1/7 Collaborative Genomic Studies of Tourette Disorder.
1/7 抽动秽语症的合作基因组研究。
基本信息
- 批准号:10176595
- 负责人:
- 金额:$ 134.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-06-15 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAsiansAttention deficit hyperactivity disorderBiocompatible MaterialsBiologicalBiologyBrainC2 DomainCell modelCellsChildClinicalClinical DataCodeCommunitiesCopy Number PolymorphismDataData AnalysesDevelopmentDimensionsEnsureEuropeFamilyFamily StudyFoundationsFundingGenesGeneticGenetic RiskGenomeGenomicsGenotypeGilles de la Tourette syndromeGoalsHealth BenefitHumanIn VitroIndividualInternationalInvestigationJournalsLeadLinkMethodsMolecularMotor TicsNational Institute of Mental HealthNatureNeuritesNeuronsObsessive-Compulsive DisorderParentsPathologicPeptide Sequence DeterminationPhenotypePoint MutationPopulationPrevalenceProcessPublic HealthPublishingRecurrenceReportingResearch DesignResearch PersonnelResearch Project GrantsRestSamplingScienceScientistSingle Nucleotide PolymorphismSiteSourceSouth KoreaStructureSupervisionTestingTimeVariantVocal TicsWorkautism spectrum disorderaxonal pathfindingbasebiological systemsclinical research sitecohortcomorbidityde novo mutationdisorder riskeffective therapyexome sequencingexperiencefunctional genomicsgene discoverygenomic datagenomic locushuman genomicsin silicoinduced pluripotent stem cellinduced pluripotent stem cell technologyinsertion/deletion mutationmultidimensional dataneuropsychiatric disordernovelphenotypic dataprobandrare variantrecruitrisk variantsuccesstreatment strategyvariant detection
项目摘要
PROJECT SUMMARY
Despite strong evidence for a genetic contribution to Tourette disorder (TD), progress in the identification of
specific risk genes has been, until quite recently, halting. However, building upon NIMH's support for our initial
efforts to ascertain TD trios as well as our highly successful experience with genomic investigations of autism
spectrum disorders (ASD), we have now demonstrated a clear path forward for reliable, systematic gene
discovery in TD. Our TD work, recently published in the journal Neuron, identified one high confidence and three
probable novel TD risk genes collectively pointing to neurite outgrowth and axon pathfinding as potential
pathological mechanisms1. More importantly, however, our findings demonstrate, for the first time, a clear excess
of de novo damaging point mutations in individuals with TD, with effect sizes that rival our recent findings in ASD.
This discovery strongly suggests that sequencing of larger cohorts will reliably and rapidly lead to the
identification of many more highly penetrant risk genes. Moreover, our recent work suggests an increased yield
of highly penetrant damaging de novo variants in probands who are affected both with TD and obsessive
compulsive disorder or attention deficit hyperactivity disorder, suggesting that our efforts may well also offer
avenues to study the overlap in genetic risks for these often-comorbid conditions. Our current application
proposes to: (1) expand our well characterized TD trio cohort by an additional 1,000 simplex trios and make the
phenotypic data and biological materials widely and rapidly available to the broad scientific community; (2)
accelerate gene discovery, via genotyping (for large de novo CNV identification) and whole exome sequencing
(for de novo single nucleotide variant, insertion/deletion variant, and small CNV identification) of these additional
TD trios, making these data rapidly and widely available as well; (3) extend the process of in silico and in vitro
genomics investigations to elaborate the biology of TD with the long term goal of developing novel and more
effective treatment strategies; and (4) begin biological characterization of TD variants using iPSC-derived
neuronal cells. Given the potentially debilitating nature of TD alone, and a population prevalence of
approximately 1 in 100 individuals, such advances would confer a significant public health benefit. The study
design again rests heavily on the collaborative R01 mechanism that will bring together deep experience with the
TD phenotype at multiple sites across the globe with scientists with a strong track record of success in rare
variant human genomics and gene discovery. Specifically, the proposal includes seven primary US sites, four
direct subcontracts (two USA sites for clinical supervision and data analysis and two foreign coordinating sites),
and fourteen secondary clinical sites within Europe and South Korea.
