4/7 Psychiatric Genomics Consortium: Finding actionable variation

4/7 精神病学基因组学联盟：寻找可行的变异

基本信息

批准号：
9431809
负责人：
Jonathan Sebat
金额：
$ 9.62万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9431809
关键词：
Affect Alleles Applied Research Basic Science Biological Biology Biomedical Research Brain Candidate Disease Gene Central Nervous System Diseases Clinical Code Collaborations Comorbidity Copy Number Polymorphism Country Data Descriptor Development Disease Environment Epilepsy Etiology Evaluation Family Foundations Funding Genetic Genetic Risk Genetic Variation Genomics Genotype Goals Industry Ireland Knowledge Longitudinal cohort Mental disorders National Institute of Drug Abuse National Institute of Mental Health Nature Neurobiology Nucleic Acid Regulatory Sequences Paper Pathway Analysis Pattern Personality Phenotype Portraits Psychiatry Psychopharmacology Publishing Recording of previous events Research Personnel Risk Risk Factors Role Sampling Schizophrenia Science Scientist Source Statistical Methods Symptoms Therapeutic Variant Work career clinical practice clinically relevant experimental study genetic pedigree genome sequencing genome wide association study innovation insight member method development neuroimaging new therapeutic target novel open source public health relevance rare variant secondary analysis therapeutic development trait whole genome

项目摘要

DESCRIPTION (provided by applicant): The Psychiatric Genomics Consortium (http://pgc.unc.edu), now in its eighth year, is one of the most innovative experiments in the history of psychiatry. We have unified much of the field to enable rapid progress in elucidating the genetic basis of psychiatric disorders. We have 800+ investigators from 36 countries and >400K subjects. The PGC has attracted a cadre of outstanding scientists whose careers center on our work. The PGC has published 17 main papers plus 31 secondary analysis/methods development papers. The most important was the landmark Nature paper identifying 108 loci for schizophrenia (SCZ). Due to our open-source approach, there are 75+ papers that use PGC results, and we know of numerous groups that are using our findings to direct basic and applied research (including therapeutic development). More work is needed. Large amounts of new data will be available to the PGC in the next five years (largely without NIMH funding). We have developed a rigorous set of approaches that are yielding discoveries for all of the initial five disorders (which led to adding four new disorders). We thus have the unique opportunity to rapidly and efficiently increase our knowledge of common and rare variation in order to understand the causes and comorbidities of major psychiatric disorders. Our overarching goal is to identify "actionable" variation via the empirical evaluation of the etiological, clinical, nosological, therapeutic, and biological significance of our genomic findings. We will continue the highly successful work of the PGC in understanding the roles of common genetic variation by: (a) comprehensively analyzing historically large GWA samples for nine major psychiatric disorders; (b) evaluating how genetic risk scores impact development and clinical symptom patterns; (c) understand the genetic relationship among psychiatric disorders and across psychiatric disorders and many other CNS diseases. We will enhance our work on the discovery of rare variation by: (d) conducting mega-analyses of copy number variation across nine psychiatric disorders; (e) efficiently and inexpensively re-sequencing regions implicated by GWAS (200 candidate genes in 20,000 subjects); and (f) using the hundreds of clinicians in the PGC, identify rare densely affected pedigrees to enable searches for rare variants of strong effect. Successful completion of this body of work will advance knowledge of the genetic basis of multiple psychiatric disorders. Our goal is to deliver "actionable" findings, genomic results tht (a) reveal the fundamental biology, (b) inform clinical practice, and (c) deliver new therapeutic targets. This is the central idea of the PGC: to convert the family history risk factor into biologically, clinically, and therapeutically meaningful insights. We have leveraged external funding from multiple sources to minimize NIMH budgetary requests.

描述（由适用提供）：精神病基因组学联盟（http://pgc.unc.edu），现在是第八年，是精神病学史上最具创新性的实验之一。我们已经统一了大部分领域，以在阐明精神疾病的遗传基础方面的快速进步。我们有来自36个国家 /地区的800多名调查员和> 400k受试者。 PGC吸引了一群杰出科学家的干部，他们的职业中心在我们的工作上。 PGC发表了17篇主要论文以及31个二级分析/方法开发论文。最重要的是地标自然论文，鉴定了精神分裂症（SCZ）的108个基因座。由于我们的开源方法，有75篇论文使用PGC结果，我们知道许多群体都使用我们的发现来指导基础研究和应用研究（包括治疗性开发）。需要更多的工作。在未来五年内，PGC将提供大量新数据（主要没有NIMH资金）。我们已经开发了一系列严格的方法，这些方法正在为所有最初的五种疾病中的所有发现（导致添加了四个新疾病）产生发现。因此，我们有独特的机会，可以快速有效地增加对常见和罕见变化的了解，以了解主要精神疾病的原因和合并症。我们的总体目标是通过对我们的基因组发现的生态，临床，细胞学，治疗和生物学意义的经验评估来鉴定“可行”的变化。我们将继续PGC在理解常见遗传变异的作用方面的非常成功的工作：（a）彻底分析历史上大型的GWA样本中的九种主要精神疾病；（b）评估遗传风险评分如何影响发育和临床症状模式；（c）了解精神疾病，跨精神病和许多其他中枢神经系统疾病之间的遗传关系。我们将通过以下方式加强有关发现罕见变化的工作：（d）在九种精神疾病中进行拷贝数变化的大型分析；（e）GWAS（20,000名受试者中有200个候选基因）实施的有效且廉价地重新确定了区域；（f）使用PGC中的数百名临床医生，确定罕见的垂直影响的谱系，以搜索稀有效果的稀有变体。成功完成这项工作将提高对多种精神疾病的遗传基础的了解。我们的目标是提供“可行的”发现，基因组结果（a）揭示了基本生物学，（b）为临床实践提供信息，以及（c）提供新的治疗靶标。这是PGC的核心思想：将家族史风险因素转化为生物学，临床和治疗意义上的见解。我们从多个来源利用了外部资金来最大程度地减少NIMH预算请求。