Genetic and Epigenetic Effects on Childhood Cognitive Trajectories

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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.