"4/5 International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome"

“4/5 22q11.2 缺失综合征大脑与行为国际联盟”

基本信息

批准号：
8911375
负责人：
Ann Swillen
金额：
$ 33.06万
依托单位：
KATHOLIEKE UNIVERSITEIT LEUVEN
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-26 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8911375
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

项目摘要

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）：国际 22q11.2 缺失综合征大脑与行为联盟 (22q11DS) 是一个由 22 个机构组成的协作 RO1，拥有 1 个基因组和 4 个表型领先位点。此次合作将基因组学与神经精神病学和神经行为学范式相结合，以增进对精神分裂症 (SZ) 发病机制和相关表型的理解。该联盟提供了迄今为止最大的可用样本，其中包括 1000 个具有 22q11DS 遗传和表型特征的个体。患有 22q11DS 的青少年和年轻人 (~25-30%) 存在发生 SZ 的巨大风险，其疾病表现和病程与普通人群中的 SZ 相似 (~1%)。联盟站点已经建立了合作关系，在应用综合基因组和大脑行为策略来研究 22q11DS 和 SZ 的整个生命周期方面拥有丰富的经验。我们将通过关注 SZ 和精神病出现的综合共识来检查神经精神特征。将跨领域研究神经行为测量，确定其与精神病的关系（具体目标 1）。我们将对 600 名 22q11DS 个体进行全基因组测序 (WGS)，以揭示可能导致 SZ 和精神病的神经精神和神经行为表型异质性的遗传变异。成人和儿童群体表型和基因组测量的融合将允许检查影响 SZ 和早期精神病表达的共享遗传变异。我们将对 300 名使用表型“极端”的成年人进行全基因组测序：150 名患有 SZ 的 22q11DS 个体和 150 名没有精神病症状的 22q11DS 个体，以及 300 名患有认知能力下降和精神病倾向的 22q11DS 表型的儿童参与者。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 中进行追踪（具体目标 2）。随着不同的方法和仪器被应用于评估 22q11DS 的神经精神和神经行为表型，该联盟可以通过开发和试点挖掘精神病理学和大脑功能主要维度的通用措施来推进该领域的发展。这将加强表型和基因组数据的整合，为国际系统方法奠定基础，并为纵向研究提供框架。这种方法将与 RDoC 以及基因组和神经科学范式的整合相一致（具体目标 3）。国际联盟建立的资源将成为一个数据共享平台，因为创建的工具、收集的标本和高保真数据将被放置在公共领域（具体目标 4）。拟议的项目将是一项前所未有的国际举措，旨在检查与 SZ 相关的常见缺失并阐明其基因组和行为基础。除了能够更好地了解 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 SZ 的途径，从而为新的治疗方法提供信息。