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

描述(申请人提供)：22q11.2缺失综合征中的大脑和行为国际联合会(22q11DS)是一个由22个机构组成的合作RO1，有一个基因组和四个表型领先站点。这项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可获得的最大样本，包括具有22q11DS的1000名遗传和表型特征个体。在患有22q11DS的青少年和青壮年(~25%-30%)中，其疾病表现和病程与普通人群中的SZ相似(~1%)，发生SZ的风险很大。联盟网站已经在应用整合基因组和脑行为策略研究22q11DS和SZ方面建立了合作关系，并在整个生命周期内拥有丰富的经验。我们将通过集中于SZ和精神病的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，确定它们与精神病的关系(具体目标1)。我们将对600名带有22q11DS的个体进行全基因组测序，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。在成人和儿童人群中，表型和基因组指标的趋同将允许对影响SZ和早期精神病表达的共同遗传变异进行检查。我们将对300名成年人进行WGS：150名患有SZ的22q11DS患者和150名没有精神病症状的22q11DS患者，以及300名22q11DS儿童参与者的22q11DS认知功能减退和精神病倾向表型。随后将对整个样本中所有常见的SNP和CNV进行关联分析。已发现的基因组变异将在未删除的SZ GWAS中进行(特定目标2)。随着不同的方法和工具被应用于评估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利用精神病理学和大脑功能的主要维度的共同措施来推动该领域的发展。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。这一方法将与RDoC以及基因组和神经科学范式的整合(具体目标3)保持一致。国际联合会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放在公共领域(具体目标4)。这项提议的项目将是一项史无前例的国际倡议，旨在检查与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SZ的途径，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.