Exploring the Role of the Brain Transcriptome in Cognitive Decline

描述（由申请人提供）： 对与年龄相关的认知衰退和痴呆的遗传和表观遗传结构的探索正在迅速加速。全基因组关联扫描方法已被证明在其他人类疾病中非常有效，现在已经开始在与衰老相关的中枢神经系统疾病中产生红利。现在的挑战是了解与疾病相关的DNA序列变异在大脑中的功能后果。在这项提案中，我们探索了与认知能力下降有关的几个离散脑区的转录组，以发现哪些RNA种类、亚型和更广泛的RNA谱与随着年龄的增长而发生的中枢神经系统功能障碍相关。这些转录组谱是从两个队列研究的受试者收集的死后组织中收集的，这两个队列研究已经积累了关于其受试者的纵向认知数据：宗教秩序研究（探索性队列）和记忆与衰老项目（验证性队列）。两个队列总共将有超过1200名个体纳入研究。我们使用下一代测序来创建这些转录组的方法将允许对大脑转录调控的复杂性进行无与伦比的透视，大脑是一种具有最多样化的可变剪接转录本内容之一的组织，其中许多可能以前没有被编目。此外，在相同的离散脑区域中分布的大量受试者将允许对RNA亚型比例的个体间差异程度进行有力的评估。通过将这些转录组图谱与受试者死亡前的认知轨迹相关联，我们将能够评估哪些基因、亚型和途径可能参与认知下降。最后，全基因组基因型数据和DNA甲基化数据在相同的组织样本中的RNA表达谱的可用性为我们提供了一个独特的机会来探索连接遗传变异，染色质构象，RNA表达，认知能力下降措施和临床痴呆的因果网络。因此，我们不仅可以深入了解老年人大脑的转录组多样性，还可以了解与临床认知障碍相关的遗传和表观遗传变异对人脑产生功能性影响的方式。

DESCRIPTION (provided by applicant): The exploration of the genetic and epigenetic architecture of age-related cognitive decline and dementia is accelerating rapidly. Genome-wide association scan approaches that have proven very effective in other human disorders have now begun to yield dividends in aging-related central nervous system diseases. The challenge is now turning to understanding the functional consequences within the brain of variation in DNA sequence associated with disease. In this proposal, we explore the transcriptome of several discrete brain regions implicated in cognitive decline to discover which RNA species, isoforms, and broader RNA profiles are correlated with the functional impairment of the central nervous system that occurs with advancing age. These transcriptome profiles are collected from postmortem tissue collected from subjects of two cohort studies that have accumulated longitudinal cognitive data on their subjects: the Religious Order Study (Exploratory Cohort) and the Memory and Aging Project (Confirmatory Cohort). In total, over 1200 individuals from the two cohorts will be included in the study. Our approach using next generation sequencing to create these transcriptomes will allow an unparalleled perspective on the complexity of transcriptional regulation of the brain, which is a tissue with one of the most diverse content of alternatively spliced transcripts, many of which may not have been catalogued previously. Further, the large number of subjects profiled in the same discrete brain regions will allow a powerful assessment of the extent of interindividual variation in the proportion of RNA isoforms. By relating these transcriptome profiles to the cognitive trajectory of the subjects prior to death, we will be able to assess which genes, isoforms and pathways may be involved in cognitive decline. Finally, the availability of both genome-wide genotype data and DNA methylation data on the same tissue samples profiled for RNA expression give us a unique opportunity to explore the causal network linking genetic variation, chromatin conformation, RNA expression, cognitive decline measures, and clinical dementia. Thus, we may gain insight not only into the transcriptome diversity of the older human brain but also into the manner in which genetic and epigenetic variation associated with clinically impaired cognition exert a functional consequence on the human brain.