RNA Sequencing of the Limbic System in Bipolar Disorder

 描述(由申请人提供)：这项建议汇集了约翰霍普金斯大学医学院的情绪障碍遗传学专家和利伯脑发育研究所的翻译神经科学专家，以研究双相情感障碍(BP)的遗传基础。最近，精神病学基因组联合会(PGC)对BP进行的全基因组关联研究(GWAS)的荟萃分析导致了关于遗传与该病关联的最可靠的报告。然而，相关变异增加BP风险的神经生物学机制尚不清楚。此外，到目前为止发现的遗传变异只解释了一小部分BP的遗传性，这表明大部分因果变异和它们的分子途径 涉案人员仍不得而知。利伯研究所专门研究精神障碍的神经发育起源，以阐明疾病的生物学机制并推动新的治疗方法，该研究所收集了世界上最大的精神疾病患者和非精神疾病对照受试者的死后大脑样本之一。这些样本已经在临床、遗传学和分子水平上进行了广泛的表征。因此，它们提供了一种独特的资源，用于研究遗传因素直接导致初级受影响组织中的精神障碍的神经生物学机制。我们试图通过对Lieber大脑样本的转录本进行PGC和RNA测序来整合Gwas的发现，以阐明BP的遗传基础。该建议的具体目标是：1)从Lieber大脑样本收集中对120例BP患者和180名匹配的非精神疾病对照进行杏仁核和膝下扣带前皮质的RNA测序(这些样本的背外侧前额叶皮质和海马区的RNA测序正在完成，这是另一个免费的项目的一部分，我们将添加来自边缘系统关键区域的数据，这些区域被认为是与BP有关的关键区域)；2)测试从BP的PGC GWA中发现的全基因组显著SNPs是否与大脑关键区域的mRNA表达、剪接或长非编码RNA表达相关；3)测试BP患者与非精神病对照组大脑关键区域外显子、基因和转录水平的差异表达， 并使用这些结果来检查差异表达的基因及其涉及的途径是否在PGC Gwas数据中丰富了与BP的遗传关联；以及4)通过在线数据资源免费提供该项目的原始数据和结果。通过确定新的 我们的目标是为疾病过程中的干预提供新的靶点，从而为改进治疗提供更合理的基础。

 DESCRIPTION (provided by applicant): This proposal brings together experts in the genetics of mood disorders from the Johns Hopkins University (JHU) School of Medicine and translational neuroscience from the Lieber Institute for Brain Development to investigate the genetic underpinnings of bipolar disorder (BP). Recent meta-analysis of genome-wide association studies (GWAS) of BP conducted by the Psychiatric Genomics Consortium (PGC) have led to the strongest credible reports of genetic associations with the disorder. However, the neurobiological mechanisms by which the implicated variants increase the risk for BP are unknown. In addition, the genetic variants identified thus far explain only a small proportion of the heritability of BP, indicating that the bulk of causal variants and the molecular pathways they are involved in remain unknown. The Lieber Institute, which specializes in the neuro-developmental origins of mental disorders in order to elucidate biological mechanisms of illness and motivate new treatments, has amassed one of the largest collections in the world of post-mortem brain samples from psychiatric patients and non-mentally ill control subjects. These samples have been extensively characterized clinically, genetically, and molecularly. As a result, they provide a unique resource for examining the neurobiological mechanisms by which genetic factors contribute to mental disorders directly in the primary affected tissue. We seek to integrate findings from GWAS by the PGC and RNA-sequencing of the transcriptomes of the Lieber brain samples to elucidate the genetic basis of BP. The specific aims of the proposal are to: 1) Carry out RNA-sequencing of the amygdala and subgenual anterior cingulate cortex in 120 BP cases and 180 matched non-mentally ill controls from the Lieber brain sample collection (RNA-sequencing of the dorsolateral pre-frontal cortex and hippocampus from these samples is being completed as part of another project at no cost to the NIH, and we will add to this impressive resource data from key regions of the limbic system which are thought to be centrally involved in BP); 2) Test whether genome-wide significant SNPs identified from the PGC GWAS of BP are associated with mRNA expression, splicing, or long non-coding RNA expression across the key regions of the brain; 3) Test for differential expression at the exon, gene and transcript levels in key regions of the brain of BP case versus non-mentally ill controls, and use the results to examine if differentially expressed genes and their involved pathways are enriched for genetic associations with BP in the PGC GWAS data; and 4) Make the primary data and results from this project freely available via an online data resource. By identifying new genetic associations with BP and explicating the mechanisms by which they increase risk, we aim to provide novel targets for intervention in the disease process and, therefore, a more rational basis for improved treatments.