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（22 q11 DS）脑和行为国际联盟是22个机构的协作RO 1，具有一个基因组和四个表型分析领先位点。该合作将基因组与神经精神和神经行为范式相结合，以促进对精神分裂症（SZ）和相关表型发病机制的理解。该联盟提供了迄今为止最大的可用样本，包括1000个具有22 q11 DS遗传和表型特征的个体。患有22 q11 DS的青少年和年轻成人（~25-30%）发生SZ的风险很大，疾病表现和病程与一般人群中的SZ相似（~1%）。联盟的研究中心已经建立了合作，在应用整合基因组和脑行为策略研究22 q11 DS和SZ的整个生命周期方面拥有丰富的经验。我们将通过集中在SZ和精神病出现的综合共识来检查神经精神病学特征。将跨领域研究神经行为测量，建立其与精神病的关系（具体目标1）。我们将对600名22 q11 DS患者进行全基因组测序（WGS），以揭示可能导致SZ和精神病神经精神和神经行为表型异质性的遗传变异。在成人和儿童人群的表型和基因组措施的收敛将允许检查影响SZ和早期精神病的表达的共享遗传变异。我们将使用表型“极端”对300名成人进行WGS：150名22 q11 DS SZ个体和150名22 q11 DS无精神病症状个体，以及300名22 q11 DS表型为认知下降和精神病倾向的儿童参与者。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非缺失型SZ GWAS（特定目标2）中进行跟踪。随着不同的方法和工具被应用于评估22 q11 DS中的神经精神和神经行为表型，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，为国际上的系统方法奠定基础，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都被置于公共领域（具体目标4）。拟议的项目将是一个前所未有的国际倡议，以检查与SZ相关的常见缺失，并阐明其基因组和行为底物。除了可能更好地了解22 q11 DS的严重表现外，这些结果将有助于确定导致一般人群中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.