Identifying novel Parkinson'Âs disease genes exploring understudied Latino populations

探索未被充分研究的拉丁裔人群，识别新的帕金森病基因

• 批准号: 10462797
• 负责人: Ignacio Fernandez Mata
• 金额: $ 62.34万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462797
• 关键词: Admixture; Affect; Age; Americas; Argentina; Asian ancestry; Brazil; Candidate Disease Gene; Caribbean region; Chile; Chromosomes; Clinical Trials; Code; Collaborations; Colombia; Complex; Copy Number Polymorphism; Costa Rica; Country; Data; Data Set; Databases; Development; Diagnosis; Disease; Ecuador; Enrollment; European; Family; Family history of; Family member; Frequencies; Funding; Future; Gene Mutation; Genes; Genetic; Genetic Diseases; Genetic Variation; Genetic study; Genome; Genomics; Genotype; Goals; Haplotypes; Heritability; Hispanic Populations; Honduras; Human Genetics; Individual; Institution; International; Knowledge; LRRK2 gene; Latin America; Latin American; Latino; Latino Population; Maps; Meta-Analysis; Methods; Mexico; Mutation; Neurodegenerative Disorders; Other Genetics; PARK2 gene; PARK7 gene; PINK1 gene; Parkinson Disease; Participant; Pathogenicity; Patients; Persons; Peru; Phase; Play; Population; Population Heterogeneity; Predisposition; Puerto Rico; Recording of previous events; Reporting; Research; Rest; Risk; Role; Sampling; Screening procedure; Series; Single Nucleotide Polymorphism; South America; Surveys; Susceptibility Gene; Testing; Time; Uruguay; Variant; Work; admixture mapping; alpha synuclein; base; bioinformatics tool; case control; causal variant; cohort; disorder risk; dosage; exome; gene discovery; genetic analysis; genetic architecture; genetic resource; genetic variant; genome sequencing; genome wide association study; genome-wide; genomic locus; health disparity; improved; large datasets; multi-ethnic; nervous system disorder; new therapeutic target; novel; personalized medicine; polygenic risk score; proband; public database; recruit; risk prediction; risk variant; segregation; success; therapeutic target; therapy design; trait; whole genome

Human genetic studies have greatly accelerated progress in understanding the etiopathogenesis of Parkinson's disease (PD). To date, six causal genes (SNCA, PARK2, PINK1, DJ-1, LRRK2, and VPS35) and ninety susceptibility genes/loci (e.g., MAPT, GBA) have been identified for PD, mostly in populations of European or Asian ancestry. However, these genes explain only a small proportion of PD heritability. Thus, additional novel genes await discovery, and we believe that the highest likelihood of success is in understudied populations such as those of from Latin America. To fill in this gap we created the Latin American Research Consortium on the Genetics of PD (LARGE-PD), a growing collaboration between thirty two institutions in eleven countries across South America/Caribe (Argentina, Brazil, Chile, Colombia, Costa Rica, Ecuador, Honduras, Mexico, Peru, Puerto Rico and Uruguay). LARGE-PD is the largest PD case-control sample series in Latin America (3,857 individuals), with a target to include at least 8,000 individuals in by 2021, thus serving as a unique resource for genetic analysis in this understudied population. As LARGE-PD has progressed, several multiplex PD families (with three or more affected individuals) have been identified and enrolled. With the goal of replicating our preliminary findings and identifying novel risk-modifying variants we propose in Aim 1 to perform a Genome-Wide Association Study (GWAS) in an additional 6,000 cases and healthy controls (1:1) ascertained through LARGE-PD. Our preliminary study in a subset of LARGE-PD (N=1,498) identified 7 interesting novel candidate loci. Genotyping this additional 6,000 individuals (N= 7,498) allows replication of these findings and quadruples our statistical power to find novel associations. We will also perform the first trans-ethnic GWAS in collaboration with the largest European consortium. In Aim 2, we will perform Whole- Genome Sequencing (WGS) in 25 LARGE-PD families negative for mutations in all known PD-genes. Finally, in Aim 3 we will use all our data to generate and test a Latino specific Polygenic Risk Score (PRS), which will account for possible additive effects between all associated variants and will help improve PD risk prediction in this population. This project will identify novel PD genes associated with both familial and sporadic forms of PD using an understudied population, thus improving our knowledge of the etiopatogenesis of the disease and identifying novel therapeutic targets for the treatment of PD, not only in Latin America, but also in other countries with a growing Latino population such as the US. We will also test the validity of current PD risk prediction, based on European populations, in Latinos and generate a Latino specific risk score using our data. We also believe that our study and others like it, will reduce existing health disparities by allowing Latinos to be active participants in clinical trials and novel treatments designed to protect and/or treat individuals with specific genetic variants, the so called personalized medicine. .

人类遗传学研究极大地加速了对该病发病机制的了解 帕金森病（PD）。到目前为止，六个致病基因（SNCA，PARK 2，PINK 1，DJ-1，LRRK 2和VPS 35）和 九十个易感基因/基因座（例如，MAPT，GBA）已被确定为PD，主要在以下人群中 欧洲或亚洲血统。然而，这些基因只能解释PD遗传性的一小部分。因此，在本发明中， 更多的新基因有待发现，我们相信成功的可能性最大的是研究不足。 像拉丁美洲的人一样。为了填补这一空白，我们创建了拉丁美洲研究 帕金森病遗传学联盟（LARGE-PD）是一个由32个机构组成的合作组织， 南美洲/加勒比地区的11个国家（阿根廷、巴西、智利、哥伦比亚、哥斯达黎加、厄瓜多尔、 洪都拉斯、墨西哥、秘鲁、波多黎各和乌拉圭）。LARGE-PD是最大的PD病例对照样本系列 拉丁美洲（3，857人），目标是到2021年至少纳入8，000人，从而为 作为这个未被充分研究的群体的遗传分析的独特资源。随着大PD的发展， 已经鉴定并登记了几个多重PD家族（具有三个或更多个受影响的个体）。与 复制我们的初步发现并识别我们在目标1中提出的新型风险修饰变体的目标 在另外6,000例病例和健康对照（1：1）中进行全基因组关联研究（GWAS） 通过大型PD。我们在LARGE-PD亚组（N= 1，498）中的初步研究确定了7个 有趣的新候选基因座。对另外6,000名个体（N= 7,498）进行基因分型， 这些发现使我们发现新关联的统计能力提高了四倍。我们还将表演 跨种族GWAS与欧洲最大的财团合作。在第二个目标中，我们将执行整体- 所有已知PD基因突变阴性的25个大型PD家族的基因组测序（WGS）。最后， 在目标3中，我们将使用我们所有的数据来生成和测试拉丁美洲特定的多基因风险评分（PRS）， 解释所有相关变异之间可能的累加效应，并将有助于改善PD风险预测， 这个人口。 该项目将使用一种新的方法鉴定与家族性和散发性PD相关的新PD基因。 研究不足的人群，从而提高我们对疾病病因的认识， 治疗PD的新治疗靶点，不仅在拉丁美洲，而且在其他国家， 美国等拉美国家的人口增长。我们还将测试当前PD风险预测的有效性，基于 欧洲人群，拉丁美洲人，并使用我们的数据生成拉丁美洲人的特定风险评分。我们也相信 我们的研究和其他类似的研究将通过允许拉丁美洲人积极参与 设计用于保护和/或治疗具有特定遗传变异的个体的临床试验和新型治疗， 所谓的个性化医疗。 .