5/9: Dissecting the effects of genomic variants on neurobehavioral dimensions in CNVs enriched for neuropsychiatric disorders

5/9：剖析基因组变异对富含神经精神疾病的 CNV 中神经行为维度的影响

• 批准号: 9761154
• 负责人: JACOB A.S. VORSTMAN
• 金额: $ 54.71万
• 依托单位: HOSPITAL FOR SICK CHLDRN (TORONTO)
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-20 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761154
• 关键词: 16p11.2; 22q11.2; Affect; Algorithms; Anxiety; Anxiety Disorders; Architecture; Attention; Attention deficit hyperactivity disorder; Attentional deficit; Brain; Categories; Clinical; Cognition; Cognitive; Collaborations; Complement; Complex; Computing Methodologies; Copy Number Polymorphism; Custom; Data; Data Analytics; Data Set; Development; Developmental Course; Developmental Delay Disorders; Diagnosis; Dimensions; Disease; Early Intervention; Emotional; Emotions; Environment; Environmental Risk Factor; Evaluation; Family; Family member; Genes; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genetic study; Genomics; Goals; Heterogeneity; Hyperactive behavior; Individual; Institution; Intellectual functioning disability; International; Knowledge; Lead; Literature; Longevity; Measures; Memory; Mental Depression; Mind; Modeling; Molecular; National Institute of Mental Health; Nature; Neurocognition; Online Systems; Outcome; Patients; Phenotype; Population; Positioning Attribute; Psychiatric Diagnosis; Psychopathology; Psychotic Disorders; Public Domains; Recurrence; Resources; Risk; Sampling; Schizophrenia; Social Behavior; Specificity; Structure; Symptoms; Syndrome; Variant; Work; adverse outcome; autism spectrum disorder; base; brain behavior; case control; clinical Diagnosis; clinical phenotype; clinical predictors; cohort; experience; externalizing behavior; genetic architecture; genetic pedigree; genetic variant; genome sequencing; genome wide association study; interest; neurobehavioral; neurobiological mechanism; neuropsychiatric disorder; neuropsychiatry; personalized approach; phenomics; processing speed; prospective; rare genetic disorder; rare variant; recruit; risk prediction model; social; symptomatology; theories; tool; whole genome

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.

项目摘要 国际大脑和行为拷贝数变体联盟（IBBC-CNVS）是一个协作 9个机构的努力，具有现象学和基因组学方面的完整经验和专业知识。 22q11.2 和16p11.2局部与整个生命周期中神经精神疾病的显着风险有关。 临床表现是异质的，表现为一系列发展的神经精神疾病， 包括注意力缺陷多动，焦虑，自闭症谱系和精神病谱系障碍。服用 基于已知的均质遗传病因来确定患者的“遗传学第一”方法将允许 我们克服特发性发展的遗传和表型复杂性构成的障碍 神经精神疾病。我们假设CNVS对心理病理学产生了重要的主要影响，但是 在CNV载体中观察到的心理病理学的性质和程度是多因素的，有贡献 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命中以及其他罕见和常见变体对维度测量的影响 精神病理学可以阐明遗传机制对精神病疾病和 建立风险预测模型。值得注意的是，CNV中的心理病理学的表现和过程类似 这些特征在特发性疾病中。因此，除了研究了特定的遗传综合征之外， 跨CNV工作将确定用于发展神经精神疾病的收敛风险机制 与更广泛的人口相关。 我们建议剖析精神病，社会情感处理和神经认知的维度测量， 以及它们的遗传和环境修饰符，以阐明神经精神病的风险结构 CNV载体中的疾病。与神经精神病学有关的维度测量的前瞻性评估 疾病将应用于22q11.2和16p11.2删除和复制的2000个人群 （每组500）及其亲戚是可行的。此外，将评估分类精神诊断 在CNV载体中。前瞻性表型的招聘将利用现有的大型队列 相互CNV，其中许多已经通过一系列表型来确定和表征 措施。新的全基因组测序（WGS）将在尚未尚未发生的CNV载体中进行 测序。我们还将利用最大的可用病例对照样本中的现有遗传数据 在PGC中诊断为SZ，ASD和ADHD，以产生多基因风险评分。最后，我们将检查 有助于演示和发展课程异质性的家庭和环境因素 在CNV载体中。该项目将建立共同的现象和基因组资源。我们的概念性能力 这样的大规模研究利用了我们现有的成功合作，完整的专业知识和 实现这些目标的机构承诺。