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

 描述（由申请人提供）：精神分裂症（SCZ）基因组学取得了前所未有的进展。十年前，可能有一个可靠的发现，现在有130多个位点符合重要性和复制的共识标准。瑞典SCZ研究（S3）及其研究人员对这些进展至关重要。S3样本的遗传分析一直是多篇高知名度论文的主要部分。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项目的竞争性更新。S3可以说是任何地方最大和最好的SCZ样本：我们建议使其更大，信息更丰富。在之前的每一个R 01中，我们完成的都远远超过我们提出的。我们现在提出的目标是通过将S3的大小增加一倍，增加认知表型和创新分析来最大限度地提高S3的信息量。重要的是，这项工作是多方资助的，最大限度地提高了其他人的贡献，并最大限度地减少了NIH的预算要求。具体目标（1）通过将样本量增加一倍来扩充S3数据集，添加认知表型，进行全面的基因组表征，插补到瑞典特定的参考面板，并添加新的瑞典寄存器链接。输出：一个庞大而全面的数据集，可供分析。(2)分析：增加SCZ遗传基础的知识。将目标1的数据与世界上所有其他样本相结合，以发现令人信服的相关基因座。添加“多组学”整合：将所有可用的表观基因组和基因表达数据（例如，CommonMind，psychENCODE）。输出量：SCZ在等位基因谱中的关联，关于SCZ中涉及的遗传变异的直接生物学影响的具体假设。这项工作的成功完成-利用尖端技术和高生产力的十年之久的合作-很有可能通过鉴定更多的基因座，提供特定的生物学假设，并理解GxE作用和相互作用来推进SCZ的知识。本研究为临床前研究。虽然由于复杂性和费用而没有在这里提出，但我们将通过合作立即优先考虑任何潜在的治疗靶点（例如，与沙利文博士的同事和抗精神病专家布莱恩·罗斯博士）。由于我们的多资金模式，拟议的工作效率很高/具有成本效益。我们通过多个战略合作伙伴关系最大限度地降低了成本（同时最大限度地提高了我们可以实现的科学）。我们使用咨询公司将资金充足的调查人员带入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.