Genomic Investigations of Tourette's Disorder

抽动秽语症的基因组研究

• 批准号: 8899636
• 负责人: Thomas V Fernandez
• 金额: $ 17.96万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8899636
• 关键词: Address; Adverse effects; Anabolism; Architecture; Attention deficit hyperactivity disorder; Autopsy; Award; Biological; Biology; Brain; Brain region; Child; Childhood; Clinical; Code; Collaborations; Comorbidity; Copy Number Polymorphism; Corpus striatum structure; Data; Data Set; Databases; Detection; Development; Disease; Doctor of Medicine; Enzymes; Etiology; Gene Dosage; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genomics; Genotype; Gilles de la Tourette syndrome; Goals; Heterogeneity; Histamine; Human; Inherited; International; Interneurons; Investigation; K-Series Research Career Programs; Laboratories; Lead; Learning; Medical Students; Mentors; Mentorship; Methods; Molecular; Molecular Neurobiology; Molecular Profiling; Molecular Target; Motor Tics; Neurobiology; Neurodevelopmental Disorder; Nucleotides; Obsessive-Compulsive Disorder; Overlapping Genes; Parents; Pathway Analysis; Pathway interactions; Physicians; Positioning Attribute; Process; Productivity; Psychiatrist; RNA Splicing; Recurrence; Research; Research Proposals; Research Support; Residencies; Resolution; Resources; Risk; Role; Sampling; Scientist; Sequence Analysis; Series; Symptoms; Syndrome; Techniques; Testing; Tic disorder; Time; Traction; Training; Transcript; Variant; Vocal Tics; Weight; Work; autism spectrum disorder; base; brain tissue; career; cohort; critical period; developmental neurobiology; differential expression; disorder control; disorder risk; education planning; exome; exome sequencing; gamma-Aminobutyric Acid; genetic pedigree; genetic risk factor; genome sequencing; improved; knowledge base; loss of function mutation; medical schools; meetings; mind control; neuropsychiatry; neurotransmission; new therapeutic target; next generation sequencing; novel; novel therapeutics; rare variant; risk variant; tool; transcriptome sequencing; transcriptomics

DESCRIPTION (provided by applicant): The long-term objective of this career development award is to elucidate the neurobiology of Tourette Disorder (TD) by integrating genomics, transcriptomics, unique datasets, and novel analytic techniques. Dr. Fernandez is a practicing child psychiatrist at the Yale Child Study Center with a career goal to develop an independent research career as a psychiatric geneticist and advance our understanding of the molecular neurobiology of TD. He proposes to identify relevant risk genes, networks, and pathways that will clarify the genetic architecture of TD and point to potential molecular targets for improving treatments for this developmental neuropsychiatric disorder. Dr. Fernandez will accomplish these career and research objectives through a protected time period of research support, relevant course work, seminars, scientific meetings, and the combined guidance of his primary mentor, Matthew State, M.D., a leader in neuropsychiatric genetics, co- mentor Flora Vaccarino, M.D., a leader in developmental neurobiology, and collaborators (Drs. Nenad Sestan, Daniel Geschwind, and Bernie Devlin) who are experts in cortical development, gene network and pathway analysis, and statistical genetics, respectively. The specific aims and methods proposed under this award are entirely consistent with Dr. Fernandez's career and research objectives: (1) Concurrent with his recently-completed residency training, Dr. Fernandez identified rare gene copy number variants (CNVs) in TD subjects which overlapped with those seen in autism spectrum disorders (ASD) and implicated molecular pathways involved in GABA and histamine neurotransmission. The first aim is to confirm these prior CNV pathway and ASD-overlap findings in a larger independent replication cohort of TD subjects, in collaboration with the Tourette Syndrome Association International Consortium for Genetics (TSAICG); (2) the second aim is to learn methods for analyzing sequence and structural variation in the exomes of TD versus control subjects in order to identify rare de novo and inherited variants in parent-child trios. This will allow us to test hypotheses regarding the allelic architecture of TD and provide high resolution data for (3) the third aim, integrating this sequence and structural data with a unique dataset of gene expression in the developing brain to identify co-expression networks via established and novel statistical approaches; (4) finally, we will use our findings above to inform and explore hypotheses in a unique dataset of gene expression and whole genome sequence in postmortem brain tissue from TD and control subjects. Based on his prior record of research productivity, the proposed research aims, educational plan, mentorship team, and extensive resources of the Yale Child Study Center and School of Medicine, Dr. Fernandez is well-positioned to accomplish his career goal of becoming an independent physician scientist and clarifying the molecular mechanisms of TD, which hold promise to inform novel therapeutics.

