Neuropsychiatric Genome-Scale and RDOC Individualized Domains (N-GRID)

神经精神基因组规模和 RDOC 个体化域 (N-GRID)

• 批准号: 8929310
• 负责人: ISAAC S. KOHANE
• 金额: $ 331.36万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8929310
• 关键词: Agonist; Alcohol or Other Drugs use; Anxiety Disorders; Biological; Biological Markers; Categories; Cells; Cellular Neurobiology; Clinical; Code; Cognition; Cognitive; Complex; Computer Simulation; Consent Forms; DNA Methylation; DSM-IV; Dependency; Diagnosis; Diagnostic; Dimensions; Disease; Electronic Health Record; Emerging Technologies; Enrollment; Epigenetic Process; Equipment and supply inventories; Fibroblasts; Fruit; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genetic Variation; Genomics; Goals; Gold; Growth; Healthcare Systems; Histones; Human Genome; Human Genome Project; Individual; Informatics; Investigation; Laboratories; Maps; Measurement; Measures; Methodology; Modeling; Molecular; Moods; National Institute of Mental Health; Natural Language Processing; Neurons; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Population; Principal Investigator; Prosencephalon; Psychiatry; Public Domains; RNA; RNA Editing; RNA Splicing; Research Domain Criteria; Resources; Risk; Running; Sampling; Scheme; Small RNA; Statistical Models; Stress; Symptoms; Testing; Transcript; Transcriptional Regulation; Untranslated RNA; Update; Visit; Vocabulary; base; biobank; cell type; clinical investigation; clinical phenotype; clinically relevant; design; disorder risk; functional genomics; genome sequencing; genome-wide; high risk; induced pluripotent stem cell; insight; interest; neuropsychiatry; novel; outcome forecast; phenomenological models; prognostic; public health relevance; relating to nervous system; research study; response; technology development; transcriptome sequencing; transcriptomics

DESCRIPTION (provided by applicant): As a result of the accelerated pace of development of technologies for characterizing the human genome, the rate-limiting step for large scale genomic investigation in clinical populations is now phenotyping. This is particularly the case for neuropsychiatric (NP) illness, where phenotypes are complex, biomarkers are lacking, and the primary cell types of interest are difficult to access directly. It has become apparent that both rare and common genetic variation contributes to disease risk and that this risk crosses traditional diagnostic boundaries in psychiatry. Taking advantage of a large, already-established NP biobank could dramatically accelerate progress toward understanding the cross-disorder mechanism of action of disease liability genes. This study proposes novel applications of emerging technologies in informatics and cellular neurobiology to eliminate this phenotyping bottleneck. In doing so, it will accelerate investigation of clinical and cellular phenotypes for understanding single and multilocus/polygenic associations. Aim 1: Adapt and expand one of the largest NP cellular biobanks by parsing electronic health records with gold-standard assessment of cognition and other RDoC phenotypes. Aim 2: Define the genome-wide multidimensional functional genomics (MFG) landscape in NP disease into which the transcriptomic signature (RNA-seq) of each induced neuron (IN) representing a clinically characterized individual is projected. The projection provides the mapping from molecular to phenotypic characterization and a directionality towards healthful/neurotypical states used in Aim 3. Aim 3: Develop a probabilistic model of gene expression dependencies that will predict which small molecular perturbations are likely to shift the IN transcriptomic signature in a healthful direction in the MFG and to then update the model based on measured perturbations in the MFG. Aim 4: Select patient samples to study in greater detail for epigenetic (DNA methylation, histone marks and RNA editing) and transcriptional control particularly with regard to activity dependent changes that have been implicated in many NP diseases. Aim 5: Here we assess just how well the clinical phenotypes are informed by the genome-wide characterizations and assess which is more robust.

描述（由申请人提供）：由于表征人类基因组的技术发展速度加快，在临床人群中进行大规模基因组研究的限速步骤现在是表型。这对……尤其如此