Gene discovery in multi-ethnic late-onset Alzheimer's disease families

多种族迟发性阿尔茨海默病家族的基因发现

基本信息

批准号：
10434636
负责人：
SUZANNE M LEAL
金额：
$ 76.18万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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：
2020-06-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10434636
关键词：
Admixture Affect African American Age Algorithms Alzheimer&apos s Disease Amyloid Autopsy Awareness Brain Complex Consensus Copy Number Polymorphism Data Data Set Dementia Deposition Disease Elderly Extended Family Family Family member Frequencies Gene Expression General Population Genes Genetic Genetic Epistasis Genome Gliosis Goals Haplotypes Heritability Hispanic Americans Impaired cognition Inbreeding Incidence Individual Inherited Large-Scale Sequencing Late Onset Alzheimer Disease Memory Loss Methods Methylation Morphologic artifacts National Institute on Aging Neurofibrillary Tangles Neuropsychological Tests Not Hispanic or Latino Pathologic Pathway interactions Penetrance Pharmaceutical Preparations Phenotype Population Population Control Proteins Puerto Rican Research Risk Sample Size Single Nucleotide Polymorphism Source Susceptibility Gene Testing Variant admixture mapping apolipoprotein E-4 base case control caucasian American cognitive function cognitive performance cohort complement C2a design drug development endophenotype exome sequencing extracellular follow-up gene discovery gene network genetic linkage analysis genetic pedigree genetic risk factor genetic variant genome sequencing genome-wide insertion/deletion mutation middle age multi-ethnic neuron loss novel protective allele protective factors rare variant risk variant sex therapeutic target transcriptome sequencing transcriptomics whole genome

项目摘要

PROJECT SUMMARY Late onset Alzheimer’s disease (LOAD) is the leading cause of dementia among the middle aged and elderly. It is characterized by progressive loss of memory culminating in complete loss of cognitive function. Pathological manifestations in brain include neuronal loss, gliosis, extracellular amyloid deposits and neurofibrillary tangles. Among genetic risk factors, APOE-ε4 is the strongest, but genome association studies (GWAS) have identified and confirmed several additional loci. However, a substantial portion of the genetic source of heritability of LOAD is still unknown. Large-scale sequencing efforts in Alzheimer’s Disease are underway to identify detect putatively causal rare variant (RV) associations that might explain the missing heritability. To detect modest RV effects, large sample sizes are required. Here we propose a powerful approach to study RVs in extended families with large numbers of affected individuals where they are likely to aggregate and have stronger effect sizes. The major goal of this proposal is to harmonize phenotype and whole genome and exome sequencing (WGS and WES) data from ~1000 LOAD families and apply existing and novel family-based analytics to identify LOAD susceptibility variants and loci that can be tested as therapeutic targets. Factors such as a three to five-fold higher incidence rates of LOAD compared to the general population, clustering of putatively deleterious variants, inbreeding, low level of sequencing artifacts and the ability to control for population substructure/admixture using a family analysis design (compared to unrelated case-controls) make these families ideal for identifying LOAD associated genetic risk and protective factors. The efforts in this proposal will be in parallel with and complementary to analyses in the unrelated case-control analyses being conducted on Alzheimer’s Disease Sequencing Project (ADSP) discovery, extension replication and follow-up datasets.

项目概要晚发性阿尔茨海默病（LOAD）是中老年人痴呆的主要原因。其特征是记忆逐渐丧失，最终导致认知功能完全丧失。大脑中的表现包括神经元丢失、神经胶质增生、细胞外淀粉样蛋白沉积和神经原纤维缠结。在遗传风险因素中，APOE-ε4 最强，但基因组关联研究 (GWAS) 已发现并确认了几个额外的位点，然而，LOAD 的遗传性的遗传来源很大一部分。仍然未知。阿尔茨海默氏病的大规模测序工作正在进行中，以识别假定的罕见因果关系可能解释缺失遗传力的变异 (RV) 关联为了检测适度的 RV 效应，需要大样本。在这里，我们提出了一种有效的方法来研究大家庭中的房车。受影响的个体可能聚集并具有更强的效应规模，这是其主要目标。提案旨在协调表型、全基因组和外显子组测序（WGS 和 WES）数据约 1000 个 LOAD 系列，并应用现有的和新颖的基于系列的分析来识别 LOAD 敏感性变异以及可以作为治疗目标进行测试的因素，例如三到五倍的发病率。与一般群体相比，负载、假定有害变异的聚集、近亲繁殖、低水平的测序伪影以及使用家族分析设计控制群体亚结构/混合的能力（与不相关的病例对照相比）使这些家庭成为识别 LOAD 相关遗传风险的理想家庭该提案中的努力将与该提案中的分析并行并相互补充。阿尔茨海默病测序项目 (ADSP) 正在进行不相关的病例对照分析发现、扩展复制和后续数据集。