Alzheimer's disease genetic architecture in the Portuguese population

葡萄牙人群中的阿尔茨海默病遗传结构

• 批准号: 10159814
• 负责人: Rita Guerreiro
• 金额: $ 79.33万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10159814
• 关键词: AKAP9 gene; Admixture; Affect; African; African American; Age of Onset; Alzheimer' s Disease; Alzheimer' s disease risk; American; Asians; Biological; Biological Models; Caucasians; Clinical; Clinical Trials; Code; DNA; Data; Databases; Development; Dideoxy Chain Termination DNA Sequencing; Disease; Drug Targeting; Etiology; European; Family; Financial Hardship; Frequencies; Frontotemporal Dementia; Future; Gene Frequency; Gene Mutation; Generations; Genes; Genetic; Genetic Markers; Genetic Risk; Genetic study; Genotype; Goals; Haplotypes; Hispanics; Image; Inflammation; Inherited; Low Prevalence; Maps; Mendelian disorder; Mission; Morbidity - disease rate; Mutation; Pathogenesis; Pathogenicity; Pathway interactions; Phenotype; Population; Population Genetics; Portugal; Portuguese; Presenile Alzheimer Dementia; Prevention; Proteins; Public Health; Recording of previous events; Reporting; Research; Rest; Risk Assessment; Risk Factors; Role; Sampling; Subgroup; TREM2 gene; Therapeutic; Therapeutic Intervention; Translating; United States National Institutes of Health; Variant; bioinformatics tool; biomarker development; biomarker identification; causal variant; cohort; disorder risk; early onset; effective therapy; exome sequencing; follower of religion Jewish; genetic analysis; genetic approach; genetic architecture; genetic risk factor; genetic variant; genome sequencing; genome wide association study; insight; multi-ethnic; novel; novel therapeutics; rare variant; risk variant; therapeutic target; therapy development; whole genome

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.

项目概要 尽管一些基因、突变和遗传变异已被确定在 对于阿尔茨海默病（AD），这些发现尚未转化为有效的治疗方法。 增加我们识别成功药物靶标的机会识别新的遗传原因和风险至关重要 因此，我们的长期目标是利用遗传方法来确定 AD 的治疗靶点。 AD 的预防、延迟发作或治疗。 利用待研究人群的独特遗传背景，该应用程序的主要目的是 目标是确定与 AD 相关的新基因和遗传因素。 葡萄牙人口因其独特的遗传特征而具有相当的同质性且主要是 欧洲，该人群的遗传特征因北部和撒哈拉以南地区的贡献而丰富 此外，早发病例和西班牙裔犹太人口数量也很高。 几代受 AD 影响的家庭，表明葡萄牙人的遗传贡献很大 尽管已知的 AD 突变频率较低，但我们的初步研究也表明， 风险变异的频率与其他人群有很大不同。 具体来说，与 AD 相关的常见和罕见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) 分析和插补的组合 然后，这些数据将用于通过合并来执行多种族 GWAS。 来自其他人群的公开数据，可以增加我们的多样性和统计能力 此外，葡萄牙人家族性和早发性 AD 病例的遗传特征。 将通过对缺乏的多重家族进行全基因组测序来进行群体分析。 已知 AD 致病基因和早发性 AD 病例亚组中的编码突变将允许 鉴定对疾病有强烈影响的变异。 这些数据结合起来将能够识别常见、罕见和非常罕见的变异，这些变异在疾病中具有不同的影响。 AD 拟议的研究还将允许与全球生成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 中的遗传分析，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）报告不同人群对 AD 的不同遗传贡献。