项目摘要
尽管有强有力的证据表明抽动秽语障碍(TD)的遗传贡献,但在识别
直到最近,特定的风险基因一直处于停滞状态。然而,基于NIMH对我们最初的支持,
努力确定TD三重奏以及我们在自闭症基因组研究方面的高度成功经验
谱系障碍(ASD),我们现在已经证明了一条明确的道路,可靠的,系统的基因
发现TD我们的TD工作最近发表在《神经元》杂志上,确定了一个高置信度和三个
可能的新型TD风险基因共同指向神经突生长和轴突寻路作为潜在的
病理机制1.然而,更重要的是,我们的研究结果首次表明,
TD个体的从头破坏性点突变,其效应大小与我们最近在ASD中的发现相媲美。
这一发现有力地表明,对较大队列的测序将可靠而快速地导致对大规模群体的测序。
识别出更多的高外显风险基因。此外,我们最近的研究表明,
高渗透破坏性的从头变异的先证者谁是受TD和强迫症
强迫症或注意力缺陷多动障碍,这表明我们的努力也可能提供
研究这些经常合并症的遗传风险重叠的途径。我们目前的应用
建议:(1)通过额外的1,000个简单的三人组来扩展我们的TD三人组队列,并使
表型数据和生物材料广泛和迅速地提供给广大科学界;(2)
通过基因分型(用于大规模从头CNV识别)和全外显子组测序加速基因发现
(for从头单核苷酸变异、插入/缺失变异和小CNV鉴定)。
TD trios,使这些数据快速和广泛提供,以及(3)扩展的过程中,在电脑和体外
基因组学研究,以阐述TD的生物学,长期目标是开发新的和更多的
有效的治疗策略;和(4)开始使用iPSC衍生的TD变体的生物学表征。
神经元细胞考虑到TD本身的潜在致弱性,以及
大约每100人中有1人,这种进步将带来重大的公共卫生效益。研究
设计再次在很大程度上依赖于协作R 01机制,该机制将把深度经验与
在地球仪的多个地点进行TD表型研究,科学家在罕见的
变异人类基因组学和基因发现。具体而言,该提案包括七个主要的美国网站,四个
直接分包(两个美国临床监督和数据分析中心和两个国外协调中心),
以及欧洲和韩国的14个二级临床研究中心。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Gary A. Heiman其他文献
Myoclonus dystonia
肌阵挛肌张力障碍
- DOI:
- 发表时间:
2002 - 期刊:
- 影响因子:9.9
- 作者:
R. Saunders;J. Shriberg;Gary A. Heiman;D. Raymond;K. Wendt;Patricia L. Kramer;K. Schilling;R. Kurlan;Christine Klein;L. Ozelius;N. Risch;S. Bressman - 通讯作者:
S. Bressman
Gary A. Heiman的其他文献
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{{ truncateString('Gary A. Heiman', 18)}}的其他基金
1/7 Collaborative Genomic Studies of Tourette Disorder.
1/7 抽动秽语症的合作基因组研究。
- 批准号:
10381582 - 财政年份:2018
- 资助金额:
$ 134.18万 - 项目类别:
1/8-Collaborative genomic studies of Tourette Disorder
1/8-抽动秽语症的合作基因组研究
- 批准号:
8182787 - 财政年份:2011
- 资助金额:
$ 134.18万 - 项目类别:
1/8-Collaborative genomic studies of Tourette Disorder
1/8-抽动秽语症的合作基因组研究
- 批准号:
8333310 - 财政年份:2011
- 资助金额:
$ 134.18万 - 项目类别:
1/8-Collaborative genomic studies of Tourette Disorder
1/8-抽动秽语症的合作基因组研究
- 批准号:
8514074 - 财政年份:2011
- 资助金额:
$ 134.18万 - 项目类别:
1/8-Collaborative genomic studies of Tourette Disorder
1/8-抽动秽语症的合作基因组研究
- 批准号:
8664968 - 财政年份:2011
- 资助金额:
$ 134.18万 - 项目类别:
Shared Genetic Risk for Epilepsy and Depression
癫痫和抑郁症的共同遗传风险
- 批准号:
7871319 - 财政年份:2007
- 资助金额:
$ 134.18万 - 项目类别:
Shared Genetic Risk for Epilepsy and Depression
癫痫和抑郁症的共同遗传风险
- 批准号:
7503343 - 财政年份:2007
- 资助金额:
$ 134.18万 - 项目类别:
Shared Genetic Risk for Epilepsy and Depression
癫痫和抑郁症的共同遗传风险
- 批准号:
7314295 - 财政年份:2007
- 资助金额:
$ 134.18万 - 项目类别:
Shared Genetic Risk for Epilepsy and Depression
癫痫和抑郁症的共同遗传风险
- 批准号:
7651096 - 财政年份:2007
- 资助金额:
$ 134.18万 - 项目类别:
Shared Genetic Risk for Epilepsy and Depression
癫痫和抑郁症的共同遗传风险
- 批准号:
8100168 - 财政年份:2007
- 资助金额:
$ 134.18万 - 项目类别:
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