Therapeutic target discovery in ADSP data via comprehensive whole-genome analysis incorporating ethnic diversity and systems approaches

通过结合种族多样性和系统方法的全面全基因组分析，在 ADSP 数据中发现治疗靶点

• 批准号: 10247242
• 负责人: ERIC A. BOERWINKLE
• 金额: $ 11.27万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247242
• 关键词: Alzheimer' s Disease; Alzheimer' s disease risk; Award; Biochemical Pathway; Biochemistry; Bioinformatics; Biology of Aging; Cause of Death; Complex; Data; Dementia; Development; Disease; Educational workshop; Elderly; Evaluation; Family; Genes; Genetic; Genomic Segment; Goals; Haplotypes; Human; Human Genetics; International; Joints; Late Onset Alzheimer Disease; Mentorship; Meta-Analysis; Methods; Neurobiology; Neurodegenerative Disorders; Parents; Presenile Alzheimer Dementia; Research; Research Activity; Research Project Grants; Role; Sampling; Single Nucleotide Polymorphism; Societies; Structure; Subgroup; System; Testing; Therapeutic; Training; Training Activity; Universities; Variant; Washington; base; ethnic diversity; genetic approach; genetic pedigree; genetic variant; genome analysis; insertion/deletion mutation; interest; novel; prevent; programs; protective allele; risk variant; skills; socioeconomics; statistics; symposium; therapeutic target; whole genome

Project Summary/Abstract The goal of this two-year Research Diversity Supplement for the “Therapeutic target discovery in ADSP data via comprehensive whole-genome analysis incorporating ethnic diversity and systems approaches” parent award (U01AG058589) is to provide Dr. Nafikov with necessary skills to establish an independent research program in genetics of Alzheimer’s and other neurodegenerative diseases. Alzheimer’s disease (AD) is one of the leading causes of death in the elderly, cannot be cured or prevented, and is projected to impose a huge socioeconomic burden on our society by the middle of this century. Although significant efforts have been made to uncover the genetics of earlier-onset AD, the genetic basis of more common late-onset form of the disease awaits discovery. Thus, the overall objective of the current proposal is to identify new genes and/or biochemical pathways for late-onset AD (LOAD) using haplotype-based variant prioritization method developed by Dr. Nafikov and colleagues for pedigree-based analysis. Because haplotypes can allow evaluation of the joint effects of multiple rare genetic variants, recently implicated in complex diseases such as LOAD, the proposed analytical approach will test the role of these variants in the disease development. First, haplotype-based variant prioritization will be performed within already-defined linkage regions in families from the AD Sequencing Project (ADSP). A list of potential AD risk variants will be prioritized further using bioinformatics and omics integrative analyses. Second, replication analysis and integration of findings in all available ADSP samples will be performed using haplotype association analysis within genomic regions of interest in subgroups of the ADSP samples, followed by possible meta analyses across subgroups. Dr. Nafikov’s research activities will contribute to the following aims of the parent award: Aim 1: To fully characterize known AD loci and to identify novel protective and risk variants for AD by exploiting the full range of genetic variability revealed by WGS including single nucleotide polymorphisms, small insertion/deletions, and structural variants and Aim 3: To functionally characterize genes, gene networks, and systems, via bioinformatics and omics integrative analyses to identify putative therapeutic targets. The training activities for this award will take place at the University of Washington under the mentorship of Dr. Ellen Wijsman, who is internationally recognized experts in Statistical and Human Genetics. Dr. Nafikov has a background in biochemistry and statistics but will be trained in Human and Statistical Genetics. The training component of the award will include participation in seminars, conferences, and workshops on Statistical Genetics, Neurobiology, and Biology of Aging. 1

项目摘要/摘要 这两年的研究多样性补充的目标是“治疗目标发现 在ADSP数据中通过全面的全基因组分析编码种族多样性和 系统方法”父母奖（U01AG058589）是为Nafikov博士提供必要的 在阿尔茨海默氏症和其他人的遗传学方面建立独立研究计划的技能 神经退行性疾病。阿尔茨海默氏病（AD）是死亡的主要原因之一 较早的，无法治愈或预防，预计会施加巨大的社会经济 到本世纪中叶，我们的社会负担负担。尽管已经做出了重大努力 要揭示早期发作AD的遗传学，这是更常见的晚发形式的遗传基础 疾病等待发现。这是当前提议的总体目标是确定 使用基于单倍型的新基因和/或生化途径用于晚期AD（负载） Nafikov博士及其同事开发了基于血统的变体优先级方法 分析。因为单倍型可以评估多个稀有遗传的关节效应 最近在复杂疾病（例如负载）中实施的变体，提议的分析 方法将测试这些变体在疾病发展中的作用。首先，基于单倍型 在家庭中已经定义明确的联系区域中，将进行变异优先级。 广告测序项目（ADSP）。潜在的AD风险变体列表将进一步优先考虑 使用生物信息学和OMICS综合分析。第二，复制分析和 将使用单倍型进行所有可用ADSP样本中的调查结果集成 ADSP样品亚组的基因组中的关联分析， 然后进行跨亚组的元分析。纳菲科夫博士的研究活动将 为父母奖的以下目的做出贡献：目标1：完全表征已知的广告基因座 并通过利用一系列通用范围来识别AD的新型保护和风险变体 WG揭示的可变性，包括单核苷酸多态性，小 插入/缺失以及结构变体和目标3：在功能上表征基因，基因 通过生物信息学和OMICS集成分析来识别推定的网络和系统 治疗靶标。该奖项的培训活动将在大学举行 华盛顿在国际认可的艾伦·维斯曼（Ellen Wijsman）的心态下 统计和人类遗传学专家。 Nafikov博士具有生物化学和 统计数据，但将接受人类和统计遗传学的培训。培训部分 奖项将包括参加统计的半手，会议和研讨会 遗传学，神经生物学和衰老的生物学。 1