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 尽管数十年的研究精神疾病仍然是曼联的主要残疾来源 国家和世界各地。对于那些寻求开发新疗法的人来说，一个主要挑战是 精神疾病的临床症状已得到认可，许多基本的病理大脑发育已经 已经发生并且可能是不可逆转的。因此，我们最大的希望能够显着影响护理和外部 这些毁灭性的疾病是通过预防和非常早期的干预，我们的拟议研究 将通过将基因组学与纵向，小儿成像数据和行为表型整合到启用 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 与精神疾病有关，通过影响早期神经发育和建立来增加风险 脑电路的。该假设得到了几项进行功能基因组的大规模研究的支持 赋予多种精神疾病风险的基因座的表征，并揭示了基因的富集 神经系统的发展以及我们小组的创新研究，我们发现 阿尔茨海默氏病和精神疾病的假定风险基因的变化与大脑变化有关 出生和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 基于横截面数据，收集到附近。更充分地了解DNA变体如何影响 在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 需要大量的纵向研究。我们提出的研究将满足这一需求，并测试我们的中心假设 ESI通过1）在19个大而多样的范围 来自美国，欧洲，南非和亚洲的婴儿和小儿队列（n = 6809，最多有两个或更多 纵向大脑扫描和发育适当的冲动，焦虑和侵略性的措施 havior）; 2）确定普通遗传变异（包括与精神疾病相关的遗传变异）如何影响 从结构MRI，扩散张量成像（DTI）和静止的发展成像表型（DIPS） 州fMRI； 3）识别遗传影响下降与临床上升性行为之间的关系 - IOR使用强大的多元分析方法。我们的研究团队包括婴儿的世界思想领袖 成像，理解复杂性状的基因组方法以及婴儿和年轻人的行为评估 儿童，都一起作为婴儿期成像基因组学组织（起源）。我们也是一部分 谜团的财团，并将利用这个非常成功的群体的智力资源。 ap- Plication的专注于婴儿期和幼儿，纵向设计以及利用独特的创新性 研究人员的全球联盟创建有史以来最大的成像基因组学数据集，该数据集专注于婴儿期和早期 童年。拟议的研究将产生积极的影响，因为它将增强我们的基本不足 遗传因素如何影响大脑发育的地位，并为有希望的新线条奠定了基础 研究的重点是对患有精神疾病的高风险的个体的早期干预。