Genomic Investigations of Tourette's Disorder

描述(申请人提供)：这个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多发性抽动症(TD)的神经生物学。费尔南德斯博士是耶鲁儿童研究中心的一名执业儿童精神病学家，他的职业目标是发展作为精神病学遗传学家的独立研究生涯，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，并指出改进这种发育性神经精神障碍治疗的潜在分子靶点。费尔南德斯博士将通过一段受保护的时间段的研究支持、相关课程工作、研讨会、科学会议，以及他的主要导师、神经精神病学遗传学领先者、共同导师弗洛拉·瓦卡里诺医学博士以及分别是皮质发育、基因网络和路径分析以及统计遗传学专家的合作者(Nenad Sestan博士、Daniel Geschind博士和Bernie Devlin博士)的联合指导，实现这些职业和研究目标。该奖项提出的具体目标和方法与Fernandez博士的职业生涯和研究目标完全一致：(1)在最近完成住院医师培训的同时，Fernandez博士发现TD受试者中罕见的基因拷贝数变异(CNV)与自闭症谱系障碍(ASD)中发现的基因拷贝数变异(CNV)重叠，并涉及GABA和组胺神经传递所涉及的分子途径。第一个目标是与抽动症综合征协会国际遗传学联合会(TSAICG)合作，在一个更大的TD受试者独立复制队列中证实这些先前的CNV途径和ASD重叠发现；(2)第二个目标是学习分析TD与对照受试者外显体的序列和结构变异的方法，以便在父母-孩子中识别罕见的从头开始和遗传变异 三人组。这将使我们能够测试有关TD的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大脑中基因表达的独特数据集相结合，通过已建立的和新的统计方法来识别共表达网络；(4)最后，我们将利用上述发现来说明 并在TD和对照受试者死后脑组织中基因表达和全基因组序列的独特数据集中探索假设。基于费尔南德斯博士以前的研究效率记录、提出的研究目标、教育计划、指导团队以及耶鲁大学儿童研究中心和医学院的广泛资源，费尔南德斯博士完全有能力实现他的职业目标，即成为一名独立的内科科学家，并阐明TD的分子机制，这些机制有望为新的疗法提供信息。

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.