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：
10460491
负责人：
Daniel Moreno De Luca
金额：
$ 9.9万
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 2023-02-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10460491
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 Persons 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 remote assessment schizophrenia risk social deficits stem cells trait

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 Persons 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 remote assessment schizophrenia risk social deficits stem cells trait

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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/摘要一旦被认为避免了中枢神经系统，现在已知17q12拷贝数变体（CNV）对ASD，精神分裂症和其他相关神经精神疾病的风险很高。除了神经精神病风险，17q12 CNV体现了多个罕见的多效性和可变表达性遗传变异：尽管17q12 CNV与分类精神诊断的关联已经存在 - 出色，我们尚不知道它对维度神经行为特征的影响，医学合并多样化关系与精神病表型的表达相关，背景常见的遗传变异如何影响相关的医学和行为表型的表达，或者它们如何随时间变化。有迫切需要一种可扩展的策略来研究单个稀有遗传变异的影响它们对人类表型及其生物学后果的贡献。这个K-23的总体目的建议是使用17q12 CNV作为原型，以扩大我们对精神分裂症和精神分裂症风险的理解自闭症由稀有遗传变异及其调节的因素赋予。而其他CNV也是与神经精神病风险相关，在战略上，17Q12在战略上很重要，因为仅涉及两个断点这个重排，这意味着该基因座的CNV包括相同的独特基因组序列，支持对个人进行比较。此外，该地区基因中的单个核苷酸变体（SNV）具有与特定的医学相关，但与精神科，表型无关，提供了理解的机会该地区内部的潜水基因如何导致风险增加。最后，经常性的CNV提供了oppor- 对SNV进行调查以研究基因剂量效应，我们已经利用动物的优势了以及目前正在研究该计划的主要导师实验室中正在进行的17q12 CNV的干细胞研究 Posal，Eric Morrow博士。 PI提出的提案，以利用他作为科学董事会成员的长期联系第17季度基金会建立了一个国际合作，多学科小组，专注于低估神经行为表型的删除和重复会议的风险如何。为了实现我们的过度所有人的目标并缩小了上述概述的差距，我们提议纵向评估60个人，其中17q12 dele- tions和60个人有17季度重复。在他的项目中，“一种自闭症和精神分裂的基因组方法 Phrenia风险通过17q12 CNVS”，Moreno de Luca博士将实现这些研究和职业目标通过一段时间的研究时间进行研究，半手，课程，科学会议以及专家指南 - 对他的心理和合作者的支持和支持。 PI提案在开发新型di的方面进行了高级培训基于RDOC，翻译的内表型和人类遗传学伦理的男性评估搜索。