2/2 Brain, Behavior and Genetic Studies of the 22q11 Deletion Studies

2/2 22q11 缺失研究的大脑、行为和遗传研究

基本信息

批准号：
8690149
负责人：
BEVERLY S EMANUEL
金额：
$ 88.33万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-10 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8690149
关键词：
22q11 22q11 Deletion Syndrome 22q11.2 Accounting Adolescence Adolescent and Young Adult Affect Age Alleles Anxiety Archives Attention Behavioral Behavioral Genetics Brain Brain Diseases Candidate Disease Gene Cardiac Caucasians Caucasoid Race Cell Line Cells Characteristics Cleft Palate Clinical Cognitive Collaborations Complex Congenital Heart Defects DNA Data Data Collection Data Quality Databases Development Diagnostic Diffusion Magnetic Resonance Imaging Early Diagnosis Emotions Equilibrium Face Functional Magnetic Resonance Imaging Future General Population Genes Genetic Genetic Risk Genome Genomics Genotype Goals Guidelines Housing Impairment Incidence Individual Intake Magnetic Resonance Imaging Measures Memory Mutation National Institute of Mental Health Neurobiology Neurocognition Neurocognitive Neurocognitive Deficit Pathogenesis Pathway interactions Patients Pattern Pediatric Hospitals Pennsylvania Performance Phenotype Philadelphia Principal Investigator Process Psychotic Disorders Quality Control Relative (related person)Resources Risk Sampling Schizophrenia Severities Specimen Speed Structure Subgroup Symptoms System Testing Universities Update Variant Verbal Learning base brain behavior brain volume clinical risk cohort computerized deep sequencing design disturbance in affect emerging adult endophenotype executive function experience follow-up genetic pedigree genome wide association study genome-wide insertion/deletion mutation morphometry neurobehavioral neurocognitive test neuroimaging neuropsychiatry next generation sequencing novel prodromal psychosis programs psychotic symptoms rare variant repository response skills young adult

项目摘要

DESCRIPTION (provided by applicant): Brain-Behavior and Genetic Studies of the 22q11DS is a collaborative RO1 between Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania (Penn). The collaboration combines genetic and neurobiologic paradigms to advance understanding of the pathogenesis of schizophrenia (SCZ). CHOP has established the largest available sample of over 800 patients with 22q11DS who have been well characterized by genetics and genomics. There is a substantial risk for developing SCZ in adolescents and young adults with 22q11DS (23-30%), with illness presentation and course similar to SCZ in the general population (1%). Penn has extensive experience in brain-behavior studies in SCZ including phenotypic characterization, computerized neurocognitive testing, and neuroimaging measures that provide complementary quantitative phenotypes. The goal of the collaboration is to capitalize on this unique sample of 22q11DS and obtain neuropsychiatric, neurocognitive, and neuroimaging phenotypes of brain structure and function. The design will include age- stratified measures of brain structure with Magnetic Resonance Imaging (MRI) using volume-based morphometry, and connectivity with Diffusion Tensor Imaging (DTI). Functional MRI (fMRI) studies will examine brain circuitry activated in response to neurobehavioral probes (Specific Aim 1). The neuropsychiatric, neurobehavioral and neuroimaging phenotypes in 22q11DS will be compared to patients with SCZ, those at clinical and genetic risk for SCZ, and cardiac and healthy controls. These groups are needed to establish the profile of phenotypic features and quantitative brain-behavior measures and their interactions (Specific Aim 2). To establish genetic mechanisms producing the neuropsychiatric, neurobehavioral and neuroimaging phenotypes, association with common SNPs will be examined using a genome-wide approach and selected candidate genes. Associations of copy number variants (CNVs) with SCZ quantitative phenotypes will be tested in 22q11DS samples both across the genome and within the 22q11DS region. Deep next generation sequencing on the "non-deleted" allele will be performed for genes in the 22q11DS region and selected candidate genes in patients with the deletion to determine whether specific mutations or alleles are associated with extreme values of SCZ-related endophenotypes in 22q11DS individuals (Specific Aim 3). Specimens will be sent to the NIMH repository for transformation and DNA extraction. Data collection and quality control will be maintained and verified data will be regularly uploaded to the NIMH repository (Specific Aim 4). The proposed project will be the first of its kind to take a common deletion associated with SCZ and elucidate its behavioral, neurobiological and genetic substrates. Beyond the potential for yielding a better understanding of a severe manifestation of 22q11DS, the results will help identify pathways leading to SCZ in the general population in a way that will point to novel treatments.

