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4/9: Dissecting the effects of genomic variants on neurobehavioral dimensions in CNVs enriched for neuropsychiatric disorders

4/9：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：
10092847
负责人：
Jonathan Sebat
金额：
$ 4.5万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2019-06-20 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10092847
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 neurobiological mechanism 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 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.

项目总结