Genomic Investigations of Tourette's Disorder

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、独特数据集和新颖的分析技术来阐明图雷特病（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学家，她的职业目标是作为一名精神病学遗传学家发展独立的研究事业，并推进我们对TD分子神经生物学的理解。他建议识别相关的风险基因、网络和途径，这将澄清TD的遗传结构，并指出潜在的分子靶点，以改善这种发育性神经精神疾病的治疗。Fernandez博士将通过研究支持、相关课程、研讨会、科学会议以及他的主要导师Matthew State医学博士（神经精神遗传学的领导者）、Flora Vaccarino医学博士（发育神经生物学的领导者）和合作者（Dr. Dr.）的联合指导，完成这些职业和研究目标。Nenad Sestan， Daniel Geschwind和Bernie Devlin)，他们分别是皮质发育，基因网络和途径分析以及统计遗传学方面的专家。该奖项提出的具体目标和方法与Fernandez博士的职业和研究目标完全一致：(1)在他最近完成住院医师培训的同时，Fernandez博士在TD受试者中发现了罕见的基因拷贝数变异（CNVs），这些变异与自闭症谱系障碍（ASD）中发现的基因拷贝数变异（CNVs）重叠，并涉及GABA和组胺神经传递的分子途径。第一个目标是与图雷特综合征协会国际遗传学协会（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通路和asd重叠的发现；(2)第二个目的是学习分析TD与对照组外显子组序列和结构差异的方法，以识别亲子间罕见的新生和遗传变异

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.