2/2 Large-Scale Genetic Studies of Schizophrenia in Sweden

 描述(申请人提供)：精神分裂症(SCZ)基因组学取得了前所未有的进步。十年前，可能有一个确凿的发现，现在有130多个基因座符合普遍的重要性和重复性标准。瑞典SCZ研究(S3)及其研究人员对这些进展至关重要。对S3样本的遗传分析一直是多篇备受瞩目的论文的主要部分。我们与其他团体合作良好，是PGC的领导者。还有更多的事情要做。因此，这是S3项目的一次竞争性续订。S3可以说是任何地方最大、最具特色的SCZ样本：我们建议将其做得更大、信息量更大。在之前的每一次R01中，我们完成的都远远超过了我们的计划。我们现在提出旨在通过将S3的大小增加一倍、增加认知表型和创新分析来最大化S3的信息量的目标。关键的是，这项工作是多项资助的，最大限度地增加了其他人的捐款，最大限度地减少了国家卫生研究院的预算要求。具体目标(1)通过将样本量增加一倍来扩大S3数据集，增加认知表型，进行全面的基因组特征，将其归因于瑞典特有的参考小组，并增加新的瑞典登记册联系。输出：可供分析的大型综合数据集。(2)分析：增加对SCZ遗传基础的认识。将来自AIM 1的数据与世界上所有其他样本整合，以发现令人信服的相关基因座。增加“多基因组”整合：结合、注释和严格评估结果与所有可用的表观基因组和基因表达数据(例如，CommonMind、mental ENCODE)。输出：SCZ与等位基因谱之间的关联，关于SCZ所涉及的遗传变异直接生物影响的具体假设。这项工作的成功完成--利用尖端技术和长达十年的高效合作--很有可能通过确定更多的基因座、提供具体的生物学假说以及了解GxE的作用和相互作用来促进对SCZ的了解。这项研究是临床前研究。尽管由于复杂性和费用的原因，我们在这里没有提出，但我们将立即通过合作(例如，与Sullivan博士的北卡罗来纳大学同事和抗精神病药物专家Bryan Roth博士)优先考虑任何潜在的治疗目标。由于我们的多重筹资模式，建议的工作效率很高/成本效益高。我们通过多个战略合作伙伴关系将成本降至最低(同时最大限度地利用我们所能实现的科学成果)。我们使用咨询公司将资金充足的调查人员引入S3。我们经常使用多种技术来加强协作。

 DESCRIPTION (provided by applicant): Schizophrenia (SCZ) genomics has achieved unprecedented advances. A decade ago, there was perhaps one solid finding, and there are now 130+ loci that meet consensus criteria for significance and replication. The Swedish SCZ Study (S3) and its investigators were centrally important to these advances. Genetic analyses of S3 samples have been major parts of multiple high profile papers. We cooperate well with other groups, and are leaders in the PGC. There is more to do. Thus, this is a competitive renewal for the S3 project. The S3 is arguably the largest and best-characterized SCZ sample anywhere: we propose to make it larger and more informative. In each prior R01, we accomplished far more than we proposed. We now propose aims designed to maximize the informativeness of S3 by doubling its size, adding cognitive phenotypes, and innovative analyses. Critically, this work is multi-funded and maximizes contributions from others and minimizes NIH budgetary requests. Specific Aims (1) Augment S3 dataset by doubling the sample size, add cognitive phenotypes, conduct comprehensive genomic characterization, impute to a Sweden-specific reference panel, and add new Swedish register linkages. Output: a large and comprehensive dataset ready for analysis. (2) Analysis: increase knowledge of the genetic basis of SCZ. Integrate data from Aim 1 with all other world samples to discover compellingly associated loci. Add "multi-omic" integration: combine, annotate, and rigorously evaluate results with all available epigenomic and gene expression data (e.g., CommonMind, psychENCODE). Output: SCZ associations across the allelic spectrum, specific hypotheses about the immediate biological impact of genetic variation implicated in SCZ. Successful completion of this work - capitalizing on cutting-edge technologies and a highly productive decade- long collaboration - is highly likely to advance knowledge of SCZ by identifying more loci, providing specific biological hypotheses, and understanding of GxE action and interaction. This study is preclinical. Although not proposed here due to complexity and expense, we will immediate prioritize any potential therapeutic target via collaborations (e.g., with Dr Sullivan's UNC colleague and antipsychotic expert Dr Bryan Roth). The work proposed is highly efficient / cost-effective due to our multi-funding model. We have minimized costs (while maximizing the science we can achieve) via multiple strategic partnerships. We use consultancies to bring well-funded investigators into S3. We routinely use multiple technologies to enhance collaboration.