A Large-Scale Schizophrenia Association Study in Sweden

描述（由申请人提供）：精神分裂症是一种通常具有破坏性的神经精神疾病，其病因尽管进行了大量研究，但仍不清楚。遗传因素一直与其病因密切相关。目前，有许多积极和合理的发现，但目前没有发现符合严格但适当的证据定义。关于文献中的哪些发现代表了真正的发现，哪些发现是建立下一代精神分裂症研究的基础，存在相当大的不确定性。我们的目标雄心勃勃，但却是可以实现的。我们希望帮助对精神分裂症遗传学的研究建立坚实的经验基础，经得起严格的审查。我们设计了一个运作良好的国际合作机制来实现这些目标：(1)我们通过记录联系确定了约29,000个病例，可以立即与他们取得联系。(2)我们寻求从7500例精神分裂症患者和7500例通过高质量的瑞典国家住院和人口登记确定的良好匹配对照中获得生物库DMA样本。病例和对照都将以人群为基础，并具有斯堪的纳维亚血统。收集神经认知内表型。(3)我们将严格评估10个精神分裂症候选基因。（3a）在全面定量的文献回顾之后，一个多元化的专家小组将选出10个最有希望的基因。（3b）对这些基因中的768个snp对所有病例和对照组进行基因分型，以全面捕获遗传变异，分析并与专家小组一起选择两个基因对常见变异（N=48例，Aim 3c）和罕见变异（N=1000例，Aim 3d）的全基因组转录物进行重测序。（3e）通过在病例和对照组中对重测序中发现的snp进行额外的基因分型来完成这些基因的评估，并通过调查神经认知、出生损伤（GxE相互作用）、家族史（协变量索引遗传风险）和使用前瞻性登记数据的18岁征兵数据（仅限男性，可能的内表型）的相关性来完成分析。一项全面的试点研究已经证明，我们可以实现这些目标，并有力地支持了我们假设的有效性。我们已经改进了我们的诊断程序，并且已经表明，无论是病例还是对照的错误分类都不会对疗效产生实质性的影响。这个研究团队致力于协作性的“开源”基因研究。所有表型，基因型和DMA样本将通过Kl生物银行提供。申请程序将是直接的，需要一个简短的页面申请文件：合理的科学计划，完成和归还所有未使用样本的时间表，承诺在完成后将这些样本上创建的所有数据存储到吉隆坡的中央存储库中，并同意维护这个项目的基本道德和利他原则。在短期内，这项工作的完成将提供强有力的、可能是明确的证据，证明目前最好的10个候选基因与精神分裂症的相关性。从长远来看，该样本的建立将为精神病学研究界提供一个可访问的资源。未来的项目可能包括全基因组关联和巢式病例对照研究。

DESCRIPTION (provided by applicant): Schizophrenia is an often devastating neuropsychiatric illness whose etiology remains unknown despite considerable study. Genetic factors have been strongly and consistently implicated in its etiology. Currently, there are multiple positive and plausible findings, but no finding currently meets a rigorous but appropriate definition of proof. There is considerable uncertainty about which of the findings in the literature represent true findings upon which to build the next generation of schizophrenia research. Our goals are extremely ambitious but attainable. We wish to help research into the genetics of schizophrenia move to a solid empirical foundation that can withstand rigorous scrutiny. We have designed a well-functioning international collaboration to attain these aims: (1) We have identified ~29,000 cases via record linkage who could be contacted immediately. (2) We seek to biobank DMA samples from 7,500 cases with schizophrenia and 7,500 well-matched controls ascertained via high-quality Swedish national hospitalization and population registries. Both cases and controls will be population-based and of Scandinavian ancestry. Neurocognitive endophenotypes will be collected. (3) We will rigorously evaluate 10 candidate genes for schizophrenia. (3a) Following a comprehensive quantitative literature review, a pluralistic expert panel will select the 10 most promising genes. (3b) Genotype all cases and controls for 768 SNPs in these genes to capture genetic variation comprehensively, analyze, and with the expert panel select two genes for resequencing entire genomic transcripts for both common variants (N=48 cases, Aim 3c) and functional genomic regions for rare variants (N=1000 cases, Aim 3d). (3e) Complete the evaluation of these genes by conducting additional genotyping in cases and controls for SNPs identified in re-sequencing and finalize the analyses by investigating the relevance of neurocognition, birth insults (GxE interactions), family history (covariate indexing genetic risk), and age 18 conscription data (males only, possible endophenotypes) using prospective register data. A full-scale pilot study has proven that we can achieve these aims and strongly supports the validity of our assumptions. We have improved our diagnostic procedures and have shown that power will not be substantially altered by misclassification of either cases or controls. This research team is committed to collaborative "open-source" genetic research. All phenotypes, genotypes, and DMA samples will be made available via the Kl BioBank. Application procedures will be straight-forward and require a brief page application that documents: a reasonable scientific plan, a timeline for completion and return of all unused samples, commitment to depositing all data created on these samples into a central repository at the Kl upon completion, and agreement to uphold the ethical and altruistic principles fundamental to this project. On the short-term, completion of this work will provide strong and possibly definitive evidence of the relevance of the best current set of 10 candidate genes for schizophrenia. For the long-term, establishment of this sample will provide an accessible resource for the psychiatric research community. Future projects could include whole genome association and nested case-control studies.