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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要国际脑与行为拷贝数变异联盟 (IBBC-CNVs) 是一个协作组织由 9 个在表型组学和基因组学方面具有互补经验和专业知识的机构共同努力。 22q11.2 和 16p11.2 位点与整个生命周期中神经精神疾病的显着风险相关。这临床表现多种多样，表现为一系列发育性神经精神疾病，包括注意力缺陷多动症、焦虑症、自闭症谱系障碍和精神病谱系障碍。服用基于已知的同质遗传病因来确定患者的“遗传学优先”方法将允许我们克服特发性发育的遗传和表型复杂性所造成的障碍神经精神疾病。我们假设 CNV 对精神病理学发挥着巨大的主效应，但在 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，其中包括其他罕见和常见的遗传变异以及环境因素。因此，剖析主要 CNV 命中以及其他罕见和常见变异对维度测量的影响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，CNV 中精神病理学的表现和过程类似于特发性疾病的这些特征。因此，除了所研究的特定遗传综合征之外，这样的跨 CNV 的努力将确定发育性神经精神疾病的趋同风险机制，这些疾病与更广泛的人群相关。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调节剂，以阐明风险的结构 CNV 携带者的神经精神疾病。使用相关维度测量进行前瞻性评估神经精神疾病将应用于 2000 名 22q11.2 和 16p11.2 缺失个体的队列和重复（每组 500 个）及其亲属（如果可行）。此外，明确的精神科诊断将在 CNV 运营商中进行评估。前瞻性表型招募将利用现有的大型队列携带这些相互的CNV，其中许多已经被确定并具有特征表型测量的范围。新的全基因组测序 (WGS) 将在 CNV 携带者中进行尚未测序。我们还将利用来自最大的可用病例对照的现有遗传数据在 PGC 中诊断出患有 SZ、ASD 和 ADHD 的样本。最后，对一个子集的常见变体进行分析家庭成员将使我们能够通过探索复杂遗传模型来补充我们的初步分析携带 CNV 的扩展谱系的遗传。我们有能力构思如此大规模的研究基于我们现有的成功合作、互补的专业知识和机构承诺，以实现这些目标。