2/2-A Large-Scale Schizophrenia Association Study in Sweden

描述（由申请人提供）：这是R 01 MH 077139（一项瑞典大规模精神分裂症相关性研究）竞争性更新的第二次也是最后一次提交。这个项目非常成功，所有目标都已实现，甚至超额完成。我们成功地确定了我们获得资助的病例和对照的数量（总共N~ 12，996）。我们对大约一半的样本进行了GWAS，而不是候选基因的基因分型。这些数据是两篇国际精神分裂症联盟自然论文的关键组成部分，也是精神病学GWAS联盟精神分裂症大分析的一个相当大的部分。最后，我们的瑞典样本被用于两个“大机会”NIH赠款（外显子组测序和全基因组甲基化）。我们在这里提出了新的目标，使用这个独特的样本来增加我们对SCZ的了解，并保持这个高效的团队的完整性。这里研究的样本将使SCZ的可用样本增加61%，这将为检测赋予风险或保护的网络和位点提供显著增强的能力。在目标1中，我们将完成12，996例受试者（5，851例SCZ病例，7，145例对照）的完整样本的基因组表征。这包括对所有受试者进行GWAS基因分型和新型Illumina“外显子组芯片”，以及对1,000例病例和1,000例对照进行外显子组测序。所有的检测都是由慈善机构资助的。我们要求为我们的团队提供资金，以进行严格的质量控制，估算和数据仓库。在目标2中，我们将进行旨在阐明SCZ风险或保护的遗传效应的分析。（2a）途径和网络分析：通过严格评估基因组结果是否在经典和新的经验途径中富集了较小的基因p值，确定SCZ的其他高置信度途径。（2b）进行SCZ外显子组多态性的第一次高功率基因组规模分析。新的外显子组芯片由Illumina和我们在Broad的同事开发，并捕获MAF e0.1%的错义和无义编码变异，以及MAF 0.01- 0.1%的相当大的部分。这可以识别有助于SCZ的低频错义或无义多态性。(2c)直接分析瑞典数据中的基因分型和插补常见变异，并使用PGC SCZ结果进行荟萃分析。根据需要进行验证基因分型。预期结果：10-20个新位点的全基因组显著证据。(2d)识别导致SCZ的结构变异。对CNP、indel、新插入和其他结构多态性进行首次系统评价。评估CNV与SCZ的相关性，并与外部结果进行荟萃分析。根据需要进行验证基因分型。预期结果：增加对主要CNV基因座的理解，以及新结构变异的作用。在目标3中，估计高置信度遗传效应是否被SCZ的既定流行病学风险因素所改变。对于这种复杂的性状，环境风险通常可能与因果遗传变异相互作用。对于目标2的结果，如果流行病学风险因素建模，遗传效应是加强还是减少？风险因素来自高质量的数据库，通常进行前瞻性评估（出生季节，城市/农村出生，父亲和祖父母年龄，发病前认知能力和头部创伤）。预期结果：了解特定的遗传和环境风险因素如何在SCZ中相互作用，这可能导致新的机制假说。我们的目标是迅速了解更多关于精神分裂症的遗传学，以及基因和环境如何作用和相互作用以改变疾病风险。我们建议使用该领域最大和最全面研究的样本收集来进行这项工作，其中包括遗传和环境风险因素。 公共卫生相关性：精神分裂症造成巨大的人类痛苦和社会成本。我们的目标是迅速了解更多关于精神分裂症的遗传学，以及基因和环境如何作用和相互作用以改变疾病风险。我们建议使用该领域最大和最全面研究的样本收集来进行这项工作，其中包括遗传和环境风险因素。

DESCRIPTION (provided by applicant): This is the second and final submission of the competitive renewal of R01 MH077139, A Large-Scale Schizophrenia Association Study in Sweden. This project has been very successful with all aims accomplished and, indeed, exceeded. We successfully ascertained the numbers of cases and controls for which we were funded (N~12,996 in total). Instead of candidate gene genotyping, we conducted GWAS on around half the sample. These data were key components in two International Schizophrenia Consortium Nature papers and are a sizable fraction of the Psychiatric GWAS Consortium schizophrenia mega-analysis. Finally, our Swedish sample is being used for two "grand opportunity" NIH grants (exome sequencing and genome-wide methylomics). We propose here new aims that use this unique sample to increase our knowledge of SCZ and to keep this highly productive team intact. The samples studied here will increase available samples for SCZ by 61% which will provide substantially enhanced power for detection of networks and loci that confer risk or protection. In Aim 1, we will complete the genomic characterization of the full sample of 12,996 subjects (5,851 SCZ cases, 7,145 controls). This includes GWAS genotyping and a novel Illumina "exome chip" on all subjects plus exome sequencing on 1,000 cases and 1,000 controls. All assays are funded by philanthropy. We request funds for our team to conduct rigorous quality control, imputation, and data warehousing. In Aim 2, we will conduct analyses designed to elucidate genetic effects that confer risk or protection for SCZ. ¿ (2a) Pathway and network analyses: identify additional high-confidence pathways for SCZ by rigorous assessment of whether genomic results are enriched for smaller p-values in genes in classical and novel empirical pathways. ¿ (2b) Conduct the first highly powered genome-scale analysis of exome polymorphism in SCZ. The novel exome chip was developed by Illumina and our colleagues at the Broad, and captures missense and nonsense coding variation with MAF e0.1%, and a substantial fraction with MAF 0.01-0.1%. This could identify low-frequency missense or nonsense polymorphisms that contribute to SCZ. (2c) Analyze directly genotyped and imputed common variants in the Swedish data, and meta-analyze with the PGC SCZ results. Conduct verification genotyping as required. Anticipated outcome: genome-wide significant evidence for 10-20 novel loci. (2d) Identify structural variation contributing to SCZ. Conduct the first systematic evaluations of CNPs, indels, novel insertions, and other structural polymorphisms. Evaluate CNV associations with SCZ, and meta-analyze with external results. Conduct verification genotyping as required. Anticipated outcome: increase understanding of the major CNV loci, and the role of novel structural variants. In Aim 3, estimate if high-confidence genetic effects are modified by established epidemiological risk factors for SCZ. For this complex trait, environmental risks may generally interact with causal genetic variation. For Aim 2 results, are genetic effects strengthened or lessened if epidemiological risk factors are modeled? Risk factors are from high-quality databases and were often assessed prospectively (season of birth, urban/rural birth, paternal and grandparental age, pre-morbid cognitive attainment, and head trauma). Anticipated outcome: understanding of how specific genetic and environmental risk factors interact in SCZ that could lead to new mechanistic hypotheses. Our goal is rapidly to learn more about the genetics of schizophrenia and how genes and environment might act and interact to alter disease risk. We propose to do this using the largest and most comprehensively studied sample collection in the field and which includes both genetic and environmental risk factors. PUBLIC HEALTH RELEVANCE: Schizophrenia causes enormous human suffering and cost to society. Our goal is rapidly to learn more about the genetics of schizophrenia and how genes and environment might act and interact to alter disease risk. We propose to do this using the largest and most comprehensively studied sample collection in the field and which includes both genetic and environmental risk factors.