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

• 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
• 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

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）：本提案旨在发现染色体1p候选区域内改变PD易感性和/或发病年龄的新基因。这种基因的表征及其参与的途径将进一步加深我们对导致PD选择性神经变性的分子事件的理解。这一知识可能有助于确定新的治疗靶点，可以用来预防和更好地治疗这种疾病。公共卫生相关性：帕金森病（PD）影响60岁以上人口的1-2%，因此构成了公共卫生的一个主要问题。目前的治疗策略只是姑息性的，为了开发更明确的神经保护疗法，更好地了解PD的分子机制是必要的。在这方面，人类基因研究是一个有价值的工具。最近在两个独立的连锁研究中，在染色体1p上发现了一个新的PD候选区域。然而，该地区疾病基因的身份尚未确定。在这项应用中，我们建议使用从美国各地招募的300个多重PD家族的7600个单核苷酸多态性（snp）来精细绘制候选区间。基于FBAT的方法将用于识别改变PD风险或发病年龄的snp。将进行探索性分析以测试基因与环境的相互作用。然后，我们将在2000名受试者的独立病例对照样本中验证符合预定义显著性阈值的标记。最后，将进行广泛的生物信息学分析，以收集假定的功能风险变异列表，随后将通过体外试验测试对基因表达和/或蛋白质功能的影响。这项工作有可能发现一个新的疾病基因，这可能为PD的发病机制提供重要的见解，最终转化为改进的诊断、预防和治疗策略。