4/7-Collaborative genomic studies of Tourette Disorder
4/7-抽动秽语症的合作基因组研究
基本信息
- 批准号:10598206
- 负责人:
- 金额:$ 21.38万
- 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:2018-06-10 至 2023-09-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAttention deficit hyperactivity disorderBiocompatible MaterialsBiologicalBiologyCellsChildClinical DataCodeCommunitiesDataDevelopmentEuropeFamilyGenesGeneticGenetic RiskGenomeGenomicsGenotypeGilles de la Tourette syndromeGoalsHealth BenefitIn VitroIndividualInternationalInvestigationJournalsLeadMolecularMotor TicsNational Institute of Mental HealthNatureNeuritesNeuronsObsessive-Compulsive DisorderParentsPathologicPeptide Sequence DeterminationPersonsPhenotypePoint MutationPopulationPrevalenceProcessPublic HealthPublishingRecurrenceResearch DesignResearch Project GrantsRestScientistSingle Nucleotide PolymorphismSiteSouth KoreaSupervisionTimeVariantVocal TicsWorkautism spectrum disorderaxonal pathfindingclinical research sitecohortcomorbidityde novo mutationdisorder riskeffective therapyexome sequencingexperiencegene discoverygenomic datahuman genomicsin silicoinduced pluripotent stem cellinsertion/deletion mutationneuropsychiatric disordernovelphenotypic dataprobandrare variantrecruitrisk variantsuccesstreatment strategy
项目摘要
PROJECT SUMMARY/ABSTRACT
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 1,025 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, three direct subcontracts (one USA site for clinical supervision and two foreign
coordinating sites), and fourteen secondary clinical sites within Europe and South Korea.
项目总结/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,
三个可能的新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个体中过量的从头破坏性点突变,其效应大小与我们最近的研究结果相当。
ASD的发现这一发现有力地表明,对较大群体的测序将可靠而快速地进行。
从而鉴定出更多的高外显风险基因。此外,我们最近的研究表明,
在同时患有TD和TD的先证者中,
强迫症或注意力缺陷多动障碍,这表明我们的努力很可能
还提供了研究这些经常合并症的遗传风险重叠的途径。我们目前
申请提出:(1)通过额外的1,025个单纯三人组来扩展我们的充分表征的TD三人组队列
并使表型数据和生物材料广泛和快速地提供给广大的科学家,
(2)通过基因分型(用于大的从头CNV鉴定)和整个
外显子组测序(用于从头单核苷酸变异、插入/缺失变异和小CNV
识别)这些额外的TD三人组,使这些数据迅速和广泛提供;(3)扩大
计算机模拟和体外基因组学研究的过程,以长期阐述TD的生物学
开发新的和更有效的治疗策略的目标;和(4)开始生物学表征
使用iPSC衍生的神经元细胞的TD变体。考虑到TD本身的潜在衰弱性质,
人口患病率约为1/100人,这种进步将赋予重大的公众
健康福利。研究设计再次严重依赖于协作R 01机制,
在地球仪的多个研究中心,
在罕见变异人类基因组学和基因发现方面的成功记录。具体而言,该提案包括
七个主要美国研究中心,三个直接分包(一个美国研究中心进行临床监督,两个国外研究中心
协调中心),以及欧洲和韩国的14个二级临床中心。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Implementation of the Mini-Child Tourette Syndrome Impairment Scale: Relationships to Symptom Severity and Treatment Decisions.
- DOI:10.1177/0883073820967518
- 发表时间:2021-03
- 期刊:
- 影响因子:1.9
- 作者:Garris JF;Huddleston DA;Jackson HS;Horn PS;Gilbert DL
- 通讯作者:Gilbert DL
Investigation of previously implicated genetic variants in chronic tic disorders: a transmission disequilibrium test approach.
- DOI:10.1007/s00406-017-0808-8
- 发表时间:2018-04
- 期刊:
- 影响因子:4.7
- 作者:Abdulkadir M;Londono D;Gordon D;Fernandez TV;Brown LW;Cheon KA;Coffey BJ;Elzerman L;Fremer C;Fründt O;Garcia-Delgar B;Gilbert DL;Grice DE;Hedderly T;Heyman I;Hong HJ;Huyser C;Ibanez-Gomez L;Jakubovski E;Kim YK;Kim YS;Koh YJ;Kook S;Kuperman S;Leventhal B;Ludolph AG;Madruga-Garrido M;Maras A;Mir P;Morer A;Müller-Vahl K;Münchau A;Murphy TL;Plessen KJ;Roessner V;Shin EY;Song DH;Song J;Tübing J;van den Ban E;Visscher F;Wanderer S;Woods M;Zinner SH;King RA;Tischfield JA;Heiman GA;Hoekstra PJ;Dietrich A
- 通讯作者:Dietrich A
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DONALD L GILBERT其他文献
DONALD L GILBERT的其他文献
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{{ truncateString('DONALD L GILBERT', 18)}}的其他基金
4/7-Collaborative genomic studies of Tourette Disorder
4/7-抽动秽语症的合作基因组研究
- 批准号:
10376262 - 财政年份:2018
- 资助金额:
$ 21.38万 - 项目类别:
4/7-Collaborative genomic studies of Tourette Disorder
4/7-抽动秽语症的合作基因组研究
- 批准号:
10159309 - 财政年份:2018
- 资助金额:
$ 21.38万 - 项目类别:
GABAergic Sensorimotor Dysfunction in Tourette Syndrome
抽动秽语综合征中的 GABA 能感觉运动障碍
- 批准号:
9897546 - 财政年份:2016
- 资助金额:
$ 21.38万 - 项目类别:
GABAergic Sensorimotor Dysfunction in Tourette Syndrome
抽动秽语综合征中的 GABA 能感觉运动障碍
- 批准号:
9262305 - 财政年份:2016
- 资助金额:
$ 21.38万 - 项目类别:
1/2 - Anomalous Motor System Physiology in ADHD: Biomarker Validation and Modeling Domains of Function
1/2 - ADHD 中的异常运动系统生理学:生物标志物验证和功能建模领域
- 批准号:
10434826 - 财政年份:2012
- 资助金额:
$ 21.38万 - 项目类别:
1/2 - Anomalous Motor System Physiology in ADHD: Biomarker Validation and Modeling Domains of Function
1/2 - ADHD 中的异常运动系统生理学:生物标志物验证和功能建模领域
- 批准号:
10647672 - 财政年份:2012
- 资助金额:
$ 21.38万 - 项目类别:
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