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能力下降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序列变异对大脑功能的影响。在本研究中，我们探索了与认知能力下降相关的几个离散大脑区域的转录组，以发现哪些RNA种类、同种异构体和更广泛的RNA谱与随着年龄增长而发生的中枢神经系统功能损伤相关。这些转录组谱是从两个队列研究的受试者的死后组织中收集的，这两个队列研究积累了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）。总共有1200多名来自这两个队列的人将被纳入这项研究。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有一个无与伦比的视角，大脑是一个具有最多样化的可选剪接转录物内容之一的组织，其中许多可能以前没有被编目。此外，大量受试者在相同的离散脑区被描绘，将允许对RNA同工异构体比例的个体间变异程度进行有力的评估。通过将这些转录组谱与受试者死亡前的认知轨迹联系起来，我们将能够评估哪些基因、同型体和途径可能与认知衰退有关。最后，全基因组基因型数据和DNA甲基化数据的可用性为RNA表达的相同组织样本提供了一个独特的机会来探索遗传变异、染色质构象、RNA表达、认知能力下降措施和临床痴呆之间的因果网络。因此，我们不仅可以深入了解老年人类大脑的转录组多样性，还可以了解与临床认知受损相关的遗传和表观遗传变异对人类大脑的功能影响。

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.