Genetic Architecture of Parkinson's Disease in African-American and Latino Veterans

非裔美国人和拉丁裔退伍军人帕金森病的遗传结构

• 批准号: 10703737
• 负责人: CYRUS P ZABETIAN
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703737
• 关键词: Address; Affect; African; African American; African American population; African ancestry; American; Area; Bioinformatics; Caregivers; Chromatin; Chromosome Mapping; Clinical; Collaborations; Custom; Data; Data Set; Diagnosis; Disease; Disparity; Distress; Equilibrium; Equity; European; European ancestry; Event; Exclusion; Exhibits; Family; Functional disorder; Future; Gene Frequency; Genes; Genetic; Genetic Diseases; Genetic Research; Genetic study; Genome; Genomics; Genotype; Goals; Human Genetics; Human Genome Diversity Project; Individual; Inherited; Intervention; Knowledge; Label; Latin American; Latino; Latino Population; Learning; Maps; Methods; Minor; Minority Groups; Modeling; Molecular; Molecular Genetics; Movement Disorders; Neurodegenerative Disorders; Neuronal Injury; Nursing Homes; Parkinson Disease; Participant; Pattern; Performance; Persons; Phase; Phenotype; Population; Population Genetics; Positioning Attribute; Prevalence; Process; Publishing; Quality of life; Quantitative Trait Loci; Research; Research Personnel; Resolution; Resources; Risk; Role; Sampling; Signal Transduction; Subgroup; Susceptibility Gene; Techniques; Testing; Therapeutic Intervention; Trans-Omics for Precision Medicine; Variant; Veterans; Work; admixture mapping; analysis pipeline; case control; causal variant; clinical care; clinical decision-making; clinical movement disorder; cohort; design; detection method; disorder risk; experience; gene discovery; genetic architecture; genetic information; genetic risk factor; genome sequencing; genome wide association study; genome-wide; genome-wide analysis; human data; improved; minority health disparity; mortality; nervous system disorder; novel; pandemic disease; polygenic risk score; precision medicine; programs; rare variant; risk stratification; skills; symptom treatment; targeted treatment; trait; trend; whole genome

Parkinson’s disease (PD) is the fastest growing neurological disorder and its worldwide prevalence is expected to double by the year 2040, a trend that some have labeled the “PD pandemic.” Disease disease-modifying therapies and better methods of detection in early or pre-symptomatic phases are desperately needed and data from human genetic studies have moved us much closer to those goals. Unfortunately, such studies have largely excluded individuals of non-European origin which risks further worsening existing health disparities for minority populations. The project seeks to address this gap in knowledge by studying the genetic architecture of PD in African American and Latino participants in the Million Veteran Program (MVP) and other cohorts. The research team assembled for this project has extensive expertise in clinical movement disorders, bioinformatics, molecular genetics, and statistical genetics with specialized knowledge in mapping disease genes in “admixed” (mixed ancestry) populations. This same group of investigators recently published the first and only admixture mapping analysis and genome-wide association study (GWAS) of PD ever conducted in a Latino population (based on a cohort from the Latin American Research Consortium on the Genetics of Parkinson’s Disease [LARGE-PD]). The fundamental approach will be to perform two complementary techniques (1) admixture mapping, a technique that leverages local ancestry to identify regions of the genome where ancestry from a particular ancestral population is inherited more frequently in cases vs controls, and (2) Tractor GWAS, a new analytical approach that unlike traditional GWAS methods is designed to accommodate admixed individuals. A Discovery sample will be created using cohorts from MVP and the Veterans Parkinson’s Disease Genetics Initiative (Vet- PD) and a Replication sample will be assembled from LARGE-PD and several publicly available datasets. Admixture mapping and Tractor GWAS will first be performed on the Discovery Sample, analyzing each ancestry group separately and all groups combined. We will also perform the “variant-set test for association using annotation information” (STAAR) to perform gene-centric association tests of rare variants that are not suitable for single-marker analyses (such as GWAS). These processes will be repeated in the Replication sample to validate results. Prioritization of candidate regions discovered will be performed using a combination of (1) physical position on the genome (positional mapping), (2) expression quantitative trait locus (eQTL) mapping, and (3) chromatin interaction mapping. In addition, polygenic risk scores (PRS) will be calculated. A PRS is an estimate of an individual’s genetic liability to a trait or disease, calculated according to their genotype profile and relevant GWAS data. These scores have been applied to an increasing number of diseases with the eventual goal of risk stratification followed by clinical interventions. But PRS models based on GWAS results from individuals of European origin are often less accurate when applied to non-European populations. Therefore, PRS models will be constructed from the European, African, and Latino components of the Discovery sample and their performance will be compared across all three subgroups (e.g., Latino to African American and Latino to European American). Finally, findings from this project will be cross-validated with results from any other suitable studies that become available in future years. Results from this project will provide a better understanding of the genetic architecture of PD in African Americans and Latinos which is important for two reasons. First it moves the field closer to a more equitable balance in the application of genetic information to clinical decisions in future years (e.g., PRS models). Second, it begins to unlock the potential for new PD gene discovery in non-European populations which will further our understanding of PD pathophysiology.

