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

项目摘要/总结 曾经被认为是备用的中枢神经系统，17 q12拷贝数变异（CNVs）现在已知的是， 患ASD、精神分裂症和其他相关神经精神疾病的风险非常高。除了神经- 精神病风险，17 q12 CNVs掩盖了许多罕见的 遗传变异：尽管17 q12 CNVs与分类精神病诊断的相关性已经建立， 尽管如此，我们还不知道它对维度神经行为特征的影响，如何多样化的医学合并症- 关系与精神病表型的表达相关，背景常见的遗传变异如何可能 影响相关的医学和行为表型的表达，或者这些表型如何随时间变化。有 迫切需要一种可扩展的策略来研究个体罕见遗传变异的影响， 它们对人类表型的贡献及其生物学后果。K-23的总体目标是 一项提议是使用17 q12 CNVs作为原型，以扩大我们对精神分裂症风险的理解， 罕见的遗传变异和调节它的因素赋予自闭症。虽然其他CNV也被 与神经精神风险相关，17 q12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包括相同的独特基因组序列， 个人之间的比较此外，该区域内基因中的单核苷酸变异（SNV） 与特定的医学，但不是精神病学，表型相关，提供了一个了解 该地区的基因多样性如何导致风险增加。最后，复发性CNV提供了一个机会- 研究基因剂量效应，这是我们已经在动物实验中利用的一个优势。 和17 q12 CNVs的干细胞研究，目前正在这个亲的主要导师的实验室进行， 埃里克·莫罗医生PI建议利用他作为科学委员会成员的长期协会 17 q12基金会，以建立一个国际协作的多学科小组，重点关注 缺失和重复如何赋予神经行为表型风险。为了实现我们的过度- 所有的目标和关闭上述的差距，我们建议纵向评估60个17 q12缺失的个体， 60个个体有17 q12重复。在他的项目中，“自闭症和自闭症的基因组方法- 通过17 q12 CNVs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进行研究，研讨会，课程，科学会议和专家指南- 他的导师和合作者的支持和支持。PI提出了先进的培训，在开发新的迪- 基于RDoC、翻译内表型和人类遗传重建伦理学的月经评估， 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.