3/9 Dissecting the effects of genomic variants on neurobehavioral dimensions in CNVs enriched for neuropsychiatric disorders

3/9 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: 10083537
• 负责人: CARRIE E BEARDEN
• 金额: $ 7.19万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10083537
• 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; 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; genomic locus; interest; large scale data; neurobehavioral; neuropsychiatric disorder; neuropsychiatry; personalized approach; phenomics; polygenic risk score; 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. Finally, analysis of common variants for a subset of family members will allow us to complement our primary analysis by exploring models of complex genetic inheritance in extended pedigrees that carry CNVs. 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，具有互补的经验和现象学和基因组学专业知识。 22q11.2 和16p11.2基因座与整个生命周期中神经精神疾病的显着风险有关。这 临床表现是异质的，表现为一系列发育性神经精神疾病， 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CNV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， 交叉CNV工作将确定发育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 神经认知及其遗传和环境修饰剂，以阐明 CNV载体中的神经精神疾病。与与维度措施有关的预期评估 神经精神疾病将应用于22q11.2和16p11.2删除的2000个人群 和重复（每组500）及其亲戚是可行的。此外，分类精神病诊断 将在CNV载体中进行评估。前瞻性表型招聘将利用现有的大型队列 携带这些相互CNV，其中许多已经确定和表征 表型测量范围。新的全基因组测序（WGS）将在CNV载体中进行 尚未被测序。我们还将利用最大可用病例控制的现有遗传数据 PGC中被诊断为SZ，ASD和ADHD的样品。最后，分析一个子集的常见变体 家庭成员将允许我们通过探索复杂遗传的模型来补充我们的主要分析 携带CNV的扩展血统的继承。我们构想如此大规模研究的能力使 关于我们现有的成功合作，补充专业知识和机构承诺以实现 这些目标。