RNA Sequencing of the Limbic System in Bipolar Disorder

双相情感障碍边缘系统的 RNA 测序

• 批准号: 9135512
• 负责人: Thomas Michael Hyde
• 金额: $ 78.03万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9135512
• 关键词: Affect; Amygdaloid structure; Anterior; Autopsy; Biological; Bipolar Disorder; Brain; Brain region; Collection; DSM-IV; Data; Development; Disease; Etiology; Exons; Funding; Genes; Genetic; Genetic Transcription; Genetic Variation; Genomics; Goals; Health; Heritability; Hippocampus (Brain); Institutes; Intervention; Lateral; Limbic System; Longevity; Mental disorders; Mentally Ill Persons; Meta-Analysis; Molecular; Molecular Biology; Mood Disorders; Nature; Pathway interactions; Patients; Phenotype; Process; Public Health; RNA Sequences; RNA Splicing; Reporting; Resources; Risk; Sampling; Scientist; Testing; Tissues; Toxicology; Transcript; Trust; United States National Institutes of Health; Universities; Untranslated RNA; Variant; base; cingulate cortex; cost; differential expression; disorder risk; frontal lobe; genetic association; genetic variant; genome wide association study; genome-wide; improved; mRNA Expression; medical schools; neurobiological mechanism; neuropathology; novel; risk variant; sample collection; severe mental illness; substance abuse treatment; transcriptome; transcriptome sequencing; translational neuroscience

 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.

 描述（由申请人提供）：该提案汇集了来自约翰霍普金斯大学（JHU）医学院的情绪障碍遗传学专家和来自利伯脑发育研究所的转化神经科学专家，以调查双相情感障碍（BP）的遗传基础。最近由精神病基因组学联盟（PGC）进行的BP全基因组关联研究（GWAS）的荟萃分析导致了与该疾病遗传关联的最强可信报告。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，迄今为止发现的遗传变异只能解释BP遗传性的一小部分，这表明大多数致病变异和它们所依赖的分子途径， 参与了什么仍然未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激发新的治疗方法，已经积累了世界上最大的精神病患者和非精神病对照受试者的死后大脑样本收藏之一。这些样本已在临床、遗传学和分子学上进行了广泛表征。因此，他们提供了一个独特的资源，检查神经生物学机制，遗传因素直接在主要受影响的组织有助于精神障碍。我们试图通过Lieber脑样本转录组的PGC和RNA测序整合GWAS的发现，以阐明BP的遗传基础。该提案的具体目标是：1）对来自Lieber脑样本收集的120名BP病例和180名匹配的非精神病对照者的杏仁核和膝下前扣带皮层进行RNA测序（来自这些样本的背外侧前额叶皮层和海马体的RNA测序作为另一个项目的一部分正在完成，NIH不承担任何费用，并且我们将添加来自边缘系统的关键区域的令人印象深刻的资源数据，这些区域被认为是BP的中心参与）; 2）测试从BP的PGC GWAS鉴定的全基因组显著SNP是否与跨大脑关键区域的mRNA表达、剪接或长非编码RNA表达相关; 3）测试BP病例与非精神病对照的大脑关键区域中外显子、基因和转录水平的差异表达， 并使用结果来检查差异表达基因及其相关途径是否在PGC GWAS数据中富集了与BP的遗传关联;以及4）通过在线数据资源免费提供来自该项目的主要数据和结果。通过确定新 通过研究BP的遗传相关性，并阐明其增加风险的机制，我们的目标是为疾病过程的干预提供新的靶点，从而为改进治疗提供更合理的基础。