Beta-glucocerebrosidase Mutations and PD in the Ashkenazim

描述(申请人提供)：帕金森氏病(PD)是一种复杂的疾病，具有不同的病因。在这项提案中，我们将重点关注德系犹太人(AJ)，这是一个基因孤立的群体。使用病例对照设计，我们将通过连锁不平衡来寻找遗传关联，假设共同的创始人突变(S)已传递给与其相关的单倍型的受影响个体。本研究的目的是在AJ人群中确定与帕金森病相关的疾病单核苷酸多态、单倍型和/或β-葡萄糖脑苷酶基因的创立者突变(S)，并探讨存在和不存在GBA突变的帕金森病患者的表型差异。我们的目标是通过评估和收集另外119名患有帕金森氏症的无关AJ患者和188名AJ配偶对照的DNA来实现这一点，以产生总共300个病例和300个可供分析的对照。所有帕金森氏症病例和对照都将接受全面的神经学检查，并将使用统一的帕金森氏病分级量表和高谢病症状严重程度指数和神经状况问卷进行评估，以确定有和没有GBA突变的帕金森病患者之间的表型差异。第二，生成GBA基因的高分辨率SNP图谱，确定单倍型，分析病例和对照之间的频率，并确定一个或多个与PD和/或方正突变相关的疾病单倍型/SNP。值得注意的是，最近的研究表明，GBA基因的突变可能与帕金森病有关，溶酶体/自噬途径也与帕金森病的发病有关。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a complex disorder with a heterogeneous etiology. In this proposal we will focus on Ashkenazi Jews (AJ), a genetically isolated population. Using a case-control design, we will search for genetic association by linkage disequilibrium with the assumption that a common founder mutation(s) has been transmitted to affected individuals with its associated haplotype. The objectives of this proposal are to identify disease SNPs, haplotypes and/or founder mutation(s) in the p-glucocerebrosidase (GBA) gene that are associated with Parkinson's disease in the AJ population and to explore phenotypic differences between PD cases with and without GBA mutations. We aim to do this by evaluating and collecting DNA from an additional 119 unrelated AJ individuals with Parkinson's disease and 188 AJ spouse controls to generate a total of 300 cases and 300 controls available for analysis. All Parkinson's disease cases and controls will undergo a full neurological examination and will be evaluated using the Unified Parkinson's disease rating scale and a Gaucher disease symptom severity index and neurological status questionnaire towards identifying phenotypic differences between PD cases with and without GBA mutations. Second, to generate a high resolution SNP map of the GBA gene, determine haplotypes and analyze frequencies between cases and controls and identify one or more disease haplotypes/SNPs in association with PD and or founder mutations. Significantly, recent studies suggest that mutations in the GBA gene may be associated with Parkinson's disease and the lysosomal/autophagic pathway has also been implicated in PD pathogenesis.