Dissecting Oligogenic Biomarkers in Ashkenazi Jews with Parkinson Disease

摘要：尽管帕金森病(PD)的对症治疗取得了进展，但疾病修饰 试验一直没有成功。发现识别疾病间异质性的遗传生物标记物 国家和分组为试验设计的后勤工作提供便利，并激发干预目标。几行 有证据表明，目前仅使用PD单基因亚组的分类方案是不够的，并且 没有完全反映临床病因-病理的范围，包括越来越多的证据表明少发 机械装置。因此，有必要确定更多的基因和贡献遗传生物标记物。这些 可能有助于综合评分的发展，类似于肿瘤学的实践，即多基因风险 在治疗决策中对因素进行评估。在这里，我们努力阐明基于血液的遗传 通过评估德系犹太人(AJ)背景的个人的生物标志物。除了更高的利率 帕金森病的发生以及LRRK2和GBA突变频率的增加，这些个体的特征是 同质性和方正效应，可能有助于更小的疾病相关基因的阐明 样本大小。这是作为针对GBA相关药物的PD疾病修改试验的关键时刻 靶向和LRRK2介导的治疗要么正在进行中，要么正在规划中。在目标1中，我们将向AJ PD投保 LRRK2 G2019S突变、GBA突变和NO突变，以及非显性基因携带者 非疾病非突变对照。这一目标将为帕金森病的研究提供宝贵的样本资源 疾病生物标记物计划(PDBP)和社区，以及目标2和3的DNA和RNA。 我们将进行基因组分析，以评估与帕金森病有关的通路。其中包括与a)帕金森病相关的基因。 和运动障碍相关的重叠综合征，b)溶酶体储存障碍，以及c)免疫过程。 这个目标主要是探索性的，但有很大的潜力，因为在这个群体中很容易发现突变，比如 作为GBA，具有世界性的疾病意义。在目标3中，我们的中心假设是 外周血单核细胞具有重要的功能变异，是帕金森病直接或间接致病的基础。 反映脑内髓系细胞的表达变化，如小胶质细胞，并将评估个人资料 来自特定免疫细胞的基因表达。AIM 2将为WGS和AIM 3提供RNAseq数据 社区。我们将使用最先进的生物信息学技术来评估基因组学和转录组学 在AIMS内部和之间。翻译的潜力是，基于血液的生物标记物可以很容易地进行分析 还可以提供有关疾病亚型的个人信息，从而使直接研究 新的目标和改进的临床试验设计和成功的可能性。总而言之，这种方法适用于 更好地理解帕金森病发病机制的巨大潜力，包括阐明疾病途径和 提供生物标记物以了解异质性，从而改进临床试验和个性化疾病 修改帕金森病的治疗方法。 好了！

ABSTRACT: Despite gains made in symptomatic therapies for Parkinson Disease (PD), disease-modifying trials have not been successful. Discovering genetic biomarkers that identify heterogeneity among disease states and subgroups facilitates logistics of trial design and inspires targets for intervention. Several lines of evidence indicate that current classification schema using PD single gene subgroups only are inadequate and do not fully reflect the spectrum of clinical etio-pathology, including growing evidence for oligogenic mechanisms. Thus there is a need to identify additional genes and contributing genetic biomarkers. These may help in the development of a composite score, similar to practice in oncology whereby multiple genetic risk factors are assessed in therapeutic decision-making.. Herein, we strive to elucidate blood-based genetic biomarkers through evaluation of individuals of Ashkenazi Jewish (AJ) background. In addition to a higher rate of PD and increased frequency of LRRK2 and GBA mutations, these individuals are characterized by genetic homogeneity and founder effects that may facilitate elucidation of disease-related genes with much smaller sample sizes. This is now a pivotal moment in PD disease modifying trials as agents directed at GBA related targets and LRRK2 mediated therapies are either underway or in planning. In Aim 1 we will enroll AJ PD with LRRK2 G2019S mutations, GBA mutations and no mutations, as well as non-manifesting gene carriers, and non-disease non-mutation controls. This aim will provide precious samples as resource for the Parkinson Disease Biomarker Program (PDBP) and thus the community, and DNA and RNA for Aims 2 and 3. In Aim 2 we will perform genomic analysis to evaluate pathways implicated in PD. These include genes related to a) PD and movement disorder-related overlap syndromes, b) lysosomal storage disorders, and c) immune processes. This aim is primarily exploratory but has great potential as mutations readily identified in this population, such as GBA, have worldwide disease significance. In Aim 3, our central hypothesis is that the transcriptome of peripheral monocytes harbors important functional variation that underlies the pathobiology of PD directly or reflects variation in expression in myeloid cells within the brain, such as microglia, and will evaluate profile gene expression from specific immune cells. Aim 2 will provide WGS and Aim 3 RNASeq data for the community. We will use state-of the art bioinformatics techniques to evaluate genomics and transcriptomics within and across the aims. The translational potential is that blood-based biomarkers could be readily assayed in the clinic and could also give individual information about subtype of disease thereby enabling direct study of new targets and improved clinical trial design and likelihood of success. Taken together, this approach holds great potential for better understanding PD pathogenesis, including illuminating disease pathways and providing biomarkers to understand heterogeneity, leading to improved clinical trials and personalized disease modifying therapies for PD. !