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

项目摘要/摘要 这份为期两年的《治疗靶点发现》研究多样性补充报告的目标是 在ADSP数据中，通过结合种族多样性和 系统方法“家长奖(U01AG058589)是为纳菲科夫博士提供必要的 在阿尔茨海默病和其他疾病的遗传学方面建立独立研究计划的技能 神经退行性疾病。阿尔茨海默病(AD)是#年主要的死亡原因之一。 老年人，无法治愈或预防，预计将对社会经济造成巨大的影响 到本世纪中叶给我们的社会带来负担。尽管已经做出了重大努力 揭示早发性阿尔茨海默病的遗传学，这是更常见的晚发性AD的遗传基础 这一疾病的具体情况有待发现。因此，当前提案的总体目标是确定 基于单倍型的晚发性AD(LOAD)的新基因和/或生化途径 Nafikov博士和他的同事开发的基于系谱的不同优先顺序方法 分析。因为单倍型可以评估多种稀有基因的联合效应 变种，最近涉及复杂的疾病，如负载，建议的分析 方法将测试这些变异在疾病发展中的作用。第一，基于单倍型的 将在已定义的连锁区域内执行不同的优先顺序 AD测序项目(ADSP)。潜在AD风险变种的列表将进一步确定优先顺序 利用生物信息学和组学的综合分析。第二，复制分析和 将使用单倍型整合所有可用的ADSP样本中的研究结果 ADSP样本亚群中感兴趣的基因组区域内的关联分析， 然后是可能的跨子组的Meta分析。纳菲科夫博士的研究活动将 为家长奖的下列目标作出贡献：目标1：充分描述已知的AD基因座 并通过利用全范围的基因来识别AD的新的保护性和风险变种 WGS显示的变异包括单核苷酸多态，小 插入/缺失、结构变异和目标3：从功能上表征基因、基因 网络和系统，通过生物信息学和组学综合分析来确定假定的 治疗靶点。该奖项的培训活动将在华盛顿大学举行 华盛顿在艾伦·威斯曼博士的指导下，他是国际公认的 统计学和人类遗传学方面的专家。纳菲科夫博士有生物化学和 统计学，但将在人类和统计遗传学方面进行培训。的培训部分 奖项将包括参加关于统计的研讨会、会议和讲习班 遗传学、神经生物学和衰老生物学。 1

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