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"Neal, Charles R."
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Epigenome-wide Analysis Identifies Genes and Pathways Linked to Neurobehavioral Variation in Preterm Infants
Neonatal molecular biomarkers of neurobehavioral responses (measures of brain-behavior relationships), when combined with neurobehavioral performance measures, could lead to better predictions of long-term developmental outcomes. To this end, we examined whether variability in buccal cell DNA methylation (DNAm) associated with neurobehavioral profiles in a cohort of infants born less than 30 weeks postmenstrual age (PMA) and participating in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) Study (N = 536). We tested whether epigenetic age, age acceleration, or DNAm levels at individual loci differed between infants based on their NICU Network Neurobehavioral Scale (NNNS) profile classifications. We adjusted for recruitment site, infant sex, PMA, and tissue heterogeneity. Infants with an optimally well-regulated NNNS profile had older epigenetic age compared to other NOVI infants (β
1
= 0.201, p-value = 0.026), but no significant difference in age acceleration. In contrast, infants with an atypical NNNS profile had differential methylation at 29 CpG sites (FDR < 10%). Some of the genes annotated to these CpGs included
PLA2G4E
,
TRIM9
,
GRIK3
, and
MACROD2
, which have previously been associated with neurological structure and function, or with neurobehavioral disorders. These findings contribute to the existing evidence that neonatal epigenetic variations may be informative for infant neurobehavior.
Journal Article
Epigenetic associations with neonatal age in infants born very preterm, particularly among genes involved in neurodevelopment
The time from conception through the first year of life is the most dynamic period in human development. This time period is particularly important for infants born very preterm (< 30 weeks gestation; VPT), as they experience a significant disruption in the normal developmental trajectories and are at heightened risk of experiencing developmental impairments and delays. Variations in the epigenetic landscape during this period may reflect this disruption and shed light on the interrelationships between aging, maturation, and the epigenome. We evaluated how gestational age (GA) and age since conception in neonates [post-menstrual age (PMA)], were related to DNA methylation in buccal cells collected at NICU discharge from VPT infants (n = 538). After adjusting for confounders and applying Bonferroni correction, we identified 2,366 individual CpGs associated with GA and 14,979 individual CpGs associated with PMA, as well as multiple differentially methylated regions. Pathway enrichment analysis identified pathways involved in axonogenesis and regulation of neuron projection development, among many other growth and developmental pathways (FDR q < 0.001). Our findings align with prior work, and also identify numerous novel associations, suggesting that genes important in growth and development, particularly neurodevelopment, are subject to substantial epigenetic changes during early development among children born VPT.
Journal Article
Selective Serotonin Reuptake Inhibitor (SSRI) Use during Pregnancy and Effects on the Fetus and Newborn: A Meta-Analysis
Selective serotonin reuptake inhibitors (SSRIs) are frequently used to treat depression during pregnancy and the postpartum period. These drugs are capable of crossing the placenta and being transferred to the newborn during lactation. This report reviews the available information regarding the effects of SSRIs on the fetus and newborn; including long-term neurodevelopmental outcomes.
Journal Article
Epigenome-wide association study identifies neonatal DNA methylation associated with two-year attention problems in children born very preterm
Prior research has identified epigenetic predictors of attention problems in school-aged children but has not yet investigated these in young children, or children at elevated risk of attention problems due to preterm birth. The current study evaluated epigenome-wide associations between neonatal DNA methylation and attention problems at age 2 years in children born very preterm. Participants included 441 children from the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) Study, a multi-site study of infants born < 30 weeks gestational age. DNA methylation was measured from buccal swabs collected at NICU discharge using the Illumina MethylationEPIC Bead Array. Attention problems were assessed at 2 years of adjusted age using the attention problems subscale of the Child Behavior Checklist (CBCL). After adjustment for multiple testing, DNA methylation at 33 CpG sites was associated with child attention problems. Differentially methylated CpG sites were located in genes previously linked to physical and mental health, including several genes associated with ADHD in prior epigenome-wide and genome-wide association studies. Several CpG sites were located in genes previously linked to exposure to prenatal risk factors in the NOVI sample. Neonatal epigenetics measured at NICU discharge could be useful in identifying preterm children at risk for long-term attention problems and related psychiatric disorders, who could benefit from early prevention and intervention efforts.
