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

描述（由申请人提供）：该提案旨在发现染色体1 p上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。这样一个基因的表征，以及它参与的途径，将进一步我们的分子事件，导致选择性神经退行性疾病的PD的理解。这些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：帕金森病（PD）影响1-2%的60岁以上的人口，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，更好地了解PD的分子机制是必要的。人类遗传学研究是这一奋进的宝贵工具。最近在两项独立的连锁研究中，在染色体1 p上发现了一个新的PD候选区域。然而，该区域内的疾病基因的身份尚未确定。在本申请中，我们建议使用来自美国各地的300个多重PD家族中的7，600个单核苷酸多态性（SNP）来精细映射候选间隔。基于FBAT的方法将用于鉴定改变PD风险或发病年龄的SNP。将进行探索性分析，以测试基因x环境的相互作用。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定义显著性阈值的标志物。最后，将进行广泛的生物信息学分析，以收集推定的功能风险变体列表，随后将通过体外试验检测其对基因表达和/或蛋白质功能的影响。这项工作有可能发现一个新的疾病基因，这可以为PD的发病机制提供重要的见解，最终转化为诊断，预防和治疗的改进策略。

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.