Genome sequencing of Lewy Body Dementia and Frontotemporal Dementia: a public resource for the study of Alzheimer's disease and related dementias

校内研究计划是开展这种规模的项目的理想环境。该项目将校内研究计划置于痴呆症研究的前沿，并将极大地加快该领域内基因发现的步伐。我们使用Illumina X10测序平台对3,000例LBD患者、3,000例FTD患者和2,500名神经学正常受试者进行了基因组测序。我们分析了基因组序列数据，以确定改变疾病发病风险和发病年龄的遗传基因座(即表型的遗传修饰物)。我们已经在DBGaP和AMP-PD门户网站上公开了该项目产生的基因组序列数据。这些数据作为一种新的在线资源的基石，研究人员可以访问、分析这些资源，并将其与自己的数据结合起来，以增强他们检测新基因位点的能力。这样，这个独特的数据库将随着时间的推移而扩大，并将极大地加快该领域内基因发现的步伐。 我们的基因组测序项目与NIA的战略目标是一致的。它的目的是通过解开痴呆的复杂生物学来了解衰老过程的动力学(目标A)。揭示痴呆症的生物学基础将通过提高我们对老化的大脑、阿尔茨海默病和其他神经退行性疾病的理解，改善成年人的健康、幸福感和独立性(目标D)。我们还希望，学习痴呆症的遗传学基础将为药物发现提供治疗目标，并最终导致有效干预措施的发展(目标C)。这个项目的目的是建立一个公共资源，以促进该领域内的高质量研究，并将随着时间的推移而增长(目标G和H)。

The Intramural Research Program is the ideal environment to undertake a project of this magnitude. This project places the Intramural Research Program at the forefront of dementia research and will greatly accelerate the pace of genetic discovery within the field. We performed genome sequencing of 3,000 LBD cases, 3,000 FTD cases and 2,500 neurologically normal control subjects using the Illumina X10 Sequencing platform. We analyzed the genome sequence data to identify genetic loci that alter the risk of developing disease and age at disease onset (i.e. genetic modifiers of phenotype). We have made the genome sequence data generated from this project publicly available on the dbGaP and AMP-PD web portals. These data act as the cornerstone of a new online resource that researchers can access, analyze, and combine with their own data to increase their power to detect new genetic loci. In this way, this unique database will be augmented over time and will greatly accelerate the pace of genetic discovery within the field. Our genome sequencing project is consistent with the strategic goals of the NIA. It aims to understand the dynamics of the aging process by unraveling the complex biology of dementia (Goal A). Unraveling the biology underlying dementia will improve the health, well-being and independence of adults as they age by improving our understanding of the aging brain, Alzheimer's disease, and other neurodegenerative diseases (Goal D). We also hope that learning the genetics underlying dementia will provide therapeutic targets for drug discovery and ultimately lead to the development of effective interventions (Goal C). The intent of this project was to establish a public resource that will accelerate high-quality research within the field, and that will grow over time (Goal G and H).