A Large-Scale Schizophrenia Association Study in Sweden

描述(由申请人提供)：精神分裂症是一种经常具有破坏性的神经精神疾病，尽管进行了大量研究，但其病因仍不清楚。遗传因素一直被强烈地和一贯地与其病因有关。目前，有多个积极的和看似合理的发现，但目前没有一个发现符合严格但适当的证据定义。文献中的哪些发现代表了建立下一代精神分裂症研究的真实发现，存在相当大的不确定性。我们的目标非常雄心勃勃，但是可以实现的。我们希望帮助精神分裂症的遗传学研究走向经得起严格审查的坚实的经验基础。我们设计了一个运作良好的国际合作来实现这些目标：(1)我们通过记录联系确定了大约29,000个病例，可以立即联系到他们。(2)我们寻求通过高质量的瑞典国家住院和人口登记确定的7500名精神分裂症患者和7500名匹配的对照组的DMA样本的生物库。病例和控制措施都将以人口为基础，并具有斯堪的纳维亚血统。将收集神经认知内表型。(3)严格评估精神分裂症的10个候选基因。(3A)经过全面的定量文献回顾，一个多元化的专家小组将选出10个最有希望的基因。(3B)对所有病例和对照的768个SNPs进行基因分型，以全面捕获遗传变异，并利用专家组选择两个基因，对常见变异体(N=48例，Aim 3c)和稀有变异体(N=1000例，Aim 3D)的功能基因组区域进行全基因组转录本重新测序。(3E)通过对重新测序中确定的SNPs的病例和对照进行额外的基因分型来完成对这些基因的评估，并通过使用预期登记数据调查神经认知、出生侮辱(GxE交互作用)、家族史(协变量指示遗传风险)和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。一项全面的初步研究证明，我们可以实现这些目标，并有力地支持了我们假设的正确性。我们已经改进了我们的诊断程序，并表明权力不会因病例或对照的错误分类而发生实质性变化。这个研究团队致力于协作性的“开源”基因研究。所有的表型、基因型和DNA样本都将通过Kl生物库提供。申请程序将是直截了当的，需要一个简短的页面申请文件：合理的科学计划，完成和返回所有未使用的样本的时间表，承诺在完成后将这些样本创建的所有数据存入KL的中央储存库，并同意维护对该项目至关重要的道德和利他原则。在短期内，这项工作的完成将提供强有力的、可能是确凿的证据，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，这个样本的建立将为精神病学研究界提供一个可获得的资源。未来的项目可能包括全基因组关联和嵌套病例对照研究。

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.