Advancing Tourette Syndrome genetics using bioinformatics and genome biology

利用生物信息学和基因组生物学推进抽动秽语综合征遗传学

• 批准号: 8812020
• 负责人: Jeremiah M Scharf
• 金额: $ 20.81万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8812020
• 关键词: Adult; Behavioral; Bioinformatics; Biological; Biological Process; Biology; Brain region; Chicago; Childhood; Clinical; Code; Collaborations; Complex; Complex Genetic Trait; Computational Biology; Copy Number Polymorphism; Corpus striatum structure; DNA; DNA Sequence; Data; Data Analyses; Data Set; Development; Development Plans; Diagnosis; Disease; Doctor of Philosophy; Educational workshop; Etiology; European; Family; Fingerprint; Funding; Future; Gene Expression; Gene Expression Regulation; General Hospitals; Genes; Genetic; Genetic Predisposition to Disease; Genetic Research; Genetic Risk; Genome; Genotype; Gilles de la Tourette syndrome; Goals; Grant; Health; Human; Human Genetics; Independent Scientist Award; Individual; Inherited; Institutes; International; Knock-out; Knowledge; Lead; Leadership; Massachusetts; Meta-Analysis; Modeling; Molecular; Molecular Genetics; Morbidity - disease rate; Mutation; Nervous system structure; Neurodevelopmental Disorder; Neurologist; Open Reading Frames; Parents; Pathogenesis; Pathway Analysis; Pathway interactions; Physiological; Play; Predisposition; Prevention; Process; Research; Research Personnel; Risk; Role; Sampling; Sequence Analysis; Structure; Supervision; Susceptibility Gene; System; Systems Integration; Techniques; Time; Tissue-Specific Gene Expression; Training; United States National Institutes of Health; Universities; Variant; arm; base; behavioral neurology; brain tissue; career; career development; case control; data integration; epigenetic marker; epigenomics; exome sequencing; experience; fetal; gene discovery; gene function; genetic analysis; genetic variant; genome analysis; genome wide association study; genome-wide; improved; insight; loss of function; loss of function mutation; neurogenetics; neuroimaging; neuropsychiatry; next generation; next generation sequencing; proband; programs; psychosocial; risk variant; skills; skills training

DESCRIPTION (provided by applicant): Advancing Tourette Syndrome genetics using bioinformatics and genome biology Tourette Syndrome (TS) is a childhood-onset, neuropsychiatric disorder that is highly heritable, though discovery of definitive TS susceptibilit genes has been challenging. This Independent Scientist Award (K02) will provide the candidate with additional training in bioinformatics and analysis of genome biology data to provide him with the remaining experience, knowledge and skills needed to direct a comprehensive human genetics research program aimed at discovery and functional analysis of disease variants for TS and related neurodevelopmental disorders. The research plan consists of: 1) a genome-wide association study of 3021 new TS cases and 3536 ancestry-matched controls to examine the role of common gene variants in TS susceptibility; 2) an analysis of next-generation sequencing data containing >90% of all protein-coding regions of the genome ("whole exome sequencing") in TS parent-proband trios to explore the contribution of rare, damaging loss-of-function mutations in the disorder; 3) an integrative analysis of genes implicated by the studies in Aims 1 and 2 combined with biological data of gene expression in various brain tissues across different developmental time points to identify the specific biological pathways that may underlie the TS disease process. The proposed study will be conducted at Massachusetts General Hospital in collaboration with consultants at MGH, the Broad Institute of Harvard and MIT as well as the University of Chicago, each who have complementary expertise in computational biology, analysis of next-generation sequencing data, and integration of disease-associated DNA variation with epigenomic and gene expression data. The career development plan includes a didactic component combining targeted coursework and computational biology workshops with longitudinal supervision of data analysis. This proposal provides a unique and exciting opportunity to rapidly advance the goal of identifying the biological basis of this complex and important model neuropsychiatric disorder which in the future could lead to new avenues for disease treatment and/or prevention.

描述(由申请人提供)：利用生物信息学和基因组生物学发展抽动秽语综合征遗传学尽管发现明确的TS易感基因一直具有挑战性，但Tourette综合征(TS)是一种儿童起病的神经精神障碍，具有高度的遗传性。这一独立科学家奖(K02)将为候选人提供生物信息学和基因组生物学数据分析方面的额外培训，为他提供指导全面人类遗传学研究计划所需的剩余经验、知识和技能，该计划旨在发现TS和相关神经发育障碍的疾病变异并进行功能分析。研究计划包括：1)对3021例新的TS病例和3536名祖先匹配的对照进行全基因组关联研究，以检查常见基因变异在TS易感性中的作用；2)分析包含TS亲代先证者三人组基因组所有蛋白质编码区90%的下一代测序数据(“完整外显子组测序”)，以探索罕见的、破坏性的功能丧失突变在该病中的作用；3)对AIMS 1和AIMS 2中的研究涉及的基因进行综合分析，结合不同发育时间点不同脑组织中基因表达的生物学数据，确定TS疾病过程中可能存在的特定生物学途径。这项拟议的研究将在马萨诸塞州总医院与麻省理工学院、哈佛大学博德研究所以及芝加哥大学的顾问合作进行，这些顾问在计算生物学、下一代测序数据的分析以及疾病相关DNA变异与表观基因组和基因表达数据的整合方面拥有互补的专业知识。职业发展计划包括一个教学部分，将有针对性的课程作业和计算生物学研讨会与数据分析的纵向监督相结合。这项提议提供了一个独特和令人振奋的机会，以迅速推进确定这一复杂和重要的神经精神障碍的生物学基础的目标，这在未来可能导致疾病治疗和/或预防的新途径。