Immunogenetic Determinants of Disease Risk in Neurological Disease

神经系统疾病风险的免疫遗传学决定因素

• 批准号: 8955877
• 负责人: Marcelo Fernandez-Vina
• 金额: $ 141.33万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8955877
• 关键词: 6p21; Address; Algorithms; Alleles; Automobile Driving; Bioinformatics; Biological; Cataloging; Catalogs; Central Nervous System Diseases; Clinical; Collaborations; Complex; DNA; Data; Data Set; Development; Dideoxy Chain Termination DNA Sequencing; Disease; Disease susceptibility; Elements; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genomics; Genotype; Goals; Gold; Grant; HLA-A gene; Haplotypes; Health; Human; Human Genome; Immunity; Immunogenetics; Inflammatory; Inherited; International; Investments; Knowledge; Laboratories; Leadership; Logistics; Major Histocompatibility Complex; Maps; Mediating; Medical Genetics; Methodology; Methods; Molecular; Multiple Sclerosis; Myasthenia Gravis; Nerve Degeneration; Neuromyelitis Optica; Overlapping Genes; Parkinson Disease; Participant; Pathway interactions; Patients; Pattern; Predisposition; Productivity; Publishing; Research; Research Design; Research Infrastructure; Resolution; Risk; Sampling; Schizophrenia; Scientist; Signal Transduction; Single Nucleotide Polymorphism; Site; Surveys; System; Technology; Variant; analytical method; base; central nervous system injury; cost effective; data management; design; disorder risk; genetic analysis; genetic association; genome wide association study; genotyping technology; innovation; insight; nervous system disorder; neurogenetics; neuroinflammation; neuropsychiatry; next generation sequencing; novel; pleiotropism; programs; promoter; public health relevance; response; sample collection; screening; skills; tool; trait; working group

 DESCRIPTION (provided by applicant): This project, submitted as a multi-center U19 application on behalf of the Immunogenetics of Neurological Diseases working GrOup (INDIGO), has as its primary goal to identify and characterize the repertoire of HLA and KIR genes and alleles that predispose to neurological diseases. WE focus the effort on multiple sclerosis, neuromyelitis optica, myasthenia gravis, Parkinson's disease, and schizophrenia - all diseases with established association signals in the Major Histocompatibility Complex (MHC). To achieve our goals, we have assembled a multi-disciplinary international team that brings together complementary expertise (immuno- and neuro-genetics, clinical, and computational) and a remarkable track record of productivity to carry out a study of broad scope and depth. Through this collaboration, we will leverage rich and informative datasets exceeding 15,000 study participants (cases) and connect genetics with CNS disease utilizing advanced molecular and bio-informatics tools. The study design includes 2 independent, yet interactive Projects supported by a common administrative and data/sample management infrastructure. Project 1 proposes a comprehensive sequence variation screening in nine HLA loci and association analysis with disease risk. Project 2 will assess the distribution of KIR-associated variants, KIR copy number, and KIR promoter polymorphisms in the same diseases. Both projects will take advantage of the ancestral diversity of the datasets to advance the fine mappings of the discovered associations. Naturally, we will also pursue the analysis of HLA-KIR interactions vis-à-vis disease susceptibility. Genetic pleiotropy and the identification of common immunogenetics across diseases are additional important elements of this initiative. The overarching goal of this project is to achieve a productive integration of molecular and clinical datasets to elucidate the genetic pathways that drive risk to CNS injury and neurodegeneration. The isolation of definite HLA- KIR associations with the risk of neuroinflammation and neurodegeneration could be transformative by revealing fundamental insights about primary disease mechanisms.

 描述（由申请人提供）：该项目代表神经疾病免疫遗传学工作组 (INDIGO) 作为多中心 U19 申请提交，其主要目标是鉴定和表征 HLA 和 KIR 基因和等位基因的全部特征我们重点关注多发性硬化症、视神经脊髓炎、重症肌无力、帕金森病和精神分裂症 - 在主要组织相容性复合体 (MHC) 中已确定关联信号的所有疾病 为了实现我们的目标，我们组建了一个多学科的国际团队，汇集了互补的专业知识（免疫和神经遗传学、临床和计算）和。通过此次合作，我们将利用超过 15,000 名研究参与者（病例）的丰富且信息丰富的数据集，并利用先进的分子和技术将遗传学与中枢神经系统疾病联系起来。该研究设计包括 2 个独立但互动的项目，由共同的管理和数据/样本管理基础设施支持，项目 1 提出对 9 个 HLA 位点进行全面的序列变异筛查，项目 2 将评估与疾病风险的关联分析。相同疾病中 KIR 相关变异、KIR 拷贝数和 KIR 启动子多态性的分布，这两个项目都将利用数据集的祖先多样性来推进所发现的关联的精细映射。我们还将分析 HLA-KIR 与疾病易感性之间的相互作用，并识别跨疾病的共同免疫遗传学，这是该项目的首要目标是实现多种疾病的有效整合。分子和临床数据集阐明导致中枢神经系统损伤和神经变性风险的遗传途径，分离明确的 HLA-KIR 与神经炎症和神经变性风险的关联可能具有变革意义。揭示有关原发疾病机制的基本见解。