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

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

展开

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缺失引起的。综合征是与令人惊讶的40倍精神分裂症的风险增加以及认知障碍相关，高自闭症和社会残疾的速度，执行功能缺陷以及注意力不足的明显流行率多动症（ADHD），临床上显着的图形运动无力和焦虑表现疾病。尚不清楚导致这种表型异质性的因素。我们建议评估200个具有3Q29删除的人，以更好地定义表型表现并确定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概率可能会改变精神病，认知障碍，社会功能和其他表型的风险。到促进我们的评估并减轻确定性偏见，我们开发了一个远程表型电池，这不需要前往测试地点。这种远程电池消除了我们的参与障碍研究对象和大幅度降低了成本，从而提高了我们的研究效率。使用此验证表型协议，我们将以3Q29删除的200个新研究对象进行表征，并确定完整表型频谱，性依赖性表型风险和显着的合并关系。我们也会表型生物父母在3Q29缺失综合征中的疾病负担背景下从中期表型背离，并阐明3q29缺失中表型异质性的范围综合征。我们将从研究对象中收集DNA，直接测试多基因风险对选定的表型。最后，在与NIMH赞助的基因2心理健康网络的合作中，我们将比较3q29缺失综合征的表型光谱和风险修饰符与来自2,000个样本的样本与神经发育和神经精神疾病有关的其他基因组疾病，包括 22q11.2删除和复制，16p11删除和重复，1q21删除等。最后项目，我们将对3Q29删除相关表型进行全面调查，了解 3Q29缺失综合征中的性别和多基因背景如何增加或衰减表型风险，并感谢3Q29缺失与稀有遗传疾病的更广泛景观相比与发育性脑部疾病有关。这项研究的所有基因型和表型数据将共享在包括DBGAP和NDAR在内的公共数据库中。