Alzheimer's disease genetic architecture in the Portuguese population

项目总结 尽管一些基因、突变和遗传变异已被发现在 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 增加我们识别成功药物靶点的机会识别新的遗传原因和风险至关重要 AD的影响因素。因此，我们的长期目标是使用遗传方法来确定治疗靶点 AD的预防、发病延迟或治疗。 利用一个未被研究的群体的独特遗传背景，这项应用的主要 目的寻找与阿尔茨海默病相关的新基因和新的遗传因素。拟议的研究重点放在 葡萄牙人，因为其独特的遗传特征；尽管很相似，但主要是 在欧洲，这一群体的基因图谱因来自北方和撒哈拉以南地区的贡献而变得更加丰富 非洲人以及塞法迪克犹太人口。此外，早发病例的数量很高， 有几代人患有阿尔茨海默病的家族，表明葡萄牙人有很强的遗传贡献 人群中，尽管已知AD突变的频率很低。我们的初步研究亦显示， 风险变异的频率与其他人群有很大不同。 具体来说，与阿尔茨海默病相关的常见和罕见的遗传风险变异将通过使用 全基因组基因分型、全基因组关联研究(GWAS)分析和归因的组合 在一组葡萄牙样本中。然后，这些数据将被用于执行多种族GWA，方法是将 来自其他人口的公开数据，使我们的多样性和统计能力得以增加 GWARD。此外，葡萄牙人家族性和早发性AD病例的基因特征 种群将通过进行全基因组测序来进行。多户型家庭缺失的原因分析 已知的阿尔茨海默病致病基因和早发性阿尔茨海默病患者的编码突变将使 鉴定对疾病有强烈影响的变异体。 结合这些数据，将能够识别常见的、罕见的和非常罕见的变异，这些变异具有不同的影响 广告。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 导致i)现有物种的多样性和统计能力大幅增加的种群 AD中的遗传分析，以及二)开发可公开使用的数据库和互动地图 (可通过阿尔茨海默病论坛获取)报告了不同人群对阿尔茨海默病的不同遗传贡献。

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.