Alzheimer's disease genetic architecture in the Portuguese population

项目摘要 尽管已经确定了几个基因、突变和遗传变异体在基因突变中起关键作用， 阿尔茨海默病（AD），这些发现尚未转化为有效的治疗方法。为了 增加我们确定成功药物靶点的机会，确定新的遗传原因和风险至关重要 AD的因素。因此，我们的长期目标是使用遗传方法来确定治疗靶点， 预防、延迟或治疗AD。 利用未充分研究的种群的独特遗传背景，该应用程序的主要 目的寻找与AD相关的新基因和遗传因子。拟议的研究重点是 葡萄牙人口，因为其独特的遗传概况;虽然相当同质，主要是 欧洲，这一人口的遗传概况是丰富的贡献，从北部和撒哈拉以南 非洲人和塞法迪犹太人。此外，早发病例和 有几代人受AD影响的家庭，表明葡萄牙人有很强的遗传贡献。 尽管已知AD突变的频率较低，但在人群中，我们的初步研究还表明， 风险变异的频率与其他人群有很大不同。 具体地说，将通过使用一种新的方法来鉴定与AD相关的常见和罕见遗传风险变体。 全基因组基因分型、全基因组关联研究（GWAS）分析和插补的组合 在葡萄牙样本集中。这些数据将用于执行多种族GWAS， 从其他人群中公开获得的数据，使我们的多样性和统计能力的增加， GWAS。此外，葡萄牙家族性和早发性AD病例的遗传特征 将通过进行全基因组测序来进行群体。缺乏多重家庭的分析 在已知的AD致病基因和早发性AD病例亚组中的编码突变将允许 鉴定在疾病中具有强烈影响的变体。 总之，这些数据将允许识别具有不同影响的常见、罕见和非常罕见的变异， AD.拟议的研究还将允许与世界各地产生的数据进行比较和整合 人口导致i）目前可用的多样性和统计能力大幅增加 AD的遗传分析，以及ii）开发公开可用的数据库和交互式地图 （可通过Alzforum访问）报告了不同人群对AD的不同遗传贡献。

PROJECT SUMMARY Even though several genes, mutations and genetic variants have been identified to have key roles in Alzheimer’s disease (AD), these findings have not yet been translated into effective treatments. In order to increase our chances of identifying successful drug targets it is critical to identify new genetic causes and risk factors of AD. Our long-term goal is therefore to use genetic approaches to identify therapeutic targets for the prevention, onset delay or treatment of AD. Taking advantage of the unique genetic background of an understudied population, this application’s main objective is to identify novel genes and genetic factors involved in AD. The proposed research focuses on the Portuguese population because of its unique genetic profile; although quite homogeneous and mainly European, the genetic profile of this population is enriched by contributions from North and Sub-Saharan African as well as from Sephardic Jewish populations. Moreover, the high number of early-onset cases and of families with several generations affected by AD, indicates a strong genetic contribution in the Portuguese population, despite the low frequency of known AD mutations. Our preliminary studies also show that the frequency of risk variants differs substantially from other populations. Specifically, common and rare genetic risk variants associated with AD will be identified by using a combination of whole genome genotyping, genome-wide association study (GWAS) analyses, and imputation in a Portuguese sample set. These data will then be used to perform a multi-ethnic GWAS by incorporating publicly available data from other populations, allowing the increase of diversity and statistical power of our GWAS. In addition, the genetic characterization of familial and early-onset AD cases in the Portuguese population will be carried out by performing whole genome sequencing. Analyses in multiplex families lacking coding mutations in the known AD-causing genes and in a sub-group of early-onset AD cases will allow the identification of variants with strong effects in disease. Together these data will allow the identification of common, rare and very rare variants with different effects in AD. The proposed research will also allow the comparison and integration with data generated from worldwide populations leading to i) a substantial increase in diversity and statistical power of the currently available genetic analyses in AD, and ii) the development of a publicly available database and interactive map (accessible via Alzforum) reporting the different genetic contributions to AD across populations.