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:
- 金额:$ 145.2万
- 依托单位:
- 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:
- 关键词:AllelesArchitectureAreaArtsAshkenazimBiological AssayBiologyBlood capillariesCandidate Disease GeneCatalogingCatalogsChromosomesClinicalCollaborationsComplexComputer softwareCountryDNADNA Microarray ChipDNA ResequencingDataData SetDatabasesDepositionDetectionDiagnosisDiseaseEquilibriumEtiologyFundingFutureGenerationsGeneticGenetic VariationGenomeGenomicsGenotypeGoalsHaplotypesHealth systemHeritabilityHybridsInstitutesIntramural Research ProgramIsraelLocationMapsMedical ResearchMental disordersMethodsModelingMolecularMutationNational Institute of Mental HealthNational Institute on Alcohol Abuse and AlcoholismOdds RatioPatientsPenetrancePhenotypePopulationPredispositionRecurrenceRelative (related person)ResearchResearch PersonnelResourcesRiskRoleSamplingSchizophreniaSiblingsSignal TransductionSourceSusceptibility GeneSymptomsTechnologyTwin Multiple BirthUnited StatesUnited States National Institutes of HealthUniversitiesUrsidae FamilyValidationVariantWeightWorkcapillarycase controlcohortcostdatabase of Genotypes and Phenotypesdesigndisabilityexperiencefollower of religion Jewishgenetic pedigreegenetic risk factorgenome wide association studygenome-wideinterestmembernext generationnovelpsychogeneticspublic health relevancerepositoryresponsesextraittreatment 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(由申请人提供):精神分裂症(SZ)的特征是高遗传性(~80%)和同胞复发率升高(s ~ 10),但易感基因的鉴定已被证明极具挑战性。这一申请题为“常见和罕见的遗传因素在一个种族同质性精神分裂症队列”是在响应NIMH大机会地区基因组分析的精神疾病。在这项提案中,我们的目标是进行全基因组关联研究(GWAS),然后进行广泛的下一代重测序(Illumina/Solexa技术),在一个大型(n=4000)队列的德系犹太精神分裂症患者和匹配良好的德系对照。所有的DNA已经收集,并立即准备基因分型。德系犹太人的人口,来自有限数量的创始人,可能是丰富的一个子集的常见和/或罕见的易感性等位基因,因此可能有更高的优势比以前的研究检测到的。来自私人捐助者的匹配资金将允许高质量的GWAS以大幅降低的NIH成本进行。GWAS将使用新的Illumina HumanOmni 1-Quad BeadChip,它可以识别在前几代DNA微阵列中无法获得的新风险变体(包括拷贝数变体和来自1000个基因组项目的罕见变体)。除了高效能的标准GWAS分析外,GWAS数据还将使用一种新的单倍型共享方法进行分析。这种方法的目的是确定扩展的单倍型,有选择性地共享的情况下染色体,并可能窝藏罕见的变异作为显性或隐性的风险等位基因。然后将使用Illumina(以前的Solexa)GA 2平台通过靶向重测序来询问共享的单倍型。混合常见+罕见变异范式的应用SZ的研究应用了一个概念范式,已被证明是成功的,在其他几个复杂的疾病在多个生物医学疾病和数量性状。综上所述,我们相信,这种双重方法在一个大的,良好的特点,和种族同质的人口将提供信息数据的作用,常见的和罕见的变异的遗传结构的这种破坏性和致残性疾病,以及提供一个宝贵的国家资源,为未来的研究这个独特的人口。拟议的样本将大大有助于精神病学GWAS联盟的持续努力,PI是其中的一员,并将作为结果的复制和验证的来源。
公共卫生相关性:精神分裂症(SZ)是美国第五大残疾原因。虽然具有很强的遗传性,但具体的遗传风险因素仍不清楚。我们的目标是在一个大型的、种族同质的深圳病例和对照队列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创造新的机会。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
GACT: a Genome build and Allele definition Conversion Tool for SNP imputation and meta-analysis in genetic association studies.
GACT:基因组构建和等位基因定义转换工具,用于遗传关联研究中的 SNP 估算和荟萃分析。
- DOI:10.1186/1471-2164-15-610
- 发表时间:2014
- 期刊:
- 影响因子:4.4
- 作者:Sulovari,Arvis;Li,Dawei
- 通讯作者:Li,Dawei
The time and place of European admixture in Ashkenazi Jewish history.
- DOI:10.1371/journal.pgen.1006644
- 发表时间:2017-04
- 期刊:
- 影响因子:4.5
- 作者:Xue J;Lencz T;Darvasi A;Pe'er I;Carmi S
- 通讯作者:Carmi S
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TODD LENCZ其他文献
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{{ truncateString('TODD LENCZ', 18)}}的其他基金
Cognitive Genomics as a Window on Neurodevelopment and Psychopathology
认知基因组学作为神经发育和精神病理学的窗口
- 批准号:
9902802 - 财政年份:2019
- 资助金额:
$ 145.2万 - 项目类别:
Cognitive Genomics as a Window on Neurodevelopment and Psychopathology
认知基因组学作为神经发育和精神病理学的窗口
- 批准号:
10360609 - 财政年份:2018
- 资助金额:
$ 145.2万 - 项目类别:
Pharmacogenetic Prediction of Antipsychotic Induced Weight Gain
抗精神病药物引起的体重增加的药物遗传学预测
- 批准号:
8532495 - 财政年份:2013
- 资助金额:
$ 145.2万 - 项目类别:
Pharmacogenetic Prediction of Antipsychotic Induced Weight Gain
抗精神病药物引起的体重增加的药物遗传学预测
- 批准号:
8641427 - 财政年份:2013
- 资助金额:
$ 145.2万 - 项目类别:
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
- 批准号:
7855944 - 财政年份:2009
- 资助金额:
$ 145.2万 - 项目类别:
Identifying Molecular Subtypes of Schizophrenia: A Novel Genomic Approach
识别精神分裂症的分子亚型:一种新的基因组方法
- 批准号:
7803674 - 财政年份:2008
- 资助金额:
$ 145.2万 - 项目类别:
Identifying Molecular Subtypes of Schizophrenia: A Novel Genomic Approach
识别精神分裂症的分子亚型:一种新的基因组方法
- 批准号:
7666181 - 财政年份:2008
- 资助金额:
$ 145.2万 - 项目类别:
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