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

通过 17q12 CNV 检测自闭症和精神分裂症风险的基因组方法

基本信息

批准号：
10054220
负责人：
Daniel Moreno De Luca
金额：
$ 19.71万
依托单位：
EMMA PENDLETON BRADLEY HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10054220
关键词：
17q12 Affect Animals Biological Categories Clinical Copy Number Polymorphism Data Diabetes Mellitus Diagnosis Dimensions Endocrine Ethics Focus Groups Foundations Frequencies Gene Dosage General Population Genes Genetic Genetic Variation Genomic approach Genomics Head circumference Human Human Genetics Impaired cognition Impairment Individual International Interview Kidney Kidney Diseases Knowledge Laboratories Macrocephaly Measures Medical Medical Records Mentors Microcephaly Modeling Molecular Abnormality Mutation Neuraxis Neurologic Neuropsychology Outcome Participant Patients Performance Phenotype Population Prevalence Psychiatric Diagnosis Publishing Questionnaires Recurrence Research Research Design Research Domain Criteria Risk Role Schizophrenia Severities Single Nucleotide Polymorphism Standardization Testing Time Training Urogenital Abnormalities Work autism spectrum disorder base behavioral phenotyping body system brain size career comorbidity endophenotype genetic risk factor genetic variant genome sequencing high risk meetings member multidisciplinary neurobehavioral neuropsychiatric disorder neuropsychiatry novel novel strategies pleiotropism polygenic risk score psychotic symptoms rare variant social deficits stem cells trait

项目摘要

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.

项目摘要/总结 17q12 拷贝数变异 (CNV) 一度被认为可以保护中枢神经系统，但现在已知它可以保护中枢神经系统。患有自闭症谱系障碍（ASD）、精神分裂症和其他相关神经精神疾病的风险非常高。精神风险，17q12 CNV 体现了许多罕见疾病的多效性和可变表达性遗传变异：尽管 17q12 CNV 与分类精神病学诊断之间的关联已被确定。事实证明，我们还不知道它对维度神经行为特征的影响，以及不同的医学共病如何影响关系与精神表型的表达相关，背景常见遗传变异如何可能影响相关医学和行为表型的表达，或这些表型如何随时间变化。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，以了解它们对人类表型的贡献及其生物学后果本 K-23 的总体目标。建议使用 17q12 CNV 作为原型来扩大我们对精神分裂症风险的理解自闭症是由罕见的基因变异及其调节因素造成的，而其他 CNV 也是如此。与神经精神风险相关，17q12 具有重要的战略意义，因为只有两个断点参与这种重排意味着该位点的 CNV 包含相同的独特基因组序列，从而促进此外，该区域内基因的单核苷酸变异（SNV）也存在差异。与特定的医学表型相关，但与精神表型无关，提供了了解的机会最后，复发性 CNV 提供了一个机会。与 SNV 的一致性来研究基因剂量效应，我们已经在动物身上利用了这一优势和 17q12 CNV 的干细胞研究目前正在该亲的主要导师的实验室中进行首席研究员埃里克·莫罗 (Eric Morrow) 博士建议利用他作为科学委员会成员的长期协会。 17q12 基金会成立一个国际合作、多学科小组，重点关注以下方面：理解删除和重复如何给神经行为表型带来风险。所有这些都旨在缩小上述差距，我们建议对 60 名 17q12 缺失的个体进行纵向评估在他的项目“自闭症和精神分裂症的基因组方法”中，有 60 个具有 17q12 重复的个体。通过 17q12 CNV 来降低精神分裂症风险”，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、课程作业、科学会议和专家指导在他的导师和合作者的支持和支持下，PI 提出了开发新颖的高级培训。基于 RDoC、转化内表型和人类遗传重组伦理的精神评估搜索。