Genetic and Epigenetic Effects on Childhood Cognitive Trajectories

遗传和表观遗传对儿童认知轨迹的影响

• 批准号: 10260643
• 负责人: Hudson Santos
• 金额: $ 38.56万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2022-05-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10260643
• 关键词: 15 year old; 17 year old; Accounting; Address; Adolescence; Adult; Age; Biological Specimen Banks; Birth; Blood specimen; Child; Childhood; Chronic Disease; Cognition; Cognitive; DNA Methylation; Data; Development; Distress; Early Intervention; Epigenetic Process; Exhibits; Extremely low gestational age newborn; FK506 binding protein 5; Family; Foundations; Genes; Genetic; Genetic Polymorphism; Genetic study; Genomics; Genotype; Goals; HDAC4 gene; Immune; Immune response; Immunologic Factors; Impaired cognition; Impairment; Individual; Infant; Inflammation; Intervention; Link; Mediating; Mediation; Methylation; Molecular; Neonatal; Neurodevelopmental Impairment; Pathway interactions; Pattern; Perinatal; Personal Satisfaction; Placenta; Predictive Factor; Pregnancy; Preventive therapy; Process; Quality of life; Research; Risk; Sampling; Schedule; Science; Shapes; Smoking; Source; Specimen; Stress; Survival Rate; Umbilical cord structure; Work; base; clinical practice; cognitive function; cohort; early childhood; early screening; follow-up; genetic variant; improved; innovation; neurodevelopment; personalized intervention; preterm newborn; prevent; risk stratification; whole genome

PROJECT SUMMARY/ABSTRACT Although survival rates for infants born extremely preterm (< 28 weeks’ gestation) have improved dramatically in recent decades, cognitive impairment remains a major concern. Adequate cognition is foundational for high quality of life and well-being. Compared to those born full term, extremely preterm children exhibit much higher rates of cognitive function impairment from early childhood through adulthood; and this is associated with neonatal inflammation. However, longitudinal research on cognitive function among extremely preterm children is limited. Little is known about how genetic and epigenetic factors are associated with trajectories of cognitive function, which can show longitudinal patterns such as downward/impaired, low-stable or upward-improvement. This raises a key unanswered question: are there genetic-epigenetic links to neonatal inflammation that predispose extremely preterm children to a particular trajectory of cognitive function? To address this question, we propose these specific aims: 1) Identify perinatal and neonatal immune factors predicting trajectories of cognitive function from ages 2 - 17 years among extremely preterm children; 2) Determine genetic variants and gene-by-neonatal inflammation mediation that predict trajectories of cognitive function; and 3) Examine whether DNA methylation modifies the effects of genetic variants and neonatal inflammation on trajectories of cognitive function. Our central hypothesis is that genetic variants of immune-related genes interact with neonatal immune factors to increase risk for a low-stable trajectory of cognitive function during childhood and adolescence. Additionally, we hypothesize that DNA methylation can mediate the effects of genetic variants to protect against the low-stable trajectory. These hypotheses are based on several preliminary findings from our team demonstrating that neonatal inflammation, as well as genetic and epigenetic factors regulating immune response, can influence cognitive function. This proposal leverages the Extremely Low Gestational Age Newborn (ELGAN) study, a multi-center cohort of extremely preterm children currently followed to age 15 years (N = 810), containing vast data on neurodevelopment and a unique biospecimen repository. Although ELGAN has DNA methylation data from placentas on a subset of the sample, we propose to use banked umbilical cord specimens for whole-genome genotyping and neonatal blood specimens for DNA methylation of the entire cohort. This proposal aligns with the scheduled ELGAN follow-up at 17 years of age to collect cognitive function data. This proposal has potential for significant impact on science and clinical practice related to cognitive function among extremely preterm children and is among the first to study relationships among genetic, epigenetic, immune factor and developmental trajectories of cognitive function. From this work, we can identify genes and mechanisms that can be used for risk stratification, as well as molecular processes that can be the targets of early risk-mitigating interventions to improve quality of life for children born extremely preterm. This information allows for targeted surveillance, preventative therapies and early intervention as soon after birth as possible.

项目摘要/摘要 尽管出生的婴儿的生存率极早产（妊娠28周）已经显着提高 最近几十年，认知障碍仍然是一个主要问题。足够的认知是高高的基础 生活质量和福祉。与那些出生的完整学期相比，非常早产的孩子暴露得更高 从幼儿到成年期的认知功能障碍率；这与 新生儿炎症。但是，对极端儿童的认知功能的纵向研究 有限。关于遗传和表观遗传因素与认知轨迹如何相关的知之甚少 函数，可以显示纵向模式，例如向下/受损，低稳定或向上改善。 这提出了一个关键的未解决的问题：是否存在与新生儿注入的遗传性诊断联系 易于早产儿，对认知功能的特定轨迹？为了解决这个问题， 我们提出了这些具体目的：1）确定围产期和新生儿免疫因素预测的轨迹 在极端儿童中，来自2至17岁的认知功能； 2）确定遗传变异和 预测认知功能的轨迹的逐神经炎症介导； 3）检查是否 DNA甲基化改变了遗传变异和新生儿感染对认知轨迹的影响 功能。我们的中心假设是免疫相关基因的遗传变异与新生儿免疫相互作用 在儿童期和青少年期间增加认知功能轨迹的风险的因素。 此外，我们假设DNA甲基化可以介导遗传变异的影响以防止 低稳定轨迹。这些假设基于我们团队的一些初步发现 证明新生儿炎症以及调节免疫的遗传和表观遗传因素 反应，会影响认知功能。该提议利用了极低的胎龄新生儿 （Elgan）研究，目前遵循15岁以下的极端儿童的多中心队列（n = 810）， 包含有关神经发育和独特的生物传播存储库的大量数据。虽然Elgan有DNA 来自样品子集的plecetas的甲基化数据，我们建议使用库的脐带标本 用于全基因组基因分型和新生儿血样，用于整个队列的DNA甲基化。这 提案与17岁的Elgan随访相一致，以收集认知功能数据。这 提案有可能对与认知功能有关的科学和临床实践产生重大影响 非常早产的孩子，是最早研究遗传，表观遗传，免疫之间关系的人之一 认知功能的因素和发展轨迹。从这项工作中，我们可以确定基因和 可用于风险分层的机制以及可以作为目标的分子过程 早期减轻风险的干预措施，以改善出生的儿童的生活质量。此信息 允许在出生后尽快进行有针对性的监视，预防疗法和早期干预。