6/7 Psychiatric Genomics Consortium finding actionable variation

 描述（由申请人提供）：精神病学基因组学联盟（http：pgc.unc.edu），现在已经进入第八个年头，是精神病学历史上最具创新性的实验之一。我们已经统一了该领域的大部分内容，从而能够在阐明精神疾病的遗传基础方面取得快速进展。我们有来自36个国家的800多名研究者和超过40万名受试者。PGC吸引了一批杰出的科学家，他们的职业生涯以我们的工作为中心。PGC发表了17篇主要论文和31篇次要分析/方法开发论文。最重要的是具有里程碑意义的自然论文确定了精神分裂症（SCZ）的108个位点。由于我们的开源方法，有75多篇论文使用了PGC结果，我们知道有许多团体正在使用我们的发现来指导基础和应用研究（包括治疗开发）。需要做更多的工作。在未来五年内，PGC将获得大量新数据（基本上没有NIMH的资助）。我们已经开发了一套严格的方法，这些方法正在为所有最初的五种疾病（这导致增加了四种新的疾病）带来发现。因此，我们有独特的机会，快速，有效地增加我们的知识，常见和罕见的变化，以了解主要精神疾病的原因和合并症。我们的首要目标是通过对我们的基因组发现的病因学、临床、疾病学、治疗和生物学意义的经验评估来识别“可操作的”变异。我们将继续PGC在理解常见遗传变异的作用方面非常成功的工作，通过：（a）全面分析9种主要精神疾病的历史大型GWA样本;（B）评估遗传风险评分如何影响发展和临床症状模式;（c）了解精神疾病之间的遗传关系以及精神疾病和许多其他CNS疾病之间的遗传关系。我们将通过以下方式加强我们在发现罕见变异方面的工作：（d）对九种精神疾病的拷贝数变异进行大规模分析;（e）对GWAS涉及的区域进行有效且廉价的重新测序。（20,000名受试者中的200个候选基因）;和（f）利用PGC中的数百名临床医生，鉴定罕见的密集感染谱系，以能够搜索具有强效应的罕见变体。这项工作的成功完成将促进对多种精神疾病遗传基础的认识。我们的目标是提供“可操作的”发现，即基因组结果，（a）揭示基础生物学，（B）告知临床实践，（c）提供新的治疗靶点。这是PGC的中心思想：将家族史风险因素转化为生物学，临床和治疗上有意义的见解。我们利用来自多个来源的外部资金，以尽量减少NIMH的预算要求。

 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.