Identifying novel Parkinson's disease genes exploring understudied Latino populations

人类遗传学研究极大地促进了对糖尿病病因的研究进展。 帕金森氏病(PD)。到目前为止，有6个致病基因(SNCA、PARK2、PINK1、DJ-1、LRRK2和VPS35)和 90个易感基因/位点(如MAPT、GBA)已被确定为帕金森病，主要在 欧洲人或亚洲人的祖先。然而，这些基因只解释了一小部分帕金森病的遗传性。因此， 更多的新基因等待着发现，我们相信，成功的可能性最大的是未被研究的 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 帕金森病遗传学联合会(LIG-PD)，32个机构在 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)。大PD是最大的PD病例对照样本系列 在拉丁美洲(3,857人)，目标是到2021年至少包括8,000人，从而为 作为在这一未被研究的种群中进行遗传分析的独特资源。随着大规模帕金森病的进展， 已确定并登记了几个多发性帕金森病家庭(有三个或更多受影响的个人)。使用 复制我们的初步发现并确定我们在目标1中提出的新的风险修正变体的目标是 在另外6,000例患者和健康对照中进行全基因组关联研究(1：1) 通过大PD确定。我们对大PD(N=1,498)的一个子集的初步研究确定了7 有趣的新奇候选基因。对这另外6,000个个体(N=7,498)进行基因分型可以复制 这些发现使我们发现新关联的统计能力翻了两番。我们还将执行第一个 与最大的欧洲财团合作，跨种族的GWAs。在目标2中，我们将完整地- 所有已知PD基因突变阴性的25个大PD家系的基因组测序(WGS)。最后， 在目标3中，我们将使用我们的所有数据来生成和测试拉丁裔特定的多基因风险评分(PRS)，这将 考虑到所有相关变量之间可能的相加效应，并将有助于改善对 这群人。 该项目将使用一种新的与家族性和散发性帕金森病相关的帕金森病基因 研究不足的人群，从而提高了我们对疾病病因的了解，并确定了 治疗帕金森病的新靶点，不仅在拉丁美洲，而且在其他有 不断增长的拉丁裔人口，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，并使用我们的数据生成拉丁裔特定的风险分数。我们还认为， 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 临床试验和新的治疗方法，旨在保护和/或治疗具有特定基因变异的个人， 所谓的个性化医疗。 。

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. .