Dissecting Oligogenic Biomarkers in Ashkenazi Jews with Parkinson Disease

剖析患有帕金森病的德系犹太人的寡基因生物标志物

• 批准号: 10369016
• 负责人: Laurie J. Ozelius
• 金额: $ 122.3万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10369016
• 关键词: Age; Ashkenazim; Bayesian Analysis; Bioinformatics; Biological Assay; Biological Markers; Blood; Blood Cells; Brain; Candidate Disease Gene; Cell Separation; Cells; Classification; Clinic; Clinical; Clinical Trials; Clinical Trials Design; Collection; Communities; Cytometry; DNA; Data; Data Set; Databases; Decision Making; Dementia; Deposition; Development; Disease; Disease Pathway; Disease Progression; Enrollment; Ethnic group; Etiology; Evaluation; Family history of; Founder Effect; Frequencies; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Markers; Genetic Research; Genetic Risk; Genome; Genomics; Heterogeneity; Immune; Immunologic Markers; Individual; Inflammatory; Intervention; Israel; LRRK2 gene; Logistics; Measures; Mediating; Mendelian disorder; Methods; Microglia; Modeling; Movement Disorders; Mutation; Myeloid Cells; National Institute of Neurological Disorders and Stroke; Nature; Oncology; Parkinson Disease; Participant; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patient Care; Penetrance; Peripheral; Pharmaceutical Preparations; Population; Process; Proteomics; Protocols documentation; Public Health; RNA; Resources; Role; Sample Size; Sampling; Speed; Subgroup; Syndrome; Techniques; Testing; Therapeutic; Urine; Validation; Variant; Visit; Whole Blood; base; biomarker development; blood-based biomarker; brain tissue; clinical heterogeneity; cohort; disease heterogeneity; disorder control; disorder subtype; follower of religion Jewish; gene interaction; genetic risk factor; genetic variant; genome sequencing; glucosylceramidase; illness length; improved; monocyte; mutation carrier; novel; novel therapeutics; personalized approach; prevent; programs; protective allele; randomized trial; rare variant; recruit; repository; risk variant; sample collection; success; transcriptome; transcriptome sequencing; transcriptomics; translational potential; trial design; whole genome

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. !

摘要：尽管帕金森病（PD）的对症治疗取得了进展，但疾病缓解 试验尚未成功。发现识别疾病异质性的遗传生物标志物 国家和分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，目前仅使用 PD 单基因亚组的​​分类方案是不够的，并且 不能完全反映临床病因病理学的范围，包括越来越多的寡基因证据 机制。因此，需要鉴定额外的基因和贡献的遗传生物标志物。这些 可能有助于制定综合评分，类似于肿瘤学实践，其中多种遗传风险 在治疗决策中评估因素。在此，我们努力阐明基于血液的遗传因素 通过对德系犹太人 (AJ) 背景的个体进行评估来确定生物标志物。除了较高的利率外 PD 和 LRRK2 和 GBA 突变频率增加，这些个体的特征是遗传 同质性和创始人效应可能有助于用更小的基因来阐明疾病相关基因 样本大小。作为针对 GBA 相关药物的药物，现在是 PD 疾病修饰试验的关键时刻 靶点和 LRRK2 介导的疗法正在进行或正在规划中。在目标 1 中，我们将注册 AJ PD LRRK2 G2019S 突变、GBA 突变和无突变，以及非显性基因携带者，以及 非疾病非突变控制。这一目标将为帕金森病的治疗提供珍贵的样本资源。 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来评估与 PD 相关的通路。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) 溶酶体储存障碍，以及 c) 免疫过程。 这一目标主要是探索性的，但具有巨大的潜力，因为在该人群中很容易发现突变，例如 与大湾区一样，具有世界范围的疾病意义。在目标 3 中，我们的中心假设是转录组 外周单核细胞具有重要的功能变异，这些变异直接或间接是PD病理学的基础 反映大脑内骨髓细胞（例如小胶质细胞）表达的变化，并将评估概况 特定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。转化潜力在于可以轻松测定基于血液的生物标志物 在诊所中，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。综合起来，这种方法成立 更好地了解 PD 发病机制的巨大潜力，包括阐明疾病途径和 提供生物标志物来了解异质性，从而改进临床试验和个性化疾病 修改 PD 疗法。 ！