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: 10596195
• 负责人: Rebecca Knickmeyer
• 金额: $ 102.68万
• 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/10596195
• 关键词: Aggressive behavior; Alzheimer' s Disease; Anxiety; Area; Asia; Attention deficit hyperactivity disorder; Behavior; Behavior assessment; Behavioral; Biological; Birth; Brain; Brain scan; Caring; Child; Child Behavior; Childhood; Clinical; Complex; DNA; Data; Data Set; Development; Diagnostic; Diffusion Magnetic Resonance Imaging; Disease; 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; Late-Onset Disorder; Libraries; Life; Link; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Mental disorders; Methods; Michigan; Modeling; Molecular; Multivariate Analysis; Outcome; Participant; Pathologic; Pathway interactions; Pattern; Pediatric cohort; Phenotype; 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; behavior measurement; behavioral phenotyping; behavioral study; brain circuitry; 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.

项目总结 尽管经过几十年的研究，精神障碍仍然是美国残疾的主要来源 在美国和世界各地。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是公认的，许多潜在的病理大脑发育 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出院- 这些破坏性的疾病是通过预防和非常早期的干预来实现的，我们提议的研究 将有助于通过将基因组学与纵向的儿科成像数据和行为表型分析相结合来实现 更好地理解精神疾病的发育起源。我们的中心假设是基因变异 与精神障碍相关的疾病通过影响早期神经发育和建立而增加风险 脑部电路。这一假设得到了几项进行功能基因组学的大规模研究的支持 鉴定与多种精神疾病相关的基因并揭示基因的丰富。 神经系统发育，以及我们团队的创新研究，在这些研究中，我们发现 阿尔茨海默病和精神疾病可能的危险基因变异与大脑变化有关 出生，和2)发现了与大脑发育有关的新基因和变种，使用GWAs。这些发现 是基于出生前收集的横断面数据。为了更全面地了解DNA变异是如何影响- 婴儿期和幼儿期的ESS脑发育及其对未来研究和临床的潜在意义 注意，需要进行大规模的纵向研究。我们提议的研究将满足这一需求，并检验我们的中心假设- 通过1)协调19个大型和不同类型的丰富的遗传、神经成像和行为数据 来自美国、欧洲、南非和亚洲的婴儿和儿科队列(N=6809，大多数有两个或更多 对大脑进行纵向扫描，并对冲动、焦虑和攻击性进行适当的发育测量。 Havior)；2)确定常见的遗传变异，包括那些与精神疾病有关的变异，如何影响 发育成像表型(DIP)来源于结构MRI、弥散张量成像(DTI)和静息- ING状态功能磁共振成像；以及3)确定遗传影响的DIP与临床显著行为之间的关系。 IOR使用强大的多变量分析方法。我们的研究团队包括世界思想领袖在婴儿期 成像、理解复杂特征的基因组方法以及婴幼儿的行为评估 儿童，所有人都作为婴儿期成像基因组学组织(Origin)一起工作。我们也是 并将利用这一非常成功的组织的智力资源。美联社- 折叠术的创新之处在于它对婴儿期和幼儿期的关注，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数据集 童年。拟议的研究将产生积极影响，因为它将加强我们在以下方面的基础- 了解遗传因素如何影响大脑发育，并为有希望的新品系奠定基础 研究的重点是对患精神障碍的高危人群进行早期干预。