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：尽管有症状的帕金森氏病（PD）的症状疗法，疾病改良 试验尚未成功。发现鉴定疾病异质性的遗传生物标志物 各州和亚组促进了试验设计的物流，并激发了干预目标。几行 证据表明，使用PD单基因亚组的​​当前分类模式仅是不足的，并且 请勿完全反映临床病理学的范围，包括越来越多的寡聚证据 机制。因此，有必要识别其他基因并贡献遗传生物标志物。这些 可能有助于发展复合评分，类似于肿瘤学的实践，从而多重遗传风险 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 通过评估Ashkenazi犹太人（AJ）背景的生物标志物。除了更高的速度 PD和LRRK2和GBA突变的频率增加，这些个体的特征是遗传 同质性和创始人效应，可能有助于阐明疾病相关基因的效果 样本量。现在，这是针对GBA相关的代理的PD疾病修饰试验中的关键时刻 靶标和LRRK2介导的疗法正在进行或计划中。在AIM 1中，我们将与AJ PD一起注册 LRRK2 G2019S突变，GBA突变和无突变，以及非征服基因载体和 非疾病的非命名对照。这个目标将为帕金森岛提供宝贵的样品作为资源 疾病生物标志物计划（PDBP），因此是社区，AIM 2和AIM 2的DNA和RNA。 我们将进行基因组分析以评估与PD有关的途径。这些包括与a）PD有关的基因 以及与运动障碍有关的重叠综合征，b）溶酶体储存障碍和c）免疫过程。 这个目的主要是探索性的，但具有巨大的潜力，因为突变在该人群中很容易确定，因此 作为GBA，具有全球疾病的意义。在AIM 3中，我们的中心假设是 外围单核细胞港口重要的功能变化，该功能变化是PD直接或 反映大脑内髓样细胞表达的变化，例如小胶质细胞，将评估概况 来自特定免疫细胞的基因表达。 AIM 2将提供WGS并为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 在目标内外。翻译潜力是，基于血液的生物标志物可以很容易地分析 在诊所中，还可以提供有关疾病亚型的个人信息，从而直接研究 新目标和改进的临床试验设计以及成功的可能性。综上所述，这种方法成立 更好地理解PD发病机理的巨大潜力，包括照明疾病途径和 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 修改PD的疗法。 呢