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

描述(申请人提供)：这项建议寻求在染色体1p上的候选区域发现一个新的基因(S)，该基因可以改变帕金森病的易感性和/或发病年龄。这种基因的特征，以及它参与的途径，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。这一知识可能有助于确定新的治疗靶点，可用于预防和更好地治疗这种疾病。公共卫生相关性：帕金森氏病(PD)影响1-2%的60岁以上人口，因此构成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，有必要更好地了解帕金森病的分子机制。人类基因研究是这一努力中的宝贵工具。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，该区域内的致病基因(S)的身份尚未确定。在这项应用中，我们建议使用7600个单核苷酸多态(SNPs)对来自美国各地的300个多重PD家系的候选区间进行精细定位。基于FBAT的方法将被用来识别改变帕金森病风险或发病年龄的SNPs。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先定义的显著性阈值的标记。最后，将进行广泛的生物信息学分析，以汇编一系列可能的功能风险变异，随后将通过体外分析测试这些变异对基因表达和/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(S)，它可能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。

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.