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

基本信息

批准号：
10226934
负责人：
Ignacio Fernandez Mata
金额：
$ 63.05万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
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/10226934
关键词：
Admixture Affect Age Americas Argentina Asians 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 Hispanics Honduras Human Genetics Individual Institution International Knowledge LRRK2 gene Latin America Latin American Latino Maps Meta-Analysis Methods Mexico Mutation Neurodegenerative Disorders Other Genetics PARK2 gene PARK7 gene PINK1 gene Parkinson Disease Participant Pathogenicity Patients 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 recruit risk prediction risk variant segregation success therapeutic target therapy design trait whole genome

项目摘要

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理解疾病发病机制的进展帕金森病（PD）。迄今为止，六个致病基因（SNCA、PARK2、PINK1、DJ-1、LRRK2 和 VPS35）和已鉴定出 90 个 PD 易感基因/位点（例如 MAPT、GBA），主要存在于以下人群中：欧洲或亚洲血统。然而，这些基因只能解释一小部分PD遗传性。因此，其他新基因有待发现，我们相信成功的可能性最大的是尚未得到充分研究的基因人口，例如来自拉丁美洲的人口。为了填补这一空白，我们创建了拉丁美洲研究中心 PD 遗传学联盟 (LARGE-PD)，是 32 个机构之间不断加强的合作南美洲/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 年至少包括 8,000 人，从而服务作为这一未被充分研究的人群进行遗传分析的独特资源。随着LARGE-PD的不断进步，已确定并登记了几个多重 PD 家庭（有 3 名或更多受影响个体）。和复制我们的初步发现并识别我们在目标 1 中提出的新的风险修改变体的目标对另外 6,000 例病例和健康对照进行全基因组关联研究 (GWAS) (1:1) 通过 LARGE-PD 确定。我们对 LARGE-PD 子集 (N=1,498) 的初步研究确定了 7 有趣的新颖候选基因座。对另外 6,000 名个体 (N= 7,498) 进行基因分型可复制这些发现使我们发现新关联的统计能力提高了四倍。我们也将进行第一场与欧洲最大财团合作的跨种族 GWAS。在目标 2 中，我们将执行 Whole- 25 个大型 PD 家族的基因组测序 (WGS) 所有已知 PD 基因突变均为阴性。最后，在目标 3 中，我们将使用所有数据来生成并测试拉丁裔特定的多基因风险评分 (PRS)，这将考虑所有相关变异之间可能存在的累加效应，并将有助于改善 PD 风险预测这个人口。该项目将使用一种方法来鉴定与家族性和散发性 PD 相关的新 PD 基因未充分研究的人群，从而提高我们对该疾病发病机制的了解并确定帕金森病治疗的新治疗靶点，不仅在拉丁美洲，而且在其他有帕金森症的国家拉丁裔人口不断增长，例如美国。我们还将测试当前 PD 风险预测的有效性，基于欧洲人口、拉丁裔人口，并使用我们的数据生成拉丁裔特定风险评分。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裔积极参与来减少现有的健康差距旨在保护和/或治疗具有特定遗传变异的个体的临床试验和新疗法，所谓的个性化医疗。。