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

多种族晚发性阿尔茨海默病家族的基因发现

• 批准号: 10640970
• 负责人: SUZANNE M LEAL
• 金额: $ 75.27万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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/10640970
• 关键词: Admixture; Affect; African American; Age; Algorithms; Alzheimer' 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; 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; genome sequencing; genome-wide; insertion/deletion mutation; middle age; multi-ethnic; neuron loss; novel; protective allele; protective factors; rare variant; risk variant; segregation; sex; therapeutic target; transcriptome sequencing; transcriptomics; whole genome

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.

项目摘要 阿尔茨海默氏病晚期（负载）是中年和较长的痴呆症的主要原因。 其特征是记忆的逐渐丧失最终导致完全失去认知功能。病理 大脑中的表现包括神经元丧失，神经胶质病，细胞外淀粉样蛋白沉积物和神经原纤维缠结。 在遗传危险因素中，APOE-ε4是强大的，但基因组关联研究（GWAS）已确定 并确认了其他几个基因座。但是，负载遗传力的很大一部分 仍然未知。 正在进行大规模的阿尔茨海默氏病的测序工作，以确定发现预测的因果稀有 变体（RV）协会可能解释了缺失的遗传力。为了检测适度的RV效应，大量样本 需要大小。在这里，我们提出了一种强大的方法来研究大量的大家庭 受影响的个体可能会汇总并具有更强的效果大小。主要目标 建议是协调表型，整个基因组和外显子组测序（WGS和WES）数据 〜1000个负载系列，并应用现有和新颖的基于家庭的分析来识别负载敏感性变体 以及可以作为治疗靶标测试的本地。诸如事件率高三倍的因素 与一般人群相比，负载，被预先删除的变体的聚类，近交，低水平 对伪像的测序以及使用家庭分析设计来控制人口子结构/混合的能力 （与无关的病例对照相比）使这些家族非常适合识别相关的遗传风险 和受保护因素。该提案中的努力将与分析的分析和补充 对阿尔茨海默氏病测序项目（ADSP）进行的无关病例对照分析 发现，扩展复制和后续数据集。