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Common and Rare Genetic Factors in an Ethnically Homogeneous Schizophrenia Cohort

种族同质精神分裂症队列中常见和罕见的遗传因素

基本信息

批准号：
7941720
负责人：
TODD LENCZ
金额：
$ 145.2万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7941720
关键词：
Alleles Architecture Area Arts Ashkenazim Biological Assay Biology Blood capillaries Candidate Disease Gene Cataloging Catalogs Chromosomes Clinical Collaborations Complex Computer software Country DNA DNA Microarray Chip DNA Resequencing Data Data Set Databases Deposition Detection Diagnosis Disease Equilibrium Etiology Funding Future Generations Genetic Genetic Variation Genome Genomics Genotype Goals Haplotypes Health system Heritability Hybrids Institutes Intramural Research Program Israel Location Maps Medical Research Mental disorders Methods Modeling Molecular Mutation National Institute of Mental Health National Institute on Alcohol Abuse and Alcoholism Odds Ratio Patients Penetrance Phenotype Population Predisposition Recurrence Relative (related person)Research Research Personnel Resources Risk Role Sampling Schizophrenia Siblings Signal Transduction Source Susceptibility Gene Symptoms Technology Twin Multiple Birth United States United States National Institutes of Health Universities Ursidae Family Validation Variant Weight Work capillary case control cohort cost database of Genotypes and Phenotypes design disability experience follower of religion Jewish genetic pedigree genetic risk factor genome wide association study genome-wide interest member next generation novel psychogenetics public health relevance repository response sex trait treatment response

项目摘要

DESCRIPTION (provided by applicant): Schizophrenia (SZ) is characterized by high heritability (~80%) and elevated sibling recurrence (;s ~ 10), yet the identification of susceptibility genes has proven extremely challenging. This application entitled "Common and Rare Genetic Factors in an Ethnically Homogeneous Schizophrenia Cohort" is in response to the NIMH Grand Opportunity area Genomic Profiling of Mental Disorders. In this proposal, we aim to perform a genomewide association study (GWAS), followed by extensive next-generation resequencing (Illumina/Solexa technology), in a large (n=4000) cohort of Ashkenazi Jewish patients with schizophrenia and well-matched Ashkenazi controls. All DNA has already been collected and is immediately ready for genotyping. The Ashkenazi Jewish population, derived from a limited number of founders, may be enriched for a subset of common and/or rare susceptibility alleles, which may therefore have higher odds ratios than those detected by previous studies. Matching funds from private donors will permit high-quality GWAS to be performed at substantially reduced cost to NIH. GWAS will use the new Illumina HumanOmni1-Quad BeadChip, which may permit identification of novel risk variants (including copy number variants and rare variants derived from the 1000 Genomes Project) that have been inaccessible in prior generations of DNA microarrays. In addition to well-powered standard GWAS analysis, GWAS data will be analyzed using a novel haplotype sharing approach. This approach aims to identify extended haplotypes that are shared selectively in case chromosomes, and which may harbor rare variants acting as dominant or recessive risk alleles. Shared haplotypes will then be interrogated by targeted resequencing using the Illumina (formerly Solexa) GA2 platform. The application of a hybrid common+rare variant paradigm to the study of SZ applies a conceptual paradigm that has proven successful in several other complex disorders across multiple biomedical diseases and quantitative traits. Taken together, we believe that this dual approach in a large, well characterized, and ethnically homogenous population will provide informative data on the role of common and rare variants in the genetic architecture of this devastating and disabling disorder, as well as provide an invaluable national resource for future studies of this unique population. The proposed sample will contribute substantially to the ongoing efforts of the Psychiatric GWAS Consortium, of which the PI is a member, and which will serve as a source for replication and validation of results. PUBLIC HEALTH RELEVANCE: Schizophrenia (SZ) constitutes the fifth leading cause of disability in the US. Although strongly heritable, specific genetic risk factors remain unclear. We aim to use state-of-the-art genotyping and resequencing technology in a large, ethnically homogeneous cohort of SZ cases and controls. Findings will create new opportunities for diagnosis and prediction of schizophrenia, and for understanding its biology.

描述(申请人提供)：精神分裂症(SZ)具有较高的遗传率(~80%)和较高的兄弟姐妹复发率(；S~10)，但易感基因的鉴定已被证明具有极大的挑战性。这项名为“在种族相同的精神分裂症队列中常见和罕见的遗传因素”的申请是对NIMH精神疾病大机遇区基因组图谱的响应。在这项提案中，我们的目标是在大量(n=4000)德系犹太人精神分裂症患者和匹配良好的德系犹太人对照人群中进行全基因组关联研究(GWAS)，随后进行广泛的下一代重测序(Illumina/Solexa技术)。所有的DNA都已经收集好，马上就可以进行基因分型了。来自有限数量的创始人的德系犹太人群体，可能在常见和/或罕见的易感等位基因子集上得到丰富，因此可能具有比先前研究检测到的更高的优势比。来自私人捐赠者的配套资金将使国家卫生研究院能够以大大减少的费用开展高质量的全球环境卫生活动。Gwas将使用新的Illumina Human Omni1-Quad BeadChip，它可以识别在前几代DNA微阵列中无法获得的新的风险变异(包括拷贝数变异和来自1000基因组计划的罕见变异)。除了功能强大的标准GWAS分析外，还将使用一种新的单倍型共享方法来分析GWAS数据。这种方法旨在识别在病例染色体中选择性共享的扩展单倍型，以及可能包含作为显性或隐性风险等位基因的稀有变异。共享的单倍型将通过使用Illumina(以前的Solexa)GA2平台进行有针对性的重新测序进行询问。在SZ的研究中应用了一种混合的常见+稀有变异范式，这一概念范式已被证明在跨越多种生物医学疾病和数量性状的其他几种复杂疾病中是成功的。综上所述，我们相信，在一个具有良好特征和种族同质性的庞大人口中，这种双重方法将提供有关常见和罕见变异在这种毁灭性和致残性疾病的遗传结构中所起作用的信息数据，并为未来对这一独特人口的研究提供宝贵的国家资源。拟议的样本将极大地促进精神病学Gwas联合会正在进行的努力，该联合会是该联合会的成员，并将作为复制和验证结果的来源。公共卫生相关性：精神分裂症(SZ)是美国第五大致残原因。虽然具有很强的遗传性，但具体的遗传风险因素仍不清楚。我们的目标是在大量种族相同的SZ病例和对照人群中使用最先进的基因分型和重新测序技术。这些发现将为精神分裂症的诊断和预测以及了解其生物学特性创造新的机会。