MENDELIAN RANDOMIZATION FOR UNBIAS BIOMARKER DISCOVERY FOR AD AND OTHER COMPLEX TRAITS

AD 和其他复杂性状的 UNBIAS 生物标志物发现的孟德尔随机化

基本信息

批准号：
10412041
负责人：
Oscar Harari
金额：
$ 73.32万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10412041
关键词：
Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer’s disease biomarker Amyloid beta-Protein Bioinformatics Biological Biological Markers Biological Process Bipolar Disorder Brain CD40 Ligand Catalogs Cerebrospinal Fluid Clinical Clinical Trials Cognition Complex Data Data Set Databases Dementia Deposition Diagnosis Diagnostic Disease Disease Progression Early Diagnosis Employment Ethnic Origin Etiology Evaluation Genes Genetic Genetic Variation Genetic study Genome Genomics Genotype Goals Guidelines Individual Inflammation Intervention Link Mendelian randomization Modeling Molecular Monitor Multiple Sclerosis Multivariate Analysis National Human Genome Research Institute Neurodegenerative Disorders Neurofibrillary Tangles Neuronal Injury Parietal Lobe Participant Pathway interactions Phenotype Physiological Processes Plasma Play Predisposing Factor Prevention Prognosis Proteins Proteome Proteomics Reporting Research Resources Risk Risk Assessment Role Sampling Senile Plaques Single Nucleotide Polymorphism Source Stroke TNFRSF5 gene TREM2 gene Techniques Testing Treatment Efficacy Variant base biomarker discovery brain tissue clinical diagnosis clinical risk combinatorial cost effective deep learning disease phenotype disorder risk effectiveness evaluation endophenotype exome exome sequencing genetic architecture genetic information genetic variant genome sequencing genome wide association study genome-wide improved insight non-demented novel novel marker participant enrollment predictive modeling prognostic prospective rare variant sex tau Proteins tau-1 therapeutic target trait whole genome

Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer’s disease biomarker Amyloid beta-Protein Bioinformatics Biological Biological Markers Biological Process Bipolar Disorder Brain CD40 Ligand Catalogs Cerebrospinal Fluid Clinical Clinical Trials Cognition Complex Data Data Set Databases Dementia Deposition Diagnosis Diagnostic Disease Disease Progression Early Diagnosis Employment Ethnic Origin Etiology Evaluation Genes Genetic Genetic Variation Genetic study Genome Genomics Genotype Goals Guidelines Individual Inflammation Intervention Link Mendelian randomization Modeling Molecular Monitor Multiple Sclerosis Multivariate Analysis National Human Genome Research Institute Neurodegenerative Disorders Neurofibrillary Tangles Neuronal Injury Parietal Lobe Participant Pathway interactions Phenotype Physiological Processes Plasma Play Predisposing Factor Prevention Prognosis Proteins Proteome Proteomics Reporting Research Resources Risk Risk Assessment Role Sampling Senile Plaques Single Nucleotide Polymorphism Source Stroke TNFRSF5 gene TREM2 gene Techniques Testing Treatment Efficacy Variant base biomarker discovery brain tissue clinical diagnosis clinical risk combinatorial cost effective deep learning disease phenotype disorder risk effectiveness evaluation endophenotype exome exome sequencing genetic architecture genetic information genetic variant genome sequencing genome wide association study genome-wide improved insight non-demented novel novel marker participant enrollment predictive modeling prognostic prospective rare variant sex tau Proteins tau-1 therapeutic target trait whole genome

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项目摘要

Abstract Alzheimer’s disease (AD) is the most common form of dementia but has no effective prevention or treatment. The brain proteome, ascertained in cerebrospinal fluid (CSF) have proven to be a rich source of information, reflecting Aβ plaques deposition, neurofibrillary tangles, neuronal injury and inflammation, and have helped the enrollment of participants in clinical trials. Still, additional non-invasive and cost-effective biomarkers are critical for the early detection, disease intervention and monitoring. Novel biomarkers may also help identify and characterize the additional aspects of AD, such as rate of progression and age at onset. Although genetic studies have focused on the identification of variants associated with risk through genome-wide association studies (GWAS) and whole genome and exome sequencing projects, the genetic factors modulating these additional aspects of AD are less investigated. The current proposal focuses on these understudied aspects of disease etiology, namely the role of common and rare genetic variation on quantitative diagnostic and prognostic endophenotypes of Alzheimer’s disease (AD). We will develop a unique resource – the proteome ascertained in a plasma, CSF and brain for a large number of samples – that will allow us to leverage unbiased approaches to reveal novel biomarkers and endophenotypes associated with AD and complex traits. We will utilize Mendelian Randomization to identify causal proteins involved in AD and extend our studies to other complex traits. We will use GWAS, exome-chip, whole-exome and whole-genome sequences to identify single variants, genes and pathways associated with plasma, cerebrospinal fluid (CSF) and brain protein levels of AD biomarkers.

抽象的阿尔茨海默氏病（AD）是痴呆症的最常见形式，但没有有效的预防或治疗。在脑脊液（CSF）中确定的脑蛋白质组已被证明是丰富的信息来源，反映Aβ斑块沉积，神经原纤维缠结，神经元损伤和感染，并有助于参与者参加临床试验。尽管如此，其他非侵入性和具有成本效益的生物标志物至关重要用于早期检测，疾病干预和监测。新颖的生物标志物也可能有助于识别和表征AD的其他方面，例如发作时的进展和年龄。虽然遗传研究通过全基因组关联研究的识别与风险相关的变体的识别（GWAS）以及整个基因组和外显子组测序项目，调节这些额外的遗传因素广告的各个方面的研究较少。当前的提议着重于这些知识的疾病方面病因，即常见和稀有遗传变异对定量诊断和预后的作用阿尔茨海默氏病（AD）的内表型。我们将开发独特的资源 - 蛋白质组在用于大量样品的血浆，CSF和大脑 - 这将使我们能够利用无偏的方法揭示与AD和复杂性状相关的新型生物标志物和内型型。我们将利用门德利人随机化以鉴定参与AD的因果蛋白，并将我们的研究扩展到其他复杂性状。我们将使用GWAS，外显片，全外观和全基因组序列来识别单个变体，基因和与血浆，脑脊液（CSF）和AD生物标志物的脑蛋白水平相关的途径。