The schizophrenia-associated 3q29 deletion: genetic architecture of behavioral phenotypes

精神分裂症相关的 3q29 缺失：行为表型的遗传结构

基本信息

批准号：
10579244
负责人：
MICHAEL PHILIP EPSTEIN
金额：
$ 77.82万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-24 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579244
关键词：
1q21 22q11.2 3q29 Address Anxiety Disorders Articulation Attention deficit hyperactivity disorder Attenuated Basic Science Biological Biology Brain Diseases Caring Collaborations Collection Communities DNA Data Development Dimensions Disease Enrollment Ensure Evaluation Executive Dysfunction Exhibits Feasibility Studies Frequencies Genes Genetic Genomics Genotype Goals Heterogeneity Individual Investigation Knowledge Lesion Mental Health Mental disorders National Institute of Mental Health Neurodevelopmental Disorder Parents Phenotype Population Prevalence Protocols documentation Psychoses Psychotic Disorders Registries Risk Sampling Sampling Studies Schizophrenia Severities Side Site Social Behavior Social Functioning Study Subject Surveys Symptoms Syndrome Testing Travel Universities Work autism spectrum disorder behavioral phenotyping burden of illness clinical phenotype clinical translation clinically significant cognitive ability cognitive disability cohort comorbidity cost database of Genotypes and Phenotypes disability executive function experience genetic architecture genome sequencing high risk high risk population improved neuropsychiatric disorder neuropsychiatry pandemic disease patient mobility phenotypic data proband psychosis risk public database rare genetic disorder rare variant recruit remote assessment schizophrenia risk sex social whole genome

项目摘要

Summary 3q29 deletion syndrome is caused by a typically de novo 1.6 Mb deletion of 21 genes. The syndrome is associated with an astonishing 40-fold increased risk for schizophrenia, as well as cognitive disability, a high rate of autism and social disability, executive function deficits and pronounced prevalence of attention deficit hyperactivity disorder (ADHD), clinically significant graphomotor weakness, and manifestation of anxiety disorders. The factors that contribute to this phenotypic heterogeneity are not understood. We propose to evaluate 200 individuals with the 3q29 deletion, to better define phenotypic manifestations and identify risk modifiers for key phenotypes. In particular, we seek to understand how polygenic background and sex of the proband may modify risk for psychosis, cognitive disability, social functioning, and other phenotypes. To facilitate our evaluation and attenuate ascertainment bias, we have developed a remote phenotyping battery, which does not require travel to a testing site. This remote battery removes barriers to participation for our study subjects and dramatically reduces costs, improving the efficiency of our study. Using this validated phenotyping protocol, we will characterize 200 new study subjects with the 3q29 deletion, and identify the full phenotypic spectrum, sex-dependent phenotypic risks and significant comorbid relationships. We will also phenotype biological parents to contextualize the burden of illness in 3q29 deletion syndrome relative to departure from mid-parental phenotype, and clarify the range of phenotypic heterogeneity in 3q29 deletion syndrome. We will collect DNA from our study subjects, to directly test the contribution of polygenic risk to selected phenotypes. Finally, in a collaboration with the NIMH-sponsored Genes 2 Mental Health Network, we will compare the phenotypic spectrum and risk modifiers of 3q29 deletion syndrome with >2,000 samples from other genomic disorders associated with neurodevelopmental and neuropsychiatric disorders, including 22q11.2 deletion and duplication, 16p11 deletion and duplication, 1q21 deletion, and others. At the end of this project, we will have a comprehensive survey of 3q29 deletion associated phenotypes, an understanding of how sex and polygenic background may increase or attenuate phenotypic risks in 3q29 deletion syndrome, and an appreciation for how the 3q29 deletion compares to the broader landscape of rare genetic disorders associated with developmental brain disorders. All genotype and phenotype data from this study will be shared in publicly-available databases, including dbGaP and NDAR.

概括 3q29 缺失综合征是由 21 个基因的 1.6 Mb 通常从头缺失引起的。该综合症是与精神分裂症以及认知障碍的风险增加惊人的 40 倍相关，自闭症和社交障碍、执行功能缺陷和注意力缺陷的显着患病率多动症 (ADHD)、临床显着的书写运动无力和焦虑表现失调。造成这种表型异质性的因素尚不清楚。我们建议评估 200 名 3q29 缺失个体，以更好地定义表型表现并识别风险关键表型的修饰符。特别是，我们试图了解多基因背景和性别如何先证者可能会改变精神病、认知障碍、社会功能和其他表型的风险。到为了促进我们的评估并减少确定偏差，我们开发了一种远程表型电池，不需要前往测试地点。这种远程电池消除了我们参与的障碍研究科目并大大降低成本，提高我们的研究效率。使用这个经过验证的表型分析方案中，我们将表征 200 个具有 3q29 缺失的新研究对象，并确定完整的表型谱、性别依赖性表型风险和显着的共病关系。我们也会表型亲生父母将 3q29 缺失综合征的疾病负担与偏离中亲本表型，并阐明 3q29 缺失中表型异质性的范围综合症。我们将从研究对象中收集 DNA，以直接测试多基因风险对选定的表型。最后，通过与 NIMH 赞助的 Genes 2 心理健康网络合作，我们将比较 3q29 缺失综合征的表型谱和风险修饰因子与超过 2,000 个样本与神经发育和神经精神疾病相关的其他基因组疾病，包括 22q11.2 缺失和重复、16p11 缺失和重复、1q21 缺失等。在这最后项目中，我们将对3q29缺失相关表型进行全面调查，了解性别和多基因背景如何增加或减弱 3q29 缺失综合征的表型风险，以及了解 3q29 缺失与更广泛的罕见遗传疾病的比较与大脑发育障碍有关。本研究的所有基因型和表型数据将被共享在公开可用的数据库中，包括 dbGaP 和 NDAR。