A genomic approach to autism and schizophrenia risk through 17q12 CNVs

项目摘要/摘要 17q12拷贝数变异体(CNV)曾经被认为可以避免中枢神经系统的损伤，但现在已知它会影响中枢神经系统的功能。 FER是自闭症、精神分裂症和其他相关神经精神疾病的高危人群。除了神经- 精神风险，17q12 CNV例证了多效性和可变的表现性，这是许多罕见的 遗传变异：尽管已经建立了17q12 CNV与分类精神诊断的关联。 Led，我们还不知道它对维度神经行为特征的影响，以及医疗合并症的多样性- 联系与精神疾病表型的表达相关，背景常见的遗传变异可能 影响相关的医学和行为表型的表达，或者这些表型如何随着时间的推移而变化。的确有 迫切需要一种可扩展的策略来研究个别稀有基因变异的影响，以了解 它们对人类表型的贡献及其生物学后果。这架K-23的总体目标是 建议使用17q12 CNV作为原型，以扩大我们对精神分裂症和 由罕见的基因变异和调节因素导致的自闭症。而其他CNV也一直在 17q12与神经精神疾病风险相关，具有重要的战略意义，因为只有两个断点涉及 这种重排，意味着该基因座上的CNV包括相同的唯一基因组序列，有助于 不同个体的比较。此外，该区域内基因的单核苷酸变异(SNV)具有 与特定的医学表型有关，但与精神疾病表型无关，这提供了一个了解 该区域内的基因多样性如何可能导致风险增加。最后，反复出现的CNV提供了一个相反的- 比SNV更适合研究基因剂量效应，这是我们已经在动物身上利用的一个优势 和17q12 CNV的干细胞研究目前正在该专业的主要导师的实验室进行- 波索，这是埃里克·莫罗医生。PI提议利用他作为科学委员会成员的长期联系 17q12基金会建立一个国际协作的多学科小组，专注于以下方面 研究缺失和复制如何增加神经行为表型的风险。为了实现我们的过度- 所有目标都是为了缩小上述差距，我们建议使用17q12 Dele对60个个体进行纵向评估- 17q12重复的个体和60个个体。在他的项目中，《自闭症和精神分裂症的基因组方法-- 通过17q12 CNV的精神分裂症风险“，Moreno de Luca博士将实现这些研究和职业目标 通过一段受保护的时间用于研究、研讨会、课程、科学会议和专家指南- 对他的导师和合作者的支持和支持。PI建议在开发新型DIE方面进行高级培训。 基于RDoC、翻译内表型和人类基因重组伦理学的指征评估 搜索。

PROJECT ABSTRACT/SUMMARY Once thought to spare the central nervous system, 17q12 copy number variants (CNVs) are now known to con- fer a very high risk for ASD, schizophrenia, and other related neuropsychiatric disorders. In addition to neuro- psychiatric risk, 17q12 CNVs exemplify the pleiotropy and variable expressivity that characterizes many rare genetic variants: Although the association of 17q12 CNVs with categorical psychiatric diagnosis has been estab- lished, we do not yet know its impact on dimensional neurobehavioral traits, how diverse medical comorbidi- ties correlate with the expression of psychiatric phenotypes, how background common genetic variation may affect the expression of associated medical and behavioral phenotypes, or how these change over time. There is a pressing need for a scalable strategy to study the impact of individual rare genetic variants to understand their contribution towards human phenotypes and their biological consequences. The overall aim of this K-23 proposal is to use 17q12 CNVs as an archetype to broaden our understanding of the risk for schizophrenia and autism conferred by rare genetic variants and the factors that modulate it. While other CNVs have also been associated with neuropsychiatric risk, 17q12 is strategically important as only two breakpoints are involved in this rearrangement, meaning that CNVs at this locus include the same unique genomic sequence, facilitating comparisons across individuals. In addition, single nucleotide variants (SNVs) in genes within the region have been associated with specific medical, but not psychiatric, phenotypes, offering an opportunity to understand how diverse genes within the region may contribute to increased risk. Finally, recurrent CNVs offer an oppor- tunity over SNVs to investigate gene dosage effects, an advantage we are already capitalizing on with animal and stem cell studies of 17q12 CNVs currently underway in the laboratory of the primary mentor of this pro- posal, Dr. Eric Morrow. The PI proposes to leverage his longstanding association as a scientific board member of the 17q12 foundation to develop an international collaborative, multidisciplinary group focused on under- standing of how the deletion and duplication confer risk for neurobehavioral phenotypes. To achieve our over- all aim and close the gap outlined above, we propose to longitudinally assess sixty individuals with 17q12 dele- tions and sixty individuals with 17q12 duplications. In his project, “A genomic approach to autism and schizo- phrenia risk through 17q12 CNVs”, Dr. Moreno De Luca will achieve these research and career objectives through a period of protected time for research, seminars, coursework, scientific meetings, and the expert guid- ance and support of his mentor and collaborators. The PI proposes advanced training in developing novel di- mensional assessments based on RDoC, translational endophenotypes and the ethics of human genetic re- search.