Beta-glucocerebrosidase Mutations and PD in the Ashkenazim

描述（由申请人提供）：帕金森病（PD）是一种具有异质性病因的复杂疾病。在这个提议中，我们将把重点放在德系犹太人（AJ）上，这是一个基因孤立的群体。采用病例对照设计，我们将通过连锁不平衡来寻找遗传关联，并假设一个共同的始创突变已传播给具有相关单倍型的受影响个体。本研究的目的是确定AJ人群中与帕金森病相关的p-葡糖脑苷酶（GBA）基因的疾病单核苷酸多态性、单倍型和/或始创突变，并探索有和没有GBA突变的PD病例之间的表型差异。我们的目标是通过评估和收集另外119名无血缘关系的AJ帕金森病患者和188名AJ配偶对照的DNA，以产生总共300例病例和300例对照可用于分析。所有帕金森病病例和对照组将接受全面的神经系统检查，并使用统一帕金森病评定量表和戈谢病症状严重程度指数和神经系统状态问卷进行评估，以确定有和没有GBA突变的帕金森病病例之间的表型差异。其次，生成GBA基因的高分辨率SNP图谱，确定单倍型并分析病例和对照之间的频率，确定与PD和/或创始人突变相关的一种或多种疾病单倍型/SNP。值得注意的是，最近的研究表明GBA基因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.