1/9: Dissecting the effects of genomic variants on nenriched for neuropsychiatric disorderseurobehavioral dimensions in CNVs

项目摘要 脑和行为拷贝数变异国际联盟（IBBC-CNVs）是一个合作组织， 在表型组学和基因组学方面具有互补经验和专门知识的9个机构的努力。22q11.2 16p11.2位点与终生神经精神疾病的显著风险相关。的 临床表现是异质性的，表现为一系列发育性神经精神障碍， 包括注意力缺陷多动症、焦虑症、自闭症谱系和精神病谱系障碍。以 根据已知的、同质的遗传病因确定患者的“遗传学优先”方法将允许 我们克服特发性发育障碍的遗传和表型复杂性所构成的障碍， 神经精神障碍我们假设CNVs对精神病理学有很大的主要影响，但是 在CNV携带者中观察到的精神病理学的性质和程度是多因素的， 其他罕见和常见的遗传变异，以及环境因素。因此，解剖 主要CNV命中以及额外的罕见和常见变异对 精神病理学可以阐明遗传机制对精神疾病的综合作用， 建立风险预测模型。值得注意的是，CNVs中精神病理学的表现和过程类似于 这些特发性疾病的特征。因此，除了所研究的特定遗传综合征之外， 跨CNV的努力将确定发育性神经精神障碍的会聚风险机制， 与更广泛的人群有关。 我们建议剖析精神病、社会情绪处理和神经认知的维度测量， 及其遗传和环境修饰剂，以阐明神经精神疾病风险的结构， CNV携带者的疾病。与神经精神相关的维度测量的前瞻性评估 将对2000名22q11.2和16p11.2缺失和重复的个体的队列进行研究 (500他们的亲戚和亲戚都是亲戚。此外，将评估精神病分类诊断 CNV携带者前瞻性表型分析的招募将利用携带这些基因的现有大型队列。 相反的CNVs，其中许多已经被确定和表征与一系列的表型 措施新的全基因组测序（WGS）将在尚未被证实的CNV携带者中进行。 测序我们还将利用来自最大可用病例对照样本的现有遗传数据 在PGC中诊断为SZ、ASD和ADHD，以生成多基因风险评分。最后，我们将研究 家庭和环境因素，有助于表现和发展过程的异质性 CNV携带者该项目将建立共同的表型和基因组资源。我们受孕的能力 如此大规模的研究利用了我们现有的成功合作，互补的专业知识， 实现这些目标的机构承诺。

PROJECT SUMMARY The International Consortium on Brain and Behavior Copy Number Variants (IBBC-CNVs) is a collaborative effort of 9 institutions with complementary experience and expertise in phenomics and genomics. The 22q11.2 and 16p11.2 loci are associated with significant risk for neuropsychiatric disorders across the lifespan. The clinical presentations are heterogeneous, manifesting in a range of developmental neuropsychiatric disorders, including Attention Deficit Hyperactivity, Anxiety, Autism Spectrum, and Psychosis Spectrum Disorders. Taking a `genetics first' approach of ascertaining patients based on known, homogeneous genetic etiologies will allow us to overcome barriers posed by the genetic and phenotypic complexity of idiopathic developmental neuropsychiatric disorders. We postulate that CNVs exert a large main effect on psychopathology, but the nature and degree of psychopathology observed in CNV carriers is multifactorial, with contributions from additional rare and common genetic variants, as well as environmental factors. Therefore, dissecting the effects of major CNV hits as well as additional rare and common variants on dimensional measures of psychopathology can elucidate the combined contribution of genetic mechanisms to psychiatric conditions and build models of risk prediction. Notably, the presentation and course of psychopathology in the CNVs resemble these features in idiopathic disorders. Therefore, beyond the specific genetic syndromes investigated, such a cross-CNV effort will identify convergent risk mechanisms for developmental neuropsychiatric disorders that are of relevance to the broader population. We propose to dissect dimensional measures of psychosis, social-emotional processing and neurocognition, and their genetic and environmental modifiers, to elucidate the architecture of risk for neuropsychiatric disorders in CNV carriers. Prospective evaluation with dimensional measures relevant to neuropsychiatric disorders will be applied to a cohort of 2000 individuals with 22q11.2 and 16p11.2 deletions and duplications (500 per group) and their relatives as feasible. In addition, categorical psychiatric diagnoses will be assessed in CNV carriers. Recruitment for prospective phenotyping will leverage existing large cohorts that carry these reciprocal CNVs, many of whom have already been ascertained and characterized with a range of phenotypic measures. New whole genome sequencing (WGS) will be performed in CNV carriers that have not yet been sequenced. We will also utilize existing genetic data from the largest available case-control samples diagnosed with SZ, ASD, and ADHD in the PGC to generate polygenic risk scores. Finally, we will examine family and environmental factors that contribute to the heterogeneity of presentation and developmental course in CNV carriers. This project will establish common phenomic and genomic resources. Our ability to conceive such a large-scale study capitalizes on our existing successful collaborations, complementary expertise, and institutional commitments to achieve these goals.