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

• 批准号: 10217435
• 负责人: Rebecca Knickmeyer
• 金额: $ 133.92万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 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/10217435
• 关键词: Aggressive behavior; Alzheimer' 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

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.

项目摘要 尽管经过几十年的研究，精神疾病仍然是美国残疾的主要来源。 国家和世界各地。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得到承认，许多潜在的病理性大脑发育已经被发现。 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著影响护理和外出- 是通过预防和非常早期的干预， 将有助于通过整合基因组学与纵向，儿科成像数据和行为表型， 更好地了解精神疾病的发展起源。我们的核心假设是基因变异 与精神疾病相关的疾病通过影响早期神经发育和建立 大脑回路的一部分这一假设得到了几项大规模研究的支持，这些研究进行了功能基因组学研究。 表征赋予多种精神疾病风险的基因座，并揭示基因reg- 刺激神经系统发育，以及我们小组的创新研究，我们发现， 阿尔茨海默病和精神疾病的假定风险基因的变异与大脑变化有关， 出生，以及2）使用GWAS发现了与大脑发育有关的新基因和变体。这些发现 是基于接近出生时收集的横断面数据。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。 需要进行细致、大规模、纵向的研究。我们提出的研究将满足这一需要，并测试我们的中央假说- 通过1）协调19个大型和多样化的遗传，神经成像和行为数据的丰富阵列， 来自美国的婴儿和儿科队列，欧洲、南非和亚洲（N=6809，大多数有两个或两个以上 纵向脑扫描和发展适当的冲动，焦虑和侵略性的措施， 2）确定常见的遗传变异，包括与精神疾病相关的遗传变异， 来自结构MRI、扩散张量成像（DTI）和静息- ing状态fMRI;和3）确定遗传影响的DIP和临床显著性的脑梗死之间的关系。 使用强大的多变量分析方法。我们的研究团队包括世界上的思想领袖在婴儿 影像学、理解复杂性状的基因组方法以及婴儿和幼儿的行为评估 儿童，所有人一起工作，作为婴儿成像基因组学组织（ORIGIN）。我们还参加 ENIGMA财团的成员，并将利用这个非常成功的集团的智力资源。该ap- 褶皱是创新的，其重点是婴儿和幼儿，纵向设计，并在利用一个独特的 全球研究人员联盟，创建有史以来最大的成像基因组学数据集，专注于婴儿和早期 童年.拟议的研究将产生积极的影响，因为它将提高我们的基本下- 遗传因素如何影响大脑发育的立场，并为一个有前途的新系列奠定基础， 研究的重点是对有患精神疾病高风险的个人进行早期干预。