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)，)现已进入第八个年头，是精神病学史上最具创新性的实验之一。我们统一了该领域的许多领域，以便在阐明精神障碍的遗传基础方面取得快速进展。我们有来自36个国家的800名研究人员和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篇二次分析/方法发展论文。最重要的是具有里程碑意义的《自然》论文《确定108个精神分裂症基因座》(SCZ)。由于我们的开源方法，有75篇论文使用了PGC结果，我们知道许多组织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)。还需要做更多的工作。未来五年将向PGC提供大量新数据(主要是在没有NIMH资助的情况下)。我们已经开发了一套严格的方法，这些方法正在为最初的五种障碍(导致增加四种新的障碍)产生发现。因此，我们有独特的机会快速而有效地增加我们对常见和罕见变异的知识，以便了解主要精神疾病的原因和共病。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、病因学、治疗学和生物学意义的经验性评估来确定“可操作的”变异。我们将继续PGC在了解常见基因变异的作用方面非常成功的工作：(A)全面分析九种主要精神疾病的GWA历史大样本；(B)评估遗传风险分数如何影响发育和临床症状模式；(C)了解精神疾病之间以及精神疾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发现罕见变异的工作：(D)对九种精神疾病的拷贝数变异进行大规模分析；(E)高效且廉价地对GWA涉及的区域进行重新测序(在20,000名受试者中有200个候选基因)；以及(F)利用PGC的数百名临床医生，识别罕见的密集受影响的家系，以便能够搜索具有强烈效果的罕见变异。这项工作的成功完成将促进人们对多种精神疾病的遗传基础的了解。我们的目标是提供“可操作的”发现，即(A)揭示基础生物学的基因组结果，(B)为临床实践提供信息，(C)提供新的治疗靶点。这就是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，将NIMH的预算需求降至最低。

 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.