Using Multiplex Families to map Genes that Modify Susceptibility and Age at Onset

使用多重家族来绘制改变易感性和发病年龄的基因

基本信息

批准号：
7741592
负责人：
CYRUS P ZABETIAN
金额：
$ 51.88万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7741592
关键词：
Accounting Affect Age Age-Years Alleles Area Bioinformatics Cessation of life Chromosomes Copy Number Polymorphism DNA Data Data Set Diagnosis Disease Disease susceptibility Environment European Event Family Gene Expression Gene-Modified Genes Genetic Genome Goals Human Genetics In Vitro International Knowledge Lead Light Literature Maps Mediating Methods Mitochondria Modality Molecular Nerve Degeneration Neurodegenerative Disorders Neuronal Injury Onset of illness PARK10 gene Parkinson Disease Pathogenesis Pathway interactions Pattern Phosphotransferases Population Predisposition Prevalence Prevention Procedures Process Public Health Publishing Recruitment Activity Registries Reporting Research Resolution Respiratory Chain Risk Sampling Signal Transduction Single Nucleotide Polymorphism Testing Time Translating Ubiquitin United States Variant Work abstracting aged base case control design disorder risk genetic pedigree improved in vitro Assay insight meetings new therapeutic target palliative prevent protein degradation protein function public health relevance research study sex tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): This proposal seeks to discover a new gene(s) within a candidate region on chromosome 1p that modifies PD susceptibility and/or age at onset. The characterization of such a gene, and the pathways in which it participates, will further our understanding of the molecular events that lead to selective neurodegeneration in PD. This knowledge might serve to identify novel therapeutic targets which could be used to prevent and better treat the disease. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) affects 1-2% of the population over 60 years of age and thus constitutes a major problem in public health. Current treatment strategies are only palliative and a better understanding of the molecular mechanisms underlying PD is necessary in order to develop more definitive neuroprotective therapies. Human genetic studies are a valuable tool in this endeavor. A new candidate region for PD was recently identified on chromosome 1p in two independent linkage studies. However, the identity of the disease gene(s) within this region has not yet been determined. In this application, we propose to fine-map the candidate interval using 7,600 single nucleotide polymorphisms (SNPs) in 300 multiplex PD families recruited from across the United States. FBAT- based methods will be utilized to identify SNPs which modify PD risk or age at onset. Exploratory analyses will be undertaken to test for gene x environment interactions. We will then validate markers which meet a pre-defined significance threshold in an independent case control sample of 2,000 subjects. Finally, an extensive bioinformatics analysis will be performed to assemble a list of putative functional risk variants which will subsequently be tested for effects on gene expression and/or protein function via in vitro assays. This work has the potential to discover a new disease gene(s) which could provide important insights into the pathogenesis of PD that ultimately translate into improved strategies for diagnosis, prevention, and treatment.

描述（由申请人提供）：该提案旨在在染色体1p的候选区域内发现一个新基因，该基因在发病时修改PD易感性和/或年龄。这种基因的表征及其参与的途径将进一步了解我们对导致PD中选择性神经变性的分子事件的理解。这些知识可能有助于确定可用于预防和更好地治疗疾病的新型治疗靶标。公共卫生相关性：帕金森氏病（PD）影响60岁以上人口的1-2％，因此构成了公共卫生的主要问题。目前的治疗策略仅是姑息性的，需要更好地了解PD的分子机制，以开发更确定的神经保护疗法。人类遗传研究是这项努力的宝贵工具。最近在两项独立的链接研究中，在1P染色体上发现了一个新的PD候选区域。但是，尚未确定该区域内疾病基因的身份。在此应用中，我们建议使用来自美国各地招募的300个多重PD家族中的7,600个单核苷酸多态性（SNP）对候选间隔进行细微地图。将利用基于FBAT的方法来识别在发作时修改PD风险或年龄的SNP。将进行探索性分析以测试基因X环境相互作用。然后，我们将验证在2,000名受试者的独立案例控制样本中符合预定义显着性阈值的标记。最后，将进行广泛的生物信息学分析，以组装推定的功能风险变体列表，随后将通过体外测定对基因表达和/或蛋白质功能的影响进行测试。这项工作有可能发现一种新的疾病基因，该基因可以为PD的发病机理提供重要的见解，最终转化为改进的诊断，预防和治疗的策略。