Advancing Tourette Syndrome genetics using bioinformatics and genome biology

描述（由申请人提供）：使用生物信息学和基因组生物学推进Tourette综合征遗传学Tourette综合征（TS）是一种儿童期发病的神经精神疾病，具有高度遗传性，尽管发现确定的TS易感基因具有挑战性。该独立科学家奖（K 02）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，为他提供指导全面的人类遗传学研究计划所需的剩余经验，知识和技能，旨在发现和功能分析TS和相关神经发育障碍的疾病变体。研究计划包括：1）对3021例新发TS病例和3536例祖先匹配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）分析下一代测序数据，其包含基因组的>90%的所有蛋白质编码区（“全外显子组测序”），以探索罕见的，破坏性的功能丧失突变在疾病中的作用; 3）对目标1和2中的研究所涉及的基因的综合分析，结合不同发育时间点的各种脑组织中基因表达的生物学数据，以鉴定可能是TS疾病过程的基础的特定生物学途径。拟议的研究将在马萨诸塞州总医院与MGH、哈佛布罗德研究所和麻省理工学院以及芝加哥大学的顾问合作进行，他们各自在计算生物学、下一代测序数据分析以及疾病相关DNA变异与表观基因组和基因表达数据的整合方面具有互补的专业知识。职业发展计划包括一个教学部分，结合有针对性的课程和计算生物学研讨会与数据分析的纵向监督。这项提案提供了一个独特的和令人兴奋的机会，以迅速推进的目标，确定这种复杂的和重要的模型神经精神疾病的生物学基础，在未来可能会导致疾病治疗和/或预防的新途径。

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.