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: 8970782
• 负责人: Thomas Michael Hyde
• 金额: $ 90.56万
• 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/8970782
• 关键词: Affect; Amygdaloid structure; Anterior; Autopsy; Biological; Bipolar Disorder; Brain; Brain region; Collection; DSM-IV; Data; Development; Disease; Etiology; Exons; Funding; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genetic Variation; Genomics; Goals; 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; public health relevance; risk variant; sample collection; severe mental illness; substance abuse treatment; 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（由应用程序提供）：该提案汇集了约翰·霍普金斯大学（JHU）医学和转化神经科学学院的情绪障碍遗传学专家，来自利伯大脑发展研究所，研究双相情感障碍遗传基础（BP）。精神病基因组学联盟（PGC）进行的BP的全基因组关联研究（GWA）的最新荟萃分析已导致对疾病遗传关联的有力可靠报道。但是，实施变体增加BP的风险的神经生物学机制尚不清楚。此外，迄今为止鉴定出的遗传变异仅解释了BP的遗传力的一小部分，表明大部分因果变异和分子途径它们是它们 他们参与仍然未知。 Lieber Institute专门从事精神障碍的神经发展起源，以阐明疾病的生物学机制和动机的新疗法，它积累了来自精神病患者的验尸脑样本中最大的收集之一，并且是非精神病患者和非精神分裂症的主体。这些样品已在临床，遗传和分子上广泛表征。结果，它们为检查神经生物学机制提供了独特的资源，遗传因素直接导致主要受影响组织中的精神障碍。我们试图通过PGC从GWAS和Lieber脑样本的转录组进行RNA测序来整合发现，以阐明BP的遗传基础。 The specific aims of the proposal are to: 1) Carry out RNA-sequencing of the amygdala and subgenuine 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，这些数据被认为与BP集中有关）； 2）测试从BP的PGC GWA中鉴定出的全基因组显着SNP是否与大脑关键区域的mRNA表达，剪接或长的非编码RNA表达有关； 3）测试BP病例大脑关键区域的外显子，基因和转录水平的差异表达，而不是非注射疾病的控制， 并利用结果检查是否在PGC GWAS数据中与BP的遗传关联富含不同表达的基因及其所涉及的途径； 4）通过在线数据资源免费获得该项目的主要数据和结果。通过识别新 与BP的遗传关联并阐明了它们增加风险的机制，我们旨在为疾病过程中的干预提供新的目标，从而为改善治疗方法提供更合理的基础。