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: 8289645
• 负责人: CYRUS P ZABETIAN
• 金额: $ 49.63万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8289645
• 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 Proteins; Gene-Modified; Genes; Genetic; Genome; Goals; Health; 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; 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）：该提案旨在发现 1p 号染色体候选区域内的新基因，该基因可改变 PD 易感性和/或发病年龄。这种基因的特征及其参与的途径将进一步加深我们对导致帕金森病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新的治疗靶点，用于预防和更好地治疗该疾病。公共卫生相关性：帕金森病 (PD) 影响 1-2% 的 60 岁以上人口，因此构成公共卫生的主要问题。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，有必要更好地了解 PD 的分子机制。人类遗传学研究是这一努力的宝贵工具。最近在两项独立的连锁研究中，在 1p 染色体上发现了一个新的 PD 候选区域。然而，该区域内疾病基因的身份尚未确定。在此应用中，我们建议使用从美国各地招募的 300 个多重 PD 家族中的 7,600 个单核苷酸多态性 (SNP) 来精细绘制候选区间。基于 FBAT 的方法将用于识别可改变 PD 风险或发病年龄的 SNP。将进行探索性分析来测试基因 x 环境相互作用。然后，我们将在 2,000 名受试者的独立病例对照样本中验证符合预先定义的显着性阈值的标记。最后，将进行广泛的生物信息学分析，以汇总一系列推定的功能风险变异，随后通过体外测定测试其对基因表达和/或蛋白质功能的影响。这项工作有可能发现一种新的疾病基因，它可以为帕金森病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。

项目成果

Mosaicism of alpha-synuclein gene rearrangements: report of two unrelated cases of early-onset parkinsonism.

α-突触核蛋白基因重排的镶嵌现象：两例不相关的早发性帕金森病病例的报告。

• 发表时间: 2014-05
• 影响因子: 4.1
• 作者: Perandones, C;Giugni, J C;Calvo, D S;Raina, G B;De Jorge Lopez, L;Volpini, V;Zabetian, C P;Mata, I F;Caputo, M;Corach, D;Radrizzani, M;Micheli, F E
• 通讯作者: Micheli, F E