1/5 International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome

1/5 22q11.2 缺失综合征大脑与行为国际联盟

• 批准号: 8911374
• 负责人: Raquel E Gur
• 金额: $ 66.11万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-26 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8911374
• 关键词: 22q11.2; Adolescence; Adolescent and Young Adult; Adult; Alleles; Attention; Australia; Autistic Disorder; Belgium; Bioinformatics; Brain; Brain Diseases; Canada; Childhood; Chile; Collaborations; Communication; Communities; Complex; Consensus; Copy Number Polymorphism; DNA; Data; Data Set; Databases; Development; Dimensions; Disease; Early Diagnosis; Elements; Europe; Foundations; France; General Population; Genes; Genetic; Genetic Variation; Genome; Genomic approach; Genomics; Health; Hereditary Disease; Heterogeneity; Human Genetics; Impaired cognition; Impairment; Individual; Institution; International; Ireland; Israel; Italy; Lead; London; Longevity; Longitudinal Studies; Measures; Methods; Modeling; National Heart, Lung, and Blood Institute; National Institute of Mental Health; Netherlands; Neurocognitive; Neurosciences; Participant; Pathogenesis; Pathway interactions; Patients; Phenotype; Population; Procedures; Psychopathology; Psychotic Disorders; Public Domains; Quality Control; Recording of previous events; Research Domain Criteria; Research Infrastructure; Resources; Risk; Role; Rome; Sample Size; Sampling; Schizophrenia; Single Nucleotide Polymorphism; Site; Spain; Specimen; Subgroup; Switzerland; Symptoms; Syndrome; Validation; Variant; Verbal Learning; base; behavioral genomics; brain behavior; cohort; computerized; data sharing; disturbance in affect; emerging adult; executive function; experience; genetic risk factor; genetic variant; genome sequencing; genome wide association study; genome-wide; genomic variation; instrument; neurobehavior; neurobehavioral; neuropsychiatry; next generation sequencing; novel; prospective; psychotic symptoms; social cognition; tool; working group; young adult

DESCRIPTION (provided by applicant): The International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome (22q11DS) is a collaborative RO1 of 22 institutions, with one genomic and four phenotyping leading sites. The collaboration combines genomic with neuropsychiatric and neurobehavioral paradigms to advance the understanding of the pathogenesis of schizophrenia (SZ) and related phenotypes. The Consortium provides the largest available sample to date of 1000 genetically and phenotypically characterized individuals with 22q11DS. There is a substantial risk for developing SZ in adolescents and young adults with 22q11DS (~25-30%), with illness presentation and course similar to SZ in the general population (~1%). Consortium sites have established collaborations with extensive experience in applying integrative genomic and brain-behavior strategies to study 22q11DS and SZ across the lifespan. We will examine neuropsychiatric features through an integrated consensus focusing on SZ and emergence of psychosis. Neurobehavioral measures will be investigated across domains, establishing their relation to psychosis (Specific Aim 1). We will conduct whole genome sequencing (WGS) on 600 individuals with 22q11DS to uncover genetic variation that may contribute to the heterogeneity of neuropsychiatric and neurobehavioral phenotypes of SZ and psychosis. The convergence of phenotypic and genomic measures in adult and pediatric populations will permit examination of shared genetic variants that influence the expression of SZ and early psychosis. We will perform WGS on 300 adults using phenotypic "extremes": 150 22q11DS individuals with SZ and 150 22q11DS individuals without psychotic symptoms, as well as 300 pediatric participants with 22q11DS phenotyped by cognitive decline and psychosis proneness. This will be followed by association analysis on all common SNPs and CNVs in the entire sample. The discovered genomic variation will be followed in non-deleted SZ GWAS (Specific Aim 2). As diverse approaches and instruments are applied in assessing neuropsychiatric and neurobehavioral phenotypes in 22q11DS, the Consortium can advance the field by developing and piloting common measures that tap major dimensions of psychopathology and brain function. This will enhance the integration of phenotypic and genomic data, lay the foundation for a systematic approach internationally and provide a framework for longitudinal studies. This approach will cohere with RDoC and integration of genomic and neuroscience paradigms (Specific Aim 3). The resource built by the international Consortium will be a platform for data sharing as tools created, specimens collected and high fidelity data are placed in the public domain (Specific Aim 4). The proposed project will be an unprecedented international initiative to examine a common deletion associated with SZ and elucidate its genomic and behavioral substrates. Beyond the potential for yielding a better understanding of a severe manifestation of 22q11DS, the results will help identify pathways leading to SZ in the general population in a way that will inform novel treatments.

描述（由申请人提供）：22Q11.2缺失综合征（22q11ds）的国际大脑和行为联盟是22个机构的协作RO1，其中一个基因组和4个表型领先地点。该协作将基因组与神经精神病学和神经行为范式结合在一起，以提高人们对精神分裂症（SZ）和相关表型发病机理的理解。该财团提供了最大的可用样本，迄今为止，具有22q11ds的遗传和表型表征的个体。在22q11ds（约25-30％）的青少年和年轻人中发展SZ的风险很大，疾病表现和类似于一般人群的SZ（约1％）。财团站点建立了在应用整个生命周期中研究22q11ds和SZ的综合基因组和脑行为策略方面具有丰富经验的合作。我们将通过集中的共识和精神病的出现来检查神经精神病特征。神经行为措施将在跨领域进行研究，从而确定其与精神病的关系（特定目标1）。我们将对600个患有22q11ds的个体进行全基因组测序（WGS），以发现遗传变异，这可能有助于SZ和精神病的神经精神病和神经行为表型的异质性。成人和小儿种群中表型和基因组度量的收敛性将允许检查影响SZ表达和早期精神病的共同遗传变异。我们将使用表型“极端”对300名成年人进行WG：150 22q11ds患有SZ和150 22q11ds的人，没有精神病性症状，以及300名儿科参与者，由认知能力下降和精神病primentense度进行了22q11ds。随后将对整个样本中所有常见的SNP和CNV进行关联分析。 发现的基因组变异将在未删除的SZ GWAS中遵循（特定目标2）。随着22q11ds中的神经精神病学和神经行为表型的各种方法和工具被应用于评估神经精神病学和神经行为的表型，财团可以通过制定和试行共同的措施来攻击心理病理学和大脑功能的主要维度，从而推进该领域。这将增强表型和基因组数据的整合，为在国际上进行系统的方法奠定了基础，并为纵向研究提供了框架。这种方法将与RDOC和基因组和神经科学范式的整合（特定目标3）相吻合。国际财团建立的资源将是一个数据共享的平台，随着创建的工具，收集的标本和高保真数据放置在公共领域中（特定目标4）。拟议的项目将是一项前所未有的国际倡议，旨在检查与SZ相关的共同缺失并阐明其基因组和行为底物。除了能够更好地理解22q11ds的严重表现的潜力之外，结果还将有助于识别导致普通人群中SZ的途径，从而为新颖的治疗提供依据。