Genetic and Epigenetic Effects on Childhood Cognitive Trajectories

项目摘要/摘要 尽管极早产婴儿(妊娠28周)的存活率在#年有了显著提高。 近几十年来，认知障碍仍然是一个主要的问题。适当的认知是高等 生活质量和福祉。与足月儿相比，极早产儿的表现要高得多。 从儿童早期到成年的认知功能损害率；这与 新生儿发炎。然而，对极早产儿认知功能的纵向研究 是有限的。关于遗传和表观遗传因素如何与认知轨迹相关联，我们知之甚少。 功能，可表现为向下/受损、低稳定或向上改善等纵向格局。 这提出了一个关键的悬而未决的问题：是否存在遗传-表观遗传学与新生儿炎症的联系 使极早产儿容易受到特定认知功能轨迹的影响？为了解决这个问题， 我们提出了这些特定的目标：1)识别围产期和新生儿免疫因素预测运动轨迹 极早产儿2-17岁的认知功能；2)决定遗传变异和 基因对新生儿炎症的调节，预测认知功能的轨迹；以及3)检查是否 DNA甲基化改变遗传变异和新生儿炎症对认知轨迹的影响 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 增加儿童和青春期认知功能低-稳定轨迹风险的因素。 此外，我们假设DNA甲基化可以调节遗传变异的影响，以防止 低空稳定弹道。这些假设是基于我们团队的几个初步发现 证明新生儿炎症以及遗传和表观遗传因素调节免疫 反应，会影响认知功能。这项建议利用了极低胎龄的新生儿 (Elgan)研究，一个多中心的极早产儿队列，目前跟踪调查到15岁(N=810)， 包含大量关于神经发育的数据和一个独特的生物谱系资料库。尽管埃尔根有DNA 来自胎盘甲基化数据的样本子集，我们建议使用储存的脐带样本 用于全基因组基因分型和新生儿血液样本的DNA甲基化。这 该建议与埃尔根在17岁时计划的后续行动相一致，以收集认知功能数据。这 该提案可能会对与认知功能相关的科学和临床实践产生重大影响 极早产儿，是最早研究遗传、表观遗传、免疫 认知功能的因素和发展轨迹。从这项工作中，我们可以识别基因和 可用于风险分层的机制，以及可成为目标的分子过程 早期降低风险的干预措施，以改善极早产儿童的生活质量。此信息 允许在出生后尽快进行有针对性的监测、预防性治疗和早期干预。

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.