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Identifying novel Parkinson's 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：
9973831
负责人：
Ignacio Fernandez Mata
金额：
$ 67.5万
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/9973831
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 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 nervous system disorder new therapeutic target novel personalized medicine polygenic risk score proband recruit 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. .

人类遗传学的研究大大加快了对该病发病机制的了解