描述（由申请人提供）：该职业发展奖的长期目标是通过整合基因组学，转录组学，独特的数据集和新颖的分析技术来阐明Tourette障碍（TD）的神经生物学。 Fernandez博士是耶鲁儿童研究中心的一名执业儿童精神病医生，其职业目标是发展为精神病遗传学家的独立研究职业，并促进我们对TD分子神经生物学的理解。他建议确定相关的风险基因，网络和途径，以阐明TD的遗传结构，并指向改善这种发育神经精神疾病治疗的潜在分子靶标。 Fernandez博士将通过受保护的研究支持，相关课程工作，研讨会，科学会议以及其主要导师Matthew State M.D.的共同指导来实现这些职业和研究目标。 Geschwind和Bernie Devlin）分别是皮质发展，基因网络和途径分析以及统计遗传学的专家。 根据该奖项提出的具体目的和方法与费尔南德斯博士的职业和研究目标完全一致：（1）与他最近完成的住院医师培训同时确定了稀有的基因拷贝数变体（CNV）在TD主题中与自闭症谱系（ASD）中所涉及的TD主题重叠的主体（CNV）。神经传递。第一个目的是与Tourette综合征协会国际遗传学联盟（TSAICG）合作，在较大的独立TD主题中确认这些先前的CNV途径和ASD-Overlap发现。 （2）第二个目的是学习用于分析TD与控制受试者外部序列和结构变化的方法 三重奏。这将使我们能够测试有关TD等位基因结构的假设，并为（3）第三个目标提供高分辨率数据，将该序列和结构数据与发育中的大脑中的基因表达的独特数据集成在一起，以通过已建立和新颖的统计方法识别共表达网络； （4）最后，我们将在上面使用我们的发现来告知 并探讨来自TD和对照受试者的基因表达和整个基因组序列的独特数据集和整个基因组序列的假设。根据他先前的研究生产力记录，拟议的研究目的，教育计划，指导团队以及耶鲁儿童学习中心和医学院的广泛资源，Fernandez博士井井有条，可以实现他的职业目标，即成为一名独立的医生科学家并阐明TD的分子机制，以提供新的TRE，这有望提供小说治疗。

项目成果

The Origins of Tourette Syndrome: Prenatal Risk Factors and the Promise of Birth Cohort Studies.

• DOI: 10.1016/j.jaac.2016.06.009
• 发表时间: 2016-09
• 期刊: JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY
• 影响因子: 13.3
• 作者: Leckman, James F.;Fernandez, Thomas V.
• 通讯作者: Fernandez, Thomas V.

Whole-exome sequencing in obsessive-compulsive disorder identifies rare mutations in immunological and neurodevelopmental pathways.

• DOI: 10.1038/tp.2016.30
• 发表时间: 2016-03-29
• 期刊: Translational psychiatry
• 影响因子: 6.8
• 作者: Cappi C;Brentani H;Lima L;Sanders SJ;Zai G;Diniz BJ;Reis VN;Hounie AG;Conceição do Rosário M;Mariani D;Requena GL;Puga R;Souza-Duran FL;Shavitt RG;Pauls DL;Miguel EC;Fernandez TV
• 通讯作者: Fernandez TV

What Makes You Tic? A New Lead in Tourette Syndrome Genetics.

是什么让你抽搐？

• DOI: 10.1016/j.biopsych.2015.12.018
• 发表时间: 2016
• 期刊: Biological psychiatry
• 影响因子: 10.6
• 作者: Fernandez,ThomasV

Prenatal and Perinatal Risk Factors and the Promise of Birth Cohort Studies: Origins of Obsessive-Compulsive Disorder.

产前和围产期危险因素以及出生队列研究的前景：强迫症的起源。

• DOI: 10.1001/jamapsychiatry.2016.2092
• 发表时间: 2016
• 期刊: JAMA psychiatry
• 影响因子: 25.8
• 作者: Fernandez,ThomasV;Leckman,JamesF
• 通讯作者: Leckman,JamesF