帕金森病（PD）是增长最快的神经系统疾病，其全球流行率预计 到2040年将翻一番，这一趋势被称为“PD大流行”。疾病修饰 迫切需要在早期或症状前阶段的治疗和更好的检测方法， 人类基因研究的数据使我们更接近这些目标。不幸的是，这些研究 非欧洲血统的人在很大程度上被排除在外，这有可能进一步加剧现有的健康差距， 少数民族人口。该项目旨在通过研究遗传结构来解决这一知识差距 参与百万退伍军人计划（MVP）和其他队列的非裔美国人和拉丁美洲人的PD。 为该项目组建的研究团队在临床运动障碍方面拥有广泛的专业知识， 生物信息学、分子遗传学和统计遗传学，并具有绘制疾病图谱的专业知识 基因在“混合”（混合祖先）人群中。同一组调查人员最近发表了第一份 并且只有在一个研究中进行了PD的混合作图分析和全基因组关联研究（GWAS）。 拉丁美洲人群（基于拉丁美洲遗传学研究联盟的队列） 帕金森病[LARGE-PD]）。 基本的方法将是执行两个互补的技术（1）混合映射， 一种利用当地祖先来识别基因组区域的技术，该区域的祖先来自特定的 与对照组相比，祖先群体在病例中遗传的频率更高;（2）拖拉机GWAS，一种新的分析方法， 与传统的GWAS方法不同，这种方法旨在适应混合个体。发现 将使用MVP和退伍军人帕金森病遗传学倡议（Vet- PD）和复制样本将从LARGE-PD和几个公开可用的数据集组装。 混合物测绘和拖拉机GWAS将首先在探索样品上进行，分析每个 祖先群体分开，所有群体合并。我们还将执行“关联的变量集检验 使用注释信息”（STAAR）来执行罕见变异的基因中心关联测试， 适用于单标记分析（如GWAS）。这些过程将在复制中重复 样品以验证结果。发现的候选区域的优先级将使用组合 （1）基因组上的物理位置（位置作图），（2）表达数量性状基因座（eQTL） 作图;（3）染色质相互作用作图。 此外，还将计算多基因风险评分（PRS）。PRS是对个体基因的估计， 根据他们的基因型谱和相关的GWAS数据计算出的对一种性状或疾病的易感性。这些 分数已被应用于越来越多的疾病，最终目标是危险分层 其次是临床干预。但基于GWAS的PRS模型来自欧洲血统的个体 在应用于非欧洲人群时往往不太准确。因此，PRS模型将 从欧洲，非洲和拉丁美洲的发现样本的组成部分及其 将在所有三个子组之间比较性能（例如，拉丁裔到非裔美国人和拉丁裔到 欧洲裔美国人）。最后，本项目的结果将与其他项目的结果进行交叉验证。 在未来几年内进行适当的研究。 该项目的结果将提供对非洲PD遗传结构的更好理解， 美国人和拉丁美洲人，这很重要，原因有两个。首先，它使该领域更接近于一个更公平的 在未来几年将遗传信息应用于临床决策的平衡（例如，PRS模型）。 其次，它开始释放在非欧洲人群中发现新PD基因的潜力， 进一步了解PD的病理生理学。