Journal Article
Evolutionary Sequence Modeling for Discovery of Peptide Hormones
There are currently a large number of \"orphan\" G-protein-coupled receptors (GPCRs) whose endogenous ligands (peptide hormones) are unknown. Identification of these peptide hormones is a difficult and important problem. We describe a computational framework that models spatial structure along the genomic sequence simultaneously with the temporal evolutionary path structure across species and show how such models can be used to discover new functional molecules, in particular peptide hormones, via cross-genomic sequence comparisons. The computational framework incorporates a priori high-level knowledge of structural and evolutionary constraints into a hierarchical grammar of evolutionary probabilistic models. This computational method was used for identifying novel prohormones and the processed peptide sites by producing sequence alignments across many species at the functional-element level. Experimental results with an initial implementation of the algorithm were used to identify potential prohormones by comparing the human and non-human proteins in the Swiss-Prot database of known annotated proteins. In this proof of concept, we identified 45 out of 54 prohormones with only 44 false positives. The comparison of known and hypothetical human and mouse proteins resulted in the identification of a novel putative prohormone with at least four potential neuropeptides. Finally, in order to validate the computational methodology, we present the basic molecular biological characterization of the novel putative peptide hormone, including its identification and regional localization in the brain. This species comparison, HMM-based computational approach succeeded in identifying a previously undiscovered neuropeptide from whole genome protein sequences. This novel putative peptide hormone is found in discreet brain regions as well as other organs. The success of this approach will have a great impact on our understanding of GPCRs and associated pathways and help to identify new targets for drug development.
Journal Article
Cross-national Comparison of Prenatal Methamphetamine Exposure on Infant and Early Child Physical Growth: A Natural Experiment
The current study seeks to compare the effects of prenatal methamphetamine exposure (PME) on infant and child physical growth between the USA and New Zealand (NZ). This cross-national comparison provides a unique opportunity to examine the potential impact of services provided to drug using mothers on child health. The longitudinal Infant Development, Environment and Lifestyle study of PME from birth to 36 months was conducted in the USA and NZ. The US cohort included 204 children with PME and 212 non-PME matched comparisons (NPME); the NZ cohort included 108 children with PME and 115 NPME matched comparisons. Latent growth curve models were used to examine effects of PME, country of origin, and the country × PME interaction on growth in length/height and weight. In regard to length/height, PME and country of origin were associated with initial length and growth over time. There was also a significant interaction effect, such that children with PME in the USA were shorter at birth than children with PME in NZ after controlling for other prenatal exposures, infant set, socioeconomic status, and maternal height. In regard to weight, there was only an effect of country of origin. Effects of PME on infant and child growth were shown to differ across countries, with exposed children in NZ faring better than exposed children in the USA. Implications for prevention programs and public policy are discussed.
Journal Article
Psychosocial and medical adversity associated with neonatal neurobehavior in infants born before 30 weeks gestation
BackgroundPsychosocial adversity escalates medical risk for poor outcomes in infants born <30 weeks gestation. Neonatal neurobehavior and maternal psychological and socioenvironmental assessments may identify the earliest specific intervention needs. We hypothesized that maternal prenatal anxiety, depression, and adverse medical and socioenvironmental conditions would be associated with less optimal neonatal neurobehavior at neonatal intensive care unit (NICU) discharge.MethodsWe studied 665 infants at 9 university NICUs. Risk indices of socioenvironmental, maternal, and neonatal medical factors were obtained from standardized, structured maternal interviews and medical record reviews. Brain injuries were classified by consensus ultrasonogram readings. NICU Network Neurobehavioral Scale (NNNS) exams were conducted at NICU discharge.ResultsOn the NNNS, generalized estimating equations indicated infants of mothers with prenatal anxiety had less optimal attention, and those born to mothers with prenatal depression had increased lethargy. Maternal medical complications predicted suboptimal reflexes. Socioenvironmental risk predicted lower self-regulation and movement quality. Infants with more severe neonatal medical complications had lower attention, increased lethargy, and suboptimal reflexes.ConclusionsCombined information from the observed associations among adverse prenatal maternal medical and psychosocial conditions, and neonatal complications may assist in the early identification of infants at elevated neurobehavioral risk.