描述（由申请人提供）：22q11DS 的大脑行为和遗传研究是费城儿童医院 (CHOP) 和宾夕法尼亚大学 (Penn) 之间的合作 RO1。此次合作结合了遗传和神经生物学范式，以增进对精神分裂症（SCZ）发病机制的理解。 CHOP 已建立了超过 800 名 22q11DS 患者的最大可用样本，这些患者已通过遗传学和基因组学进行了详细表征。患有 22q11DS 的青少年和年轻人 (23-30%) 存在发生 SCZ 的巨大风险，其疾病表现和病程与一般人群中的 SCZ 相似 (1%)。 Penn 在 SCZ 的大脑行为研究方面拥有丰富的经验，包括表型表征、计算机化神经认知测试和提供补充定量表型的神经影像测量。此次合作的目标是利用这一独特的 22q11DS 样本，获得大脑结构和功能的神经精神、神经认知和神经影像表型。该设计将包括使用基于体积的形态测量的磁共振成像（MRI）对大脑结构进行年龄分层测量，以及与扩散张量成像（DTI）的连接。功能性 MRI (fMRI) 研究将检查响应神经行为探针而激活的大脑回路（具体目标 1）。 22q11DS 的神经精神、神经行为和神经影像表型将与 SCZ 患者、具有 SCZ 临床和遗传风险的患者以及心脏和健康对照进行比较。这些小组需要建立表型特征和定量大脑行为测量及其相互作用的概况（具体目标 2）。为了建立产生神经精神、神经行为和神经影像表型的遗传机制，将使用全基因组方法和选定的候选基因来检查与常见 SNP 的关联。将在整个基因组和 22q11DS 区域内的 22q11DS 样本中测试拷贝数变异 (CNV) 与 SCZ 定量表型的关联。将对 22q11DS 区域的基因和缺失患者中选定的候选基因进行“非删除”等位基因的深度下一代测序，以确定特定突变或等位基因是否与 22q11DS 个体中 SCZ 相关内表型的极值相关（具体目标 3）。样本将被送往 NIMH 储存库进行转化和 DNA 提取。将维护数据收集和质量控制，并定期将验证数据上传到 NIMH 存储库（具体目标 4）。该项目将是同类项目中第一个采用与 SCZ 相关的常见缺失并阐明其行为、神经生物学和遗传底物的项目。除了有可能更好地了解 22q11DS 的严重表现之外，这些结果还将有助于确定普通人群中导致 SCZ 的途径，从而为新的治疗方法指明方向。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Neurocognitive profile in psychotic versus nonpsychotic individuals with 22q11.2 deletion syndrome.

22q11.2 缺失综合征精神病患者与非精神病患者的神经认知特征。

DOI：
发表时间：
2016-10
期刊：
影响因子：
0
作者：
Weinberger, Ronnie;Yi, James;Calkins, Monica;Guri, Yael;McDonald;Emanuel, Beverly S;Zackai, Elaine H;Ruparel, Kosha;Carmel, Miri;Michaelovsky, Elena;Weizman, Abraham;Gur, Ruben C;Gur, Raquel E;Gothelf, Doron
通讯作者：
Gothelf, Doron

22q11.2 deletion syndrome in diverse populations.

不同人群中的 22q11.2 缺失综合征。

DOI：
发表时间：
2017-04
期刊：
影响因子：
0
作者：
Kruszka, Paul;Addissie, Yonit A;McGinn, Daniel E;Porras, Antonio R;Biggs, Elijah;Share, Matthew;Crowley, T Blaine;Chung, Brian H Y;Mok, Gary T K;Mak, Christopher C Y;Muthukumarasamy, Premala;Thong, Meow;Sirisena, Nirmala D;Dissanayake
通讯作者：
Dissanayake

Anatomic Malformations of the Middle and Inner Ear in 22q11.2 Deletion Syndrome: Case Series and Literature Review.

22q11.2 缺失综合征中中耳和内耳的解剖畸形：病例系列和文献综述。