univ, Geriatr Neurosci Ctr, Affiliated Brain Hosp, Guangzhou, Peoples R China [3]Guangdong Engn Technol Res Ctr Translat Med Ment, Guangzhou, Peoples R China [4]Capital Med Univ, Xuanwu Hosp, Natl Ctr Neurol Disorders, Dept Neurol, Beijing, Peoples R China [5]Minist Educ Peoples Republ China, Neurodegenerat Lab, Beijing, Peoples R China
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关键词: Alzheimer's disease causality Mendelian randomization neurological disorders plasma proteins

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Background: Neurological disorders, such as Alzheimer's disease (AD), comprise a major cause of health-related disabilities in human. However, biomarkers towards pathogenesis or novel targets are still limited. Objective: To identify the causality between plasma proteins and the risk of AD and other eight common neurological diseases using a Mendelian randomization (MR) study. Methods: Exposure data were obtained from a genome-wide association study (GWAS) of 2,994 plasma proteins in 3,301 healthy adults, and outcome datasets included GWAS summary statistics of nine neurological disorders. Inverse variance-weighted MR method as the primary analysis was used to estimate causal effects. Results: Higher genetically proxied plasma myeloid cell surface antigen CD33 level was found to be associated with increased risk of AD (odds ratio [OR] 1.079, 95% confidence interval [CI] 1.047-1.112, p = 8.39x10(-7)). We also discovered the causality between genetically proxied elevated prolactin and higher risk of epilepsy (OR = 1.068, 95% CI = 1.034-1.102; p = 5.46x10(-5)). Negative associations were identified between cyclin-dependent kinase 8 and ischemic stroke (OR = 0.927, 95% CI = 0.896-0.959, p = 9.32x10(-6)), between neuralized E3 ubiquitin-protein ligase 1 and migraine (OR = 0.914, 95% CI = 0.878-0.952, p = 1.48x10(-5)), and between Fc receptor-like protein 4 and multiple sclerosis (MS) (OR = 0.929, 95% CI = 0.897-0.963, p = 4.27x10(-5)). Conclusion: The findings identified MR-level protein-disease associations for AD, epilepsy, ischemic stroke, migraine, and MS.

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第一作者机构: [1]Capital Med Univ, Xuanwu Hosp, Dept Neurol & Innovat Ctr Neurol Disorders, Natl Ctr Neurol Disorders, Beijing, Peoples R China
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通讯机构: [1]Capital Med Univ, Xuanwu Hosp, Dept Neurol & Innovat Ctr Neurol Disorders, Natl Ctr Neurol Disorders, Beijing, Peoples R China [5]Minist Educ Peoples Republ China, Neurodegenerat Lab, Beijing, Peoples R China [*1]Capital Med Univ, Xuanwu Hosp, Dept Neurol, 45 Changchun St, Beijing 100053, Peoples R China [*2]Capital Med Univ, Xuanwu Hosp, Innovat Ctr Neurol Disorders, 45 Changchun St, Beijing 100053, Peoples R China
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