Journal Article
Prenatal and perinatal factors associated with neonatal neurobehavioral profiles in the ECHO Program
Background
Single-cohort studies have identified distinct neurobehavioral profiles that are associated with prenatal and neonatal factors based on the NICU Network Neurobehavioral Scale (NNNS). We examined socioeconomic, medical, and substance use variables as predictors of NNNS profiles in a multi-cohort study of preterm and term-born infants with different perinatal exposures.
Methods
We studied 1112 infants with a neonatal NNNS exam from the Environmental influences on Child Health Outcomes (ECHO) consortium. We used latent profile analysis to characterize infant neurobehavioral profiles and generalized estimating equations to determine predictors of NNNS profiles.
Results
Six distinct neonatal neurobehavioral profiles were identified, including two dysregulated profiles: a hypo-aroused profile (16%) characterized by lethargy, hypotonicity, and nonoptimal reflexes; and a hyper-aroused profile (6%) characterized by high arousal, excitability, and stress, with low regulation and poor movement quality. Infants in the hypo-aroused profile were more likely to be male, have younger mothers, and have mothers who were depressed prenatally. Infants in the hyper-aroused profile were more likely to be Hispanic/Latino and have mothers who were depressed or used tobacco prenatally.
Conclusions
We identified two dysregulated neurobehavioral profiles with distinct perinatal antecedents. Further understanding of their etiology could inform targeted interventions to promote positive developmental outcomes.
Impact
Prior research on predictors of neonatal neurobehavior have included single-cohort studies, which limits generalizability of findings.
In a multi-cohort study of preterm and term-born infants, we found six distinct neonatal neurobehavioral profiles, with two profiles being identified as dysregulated.
Hypo- and hyper-aroused neurobehavioral profiles had distinct perinatal antecedents.
Understanding perinatal factors associated with dysregulated neurobehavior could help promote positive developmental outcomes.
Journal Article
DNA methylation in children with prenatal methamphetamine exposure and environmental adversity
Background
Methamphetamine (MA) use during pregnancy is a significant public health concern in the United States and affects long-term brain and behavioral development in children. We hypothesized that prenatal MA exposure would be related to greater DNA methylation of
HSD11B2
and postnatal environmental stress.
Methods
The Infant Development, Environment, and Lifestyle Study (IDEAL), a longitudinal study of prenatal MA exposure enrolled mother−infant dyads in California, Hawaii, Iowa, and Oklahoma. Prenatal exposure was defined by maternal self-report and/or meconium toxicology screening. At ages 10–11 years, 100 children were assessed for drug exposure and DNA methylation of
HSD11B2
. Hierarchical linear models were used to determine the association between prenatal MA exposure and methylation of
HSD11B2
at four CpG sites.
Results
Prenatal MA exposure (1.4% vs 0.31%,
P
< 0.01) and early childhood adversity (3.0 vs 2.0,
P
< 0.01) were associated with greater DNA methylation of
HSD11B2
at the CpG2 site. The statistically significant effects of early childhood adversity (
B
= 0.11,
P
< 0.01) and prenatal MA exposure (
B
= 0.32,
P
= 0.03) on DNA methylation remained after adjusting for covariates.
Conclusions
Prenatal MA exposure is related to postnatal childhood adversity and epigenetic alterations in
HSD11B2
, an important gene along the stress response pathway suggesting prenatal and postnatal programming effects.
Impact
Prenatal methamphetamine exposure has been associated with developmental issues in newborns, yet little is known about the stress pathophysiology of methamphetamine on neurobehavior.
This is the first evidence that prenatal methamphetamine exposure acts as a stressor, confirming the third pathophysiology of methamphetamine exposure.
Journal Article