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， 试验没有成功。发现识别疾病异质性的遗传生物标志物 国家和亚组促进试验设计的后勤工作，并激发干预目标。几行 有证据表明，目前的分类模式仅使用PD单基因亚组是不够的， 不能完全反映临床病因病理学谱，包括越来越多的证据表明， 机制等因此，需要鉴定额外的基因和贡献的遗传生物标志物。这些 可能有助于综合评分的发展，类似于肿瘤学中的实践， 在治疗决策中评估这些因素。在此，我们努力阐明血液遗传学 通过评估德系犹太人（AJ）背景的个体来评估生物标志物。除了更高的利率外， PD和LRRK2和GBA突变频率增加，这些个体的特征是遗传性 同质性和奠基者效应，可能有助于阐明疾病相关基因， 样本量。这现在是PD疾病改善试验的关键时刻，因为药物针对GBA相关 靶点和LRRK 2介导的疗法正在进行或正在规划中。在目标1中，我们将招募AJ PD， LRRK2 G2019S突变、GBA突变和无突变，以及未表现出基因携带者，和 非疾病非突变对照。为帕金森病的研究提供了宝贵的标本资源 疾病生物标志物计划（PDBP）以及社区，以及目标2和3的DNA和RNA。在目标2中 我们将进行基因组分析，以评估参与PD的途径。这些包括与a）PD相关的基因 和运动障碍相关的重叠综合征，B）溶酶体贮积症，和c）免疫过程。 这一目标主要是探索性的，但具有很大的潜力，因为在这一人群中容易鉴定出突变， 如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，这些变异直接或间接地构成了PD的病理生物学基础。 反映了脑内髓样细胞（如小胶质细胞）表达的变化，并将评估特征 从特定的免疫细胞的基因表达。Aim 2将提供WGS和Aim 3 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 在目标之内和之间。这种转化的潜力在于，可以很容易地分析基于血液的生物标志物 在临床上，还可以提供有关疾病亚型的个人信息，从而能够直接研究 新的目标和改进的临床试验设计和成功的可能性。综合考虑， 更好地了解PD发病机制的巨大潜力，包括阐明疾病途径， 提供生物标志物以了解异质性，从而改善临床试验和个性化疾病 PD的改良疗法。 !

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. !