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

• 批准号: 8141258
• 负责人: BEVERLY S EMANUEL
• 金额: $ 97.26万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-10 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8141258
• 关键词: 22q11; 22q11 Deletion Syndrome; 22q11.2; Accounting; Adolescence; Adolescent; 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; Genetic Variation; 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; cohort; computerized; 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; novel; prodromal psychosis; programs; public health relevance; repository; response; skills; young adult

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. PUBLIC HEALTH RELEVANCE: Schizophrenia (SCZ) is a complex brain disorder with genetic substrates. It often emerges in adolescence and early adulthood with devastating effects. Of individuals with 22q11DS, 23-30% develops the SCZ phenotype, providing a unique opportunity to probe the pathogenesis of SCZ. Integration of genomics and neurobiology is key to understanding the causes of deficits, leading to early detection and advancing novel treatments.

描述(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)合作的RO1。这项合作结合了遗传学和神经生物学范式，以促进对精神分裂症(SCZ)发病机制的理解。CHOP已经建立了最大的可用样本，超过800名患有22q11DS的患者，他们具有良好的遗传学和基因组学特征。患有22q11DS(23%-30%)的青少年和青壮年患SCZ的风险很大，其疾病表现和病程与普通人群中的SCZ相似(1%)。宾夕法尼亚州立大学在SCZ的脑行为研究方面拥有丰富的经验，包括表型表征、计算机化的神经认知测试和提供互补定量表型的神经成像测量。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、神经认知和神经成像表型。该设计将包括使用基于体积的形态测量的磁共振成像(MRI)对大脑结构的年龄分层测量，以及与扩散张量成像(DTI)的连接。功能磁共振成像(FMRI)研究将检测大脑回路对神经行为探针的反应(特定目标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组进行比较。需要这些小组来建立表型特征和量化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、神经行为和神经成像表型的遗传机制，将使用全基因组方法和选定的候选基因来检查与常见SNPs的关联。拷贝数变异(CNV)与SCZ数量表型的关联将在整个基因组和22q11DS区域内的22q11DS样本中进行测试。将对22q11DS区域的基因和缺失患者中选定的候选基因进行下一代深度测序，以确定特定突变或等位基因是否与22q11DS个体SCZ相关内表型的极端值有关(特定目标3)。标本将被送往NIMH储存库进行转化和DNA提取。将维持数据收集和质量控制，并定期将经核实的数据上载到国家卫生系统储存库(具体目标4)。这项拟议的项目将是第一个采用与SCZ相关的共同缺失并阐明其行为、神经生物学和遗传底物的同类项目。除了有可能更好地了解22q11DS的严重表现外，这些结果还将有助于确定在普通人群中导致SCZ的途径，这将为新的治疗方法指明方向。 公共卫生相关性：精神分裂症(SCZ)是一种具有遗传基础的复杂大脑疾病。它通常出现在青春期和成年早期，具有毁灭性的影响。在22q11DS的个体中，23-30%的人发展为SCZ表型，这为探索SCZ的发病机制提供了独特的机会。基因组学和神经生物学的结合是了解缺陷原因、导致早期发现和推进新治疗方法的关键。