Genetic Influences on Infant Brain Development: Understanding the Developmental Origins of Mental Illness

遗传对婴儿大脑发育的影响：了解精神疾病的发育起源

基本信息

批准号：
10406290
负责人：
Rebecca Knickmeyer
金额：
$ 110.67万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-17 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10406290
关键词：
Aggressive behavior Alzheimer&apos s Disease Anxiety Area Asia Attention deficit hyperactivity disorder Behavior Behavior assessment Behavioral Biological Birth Brain Brain scan Child Child Behavior Childhood Clinical Complex DNA Data Data Set Development Diffusion Magnetic Resonance Imaging Disease Duct (organ) structure Early Intervention Early identification Ethnic Origin Europe Fiber Functional Magnetic Resonance Imaging Future Genes Genetic Genetic Risk Genome Genome Scan Genomic approach Genomics Goals Growth Haplotypes Heritability Human Image Impulsivity Individual Infant Lead Libraries Life Link Longitudinal Studies Magnetic Resonance Imaging Measures Mental disorders Methods Michigan Modeling Molecular Multivariate Analysis Onset of illness Outcome Parietal Participant Pathologic Pathway interactions Pattern Pediatric cohort Phenotype Plant Roots Prevention Preventive Medicine Process Protocols documentation Quality Control Research Research Personnel Resources Rest Risk Scanning Schizophrenia Severities Single Nucleotide Polymorphism Site Source South Africa Structure Surface Symptoms Testing Thick Time United States Variant autism spectrum disorder base behavior measurement behavioral phenotyping behavioral study brain circuitry care outcomes clinical care cohort disability disorder risk early childhood executive function functional genomics genetic variant genome wide association study genomic data high risk indexing infancy innovation insight instrument longitudinal design nervous system development neural circuit neurodevelopment neuroimaging new therapeutic target novel novel therapeutics prevent prophylactic psychiatric genomics risk variant tool trait trait impulsivity

项目摘要

PROJECT SUMMARY Despite decades of research psychiatric disorders continue to be a leading source of disability in the United States and across the world. A key challenge for those seeking to develop new therapeutics is that by the time clinical symptoms of mental illness are recognized, much of the underlying pathologic brain development has already occurred and may be irreversible. Consequently, our best hope of significantly impacting care and out- comes in these devastating disorders is via prevention and very early intervention, which our proposed research will help enable, by integrating genomics with longitudinal, pediatric imaging data and behavioral phenotyping to better understand the developmental origins of mental illness. Our central hypothesis is that genetic variants associated with psychiatric disorders increase risk by influencing early neurodevelopment and the establishment of brain circuitry. This hypothesis is supported by several large-scale studies which performed functional genomic characterization of loci that confer risk for multiple psychiatric disorders and revealed enrichment for genes reg- ulating nervous system development, as well as innovative studies by our group in which we 1) discovered variation in putative risk genes for Alzheimer's disease and mental illness are associated with brain changes at birth, and 2) uncovered new genes and variants implicated in brain development, using GWAS. These findings were based on cross-sectional data, collected close to birth. To more fully understand how DNA variants influ- ence brain development in infancy and early childhood, and potential implications for future research and clinical care, large, longitudinal studies are needed. Our proposed study will meet this need, and test our central hypoth- esis by 1) harmonizing a rich array of genetic, neuroimaging, and behavioral data across 19 large and diverse infant and pediatric cohorts from the U.S., Europe, South Africa, and Asia (N=6809, most with two or more longitudinal brain scans and developmentally appropriate measures of impulsivity, anxiety, and aggressive be- havior); 2) determining how common genetic variants, including those associated with mental illness, influence developmental imaging phenotypes (DIPs) derived from structural MRI, diffusion tensor imaging (DTI), and rest- ing state fMRI; and 3) identifying relationships between genetically-influenced DIPs and clinically-salient behav- iors using powerful multivariate analysis methods. Our research team includes world thought-leaders in infant imaging, genomic approaches to understanding complex traits, and behavioral assessment of infants and young children, all working together as the Organization for Imaging Genomics of Infancy (ORIGIN). We are also part of the ENIGMA consortium and will leverage the intellectual resources of this highly successful group. The ap- plication is innovative in its focus on infancy and early childhood, longitudinal design, and in leveraging a unique global alliance of researchers to create the largest-ever imaging genomics dataset focused on infancy and early childhood. The proposed research will have a positive impact because it will enhance our fundamental under- standing of how genetic factors influence brain development and lay the groundwork for a promising new line of research focused on early intervention in individuals at high risk for developing a psychiatric disorder.

项目概要尽管经过数十年的研究，精神疾病仍然是美国残疾的主要原因各国和世界各地。对于那些寻求开发新疗法的人来说，一个关键的挑战是精神疾病的临床症状已得到认可，许多潜在的病理性大脑发育已经发生已经发生并且可能是不可逆转的。因此，我们最大的希望是显着影响护理和结果这些破坏性疾病的发生是通过预防和非常早期的干预来实现的，我们提出的研究通过将基因组学与纵向、儿科成像数据和行为表型相结合，将有助于实现更好地了解精神疾病的发展起源。我们的中心假设是遗传变异与精神疾病相关的药物通过影响早期神经发育和建立而增加风险的大脑电路。这一假设得到了几项进行功能基因组研究的大规模研究的支持赋予多种精神疾病风险的位点特征，并揭示了基因调节的富集调节神经系统发育，以及我们小组的创新研究，其中我们 1) 发现阿尔茨海默病和精神疾病的假定风险基因的变异与大脑的变化有关出生，2) 使用 GWAS 发现了与大脑发育有关的新基因和变异。这些发现是基于在出生前收集的横截面数据。为了更全面地了解 DNA 变异如何影响婴儿期和幼儿期的大脑发育，以及对未来研究和临床的潜在影响需要护理、大型、纵向研究。我们提出的研究将满足这一需求，并检验我们的中心假设 esis 通过 1) 协调 19 个大型且多样化的丰富的遗传、神经影像和行为数据来自美国、欧洲、南非和亚洲的婴儿和儿科队列（N=6809，大多数有两个或多个纵向脑部扫描以及对冲动、焦虑和攻击性行为进行适当的发育测量行为）； 2) 确定常见的遗传变异（包括与精神疾病相关的变异）如何影响发育成像表型 (DIP) 源自结构 MRI、扩散张量成像 (DTI) 和休息状态功能磁共振成像； 3）确定受遗传影响的 DIP 与临床显着行为之间的关系 iors 使用强大的多变量分析方法。我们的研究团队包括婴儿领域的世界思想领袖成像、理解复杂特征的基因组方法以及婴儿和青少年的行为评估婴儿影像基因组学组织 (ORIGIN) 共同努力。我们也是一部分 ENIGMA 联盟的成员，并将利用这个非常成功的集团的智力资源。该应用程序- 复制的创新之处在于其关注婴儿期和幼儿期、纵向设计以及利用独特的全球研究人员联盟将创建有史以来最大的专注于婴儿期和早期的成像基因组学数据集童年。拟议的研究将产生积极影响，因为它将增强我们的基础知识阐明遗传因素如何影响大脑发育，并为有希望的新系列奠定基础研究重点是对患有精神疾病的高风险个体进行早期干预。