Exploring the Role of the Brain Transcriptome in Cognitive Decline

描述(申请人提供)：对与年龄相关的认知衰退和痴呆症的遗传和表观遗传结构的探索正在迅速加速。全基因组联合扫描方法已经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。在这个建议中，我们探索与认知能力下降有关的几个离散大脑区域的转录组，以发现哪些RNA物种、异构体和更广泛的RNA图谱与随着年龄增长而发生的中枢神经系统功能损害相关。这些转录组图谱是从两项队列研究的受试者死后组织中收集的，这两项研究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)。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本的方法将允许从一个无与伦比的角度来了解大脑转录调控的复杂性，大脑是一个组织，其内容最多样化的是选择性剪接的转录本，其中许多可能以前没有被编目过。此外，大量受试者分布在相同的离散大脑区域，这将允许对RNA异构体比例的个体间差异程度进行强有力的评估。通过将这些转录组图谱与受试者死前的认知轨迹联系起来，我们将能够评估哪些基因、亚型和途径可能与认知能力下降有关。最后，在RNA表达谱分析的相同组织样本上获得全基因组基因数据和DNA甲基化数据，为我们提供了一个独特的机会来探索将遗传变异、染色质构象、RNA表达、认知衰退测量和临床痴呆联系起来的因果网络。因此，我们不仅可以洞察老年人大脑的转录组多样性，还可以洞察与临床认知受损相关的遗传和表观遗传变异对人类大脑产生功能影响的方式。

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.