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

描述（由申请人提供）：22q11.2缺失综合征脑与行为国际联盟（22q11DS）是一个由22个机构组成的合作RO1，拥有一个基因组和四个表型领先位点。该合作将基因组学与神经精神病学和神经行为范式相结合，以促进对精神分裂症（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1000个22q11DS遗传和表型特征个体样本。患有22q11DS的青少年和年轻人发生SZ的风险很大（~25-30%），其疾病表现和病程与一般人群中的SZ相似（~1%）。在应用整合基因组和脑行为策略研究22q11DS和SZ的整个生命周期方面，联盟站点已经建立了广泛的合作关系。我们将通过对SZ和精神病出现的综合共识来检查神经精神病学特征。神经行为测量将跨领域进行调查，建立它们与精神病的关系（具体目标1）。我们将对600名22q11DS患者进行全基因组测序（WGS），以发现可能导致SZ和精神病神经精神和神经行为表型异质性的遗传变异。在成人和儿童人群中，表型和基因组测量的趋同将允许检查影响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WGS: 150名患有SZ的22q11DS个体和150名无精神病症状的22q11DS个体，以及300名具有认知能力下降和精神病倾向表型的22q11DS儿童参与者。随后将对整个样本中所有常见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（Specific Aim 2）。随着22q11DS中神经精神和神经行为表型的评估方法和工具的多样化，该联盟可以通过开发和试点利用精神病理学和脑功能主要维度的通用措施来推进该领域。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以及基因组学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数据共享的平台，因为创建的工具、收集的标本和高保真数据将被置于公共领域（具体目标4）。该项目将是一项前所未有的国际倡议，旨在研究与SZ相关的常见缺失，并阐明其基因组和行为基础。除了有可能更好地理解22q11DS的严重表现外，该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。

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.