The epigenetic landscape of prematurity, as it relates to health and development Restricted; Files Only

Abstract

This dissertation investigates the intricate relationships between prenatal exposures, neonatal morbidities, and their epigenetic consequences on neurodevelopmental outcomes in infants born very preterm (VPT). The first aim evaluated how gestational age (GA) and post-menstrual age (PMA) at NICU discharge are related to DNA methylation (DNAm) in buccal cells from the Neonatal Neurobehavior Outcomes in Very Preterm Infants (NOVI) study, identifying numerous CpGs and differentially methylated regions linked to neurodevelopmental pathways. The second aim examined the association between bronchopulmonary dysplasia (BPD) severity, antenatal steroid exposure, and DNAm of the hypothalamic-pituitary-adrenal (HPA) axis genes in an Environmental influences on Child Health Outcomes (ECHO) wide analysis. Using DNAm data from buccal tissue from the NOVI Study and blood spot tissue from Extremely Low Gestational Age Newborns (ELGAN), the study found that BPD did not have a significant association with polyepigenetic glucocorticoid risk score or neonatal DNAm of HPA genes, however antenatal steroid treatment was associated with altered neonatal DNAm of HPA genes in buccal tissue. The third aim explored whether DNAm at 125 CpG sites mediates the association between neonatal morbidities and neurodevelopmental outcomes at 24 months. High-dimensional mediation analysis of infants revealed significant mediation effects, particularly for cognitive and language outcomes, with specific CpGs within genes (e.g., SMYD3, TMEM245, FGFR1OP) identified as potential mediators of multiple outcomes. The findings from this dissertation highlight the profound relationships between epigenetic modifications and the health and development of infants born VPT. By investigating the age-associated epigenetic changes, the effects of antenatal steroids and BPD on the epigenome, and the role of DNAm as a mediator of neurodevelopmental outcomes, we have illuminated critical pathways that could influence long-term health outcomes. Together, these aims not only enhance our understanding of the biological mechanisms underlying preterm birth outcomes but also pave the way for developing targeted interventions to improve the health and neurodevelopment of this vulnerable population.

Table of Contents

CHAPTER 1: Introduction .......................................................................................................... 1

CHAPTER 2: Epigenetic Associations with Neonatal Age In Infants Born Very Preterm, Particularly Among Genes Involved In Neurodevelopment ................... 4

2.1 BACKGROUND ..................................................................................................................... 5

2.2 METHODS .............................................................................................................................. 7

2.2.1 Characterization of Study Population ...................................................................................... 7

2.2.2 Age Variables ........................................................................................................................... 8

2.2.3 Description of Confounding variables ..................................................................................... 8

2.2.4 DNA methylation (DNAm) measurement, quality control, and preprocessing ....................... 9

2.2.5 Statistical Analysis ................................................................................................................... 10

2.2.6 Brain-buccal Correlation ....................................................................................................... 10

2.3 RESULTS .............................................................................................................................. 11

2.3.1 Characteristics of the study population .................................................................................. 11

2.3.2 Summary of GA and PMA EWAS ......................................................................................... 12

2.3.3 Associations with GA ............................................................................................................ 12

2.3.4 Associations with PMA ......................................................................................................... 13

2.3.5 Overrepresentation of genes in biological pathways ............................................................. 13

2.3.6 Brain-Buccal Correlations ..................................................................................................... 15

2.4 DISCUSSION ........................................................................................................................ 16

2.5 CONCLUSION...................................................................................................................... 20

2.6 AIM 1 TABLES ..................................................................................................................... 21

2.7 AIM 1 FIGURES ................................................................................................................... 27

2.8 AIM 1 SUPPLEMENTARY TABLES AND FIGURES ....................................................... 29

CHAPTER 3: Epigenetic Associations in HPA Axis Genes Related To Bronchopulmonary Dysplasia and Antenatal Steroids .................. 36

3.1 BACKGROUND ................................................................................................................... 37

3.2 METHODS ............................................................................................................................ 39

3.2.1 Characterization of the Study Population .............................................................................. 39

3.2.2 Description of Study Samples................................................................................................ 40

3.2.3 DNA Methylation (DNAm) Measurement, Quality Control, and Preprocessing .................. 41

3.2.4 Data Harmonization ............................................................................................................... 41

3.2.5 GC Score Calculation ............................................................................................................ 42

3.2.6 HPA Axis Genes ..................................................................................................................... 42

3.2.7 Data Analysis ......................................................................................................................... 43

3.3 RESULTS .............................................................................................................................. 44

3.3.1 GC Score and BPD ................................................................................................................ 44

3.3.2 HPA Axis Genes and BPD Severity ....................................................................................... 44

3.3.3 Sex-Specific HPA DNAm ...................................................................................................... 45

3.4 DISCUSSION ........................................................................................................................ 46

3.5 CONCLUSIONS ................................................................................................................... 49

3.6 AIM 2 TABLES ..................................................................................................................... 51

3.7 AIM 2 FIGURES ................................................................................................................... 55

3.8 AIM 2 SUPPLEMENTARY TABLES AND FIGURES ....................................................... 57

CHAPTER 4: DNA methylation as a mediator between neonatal morbidities and neurodevelopmental outcome in infants born very preterm .................. 58

4.1 BACKGROUND ................................................................................................................... 59

4.2 METHODS ............................................................................................................................ 61

4.2.1 Study Population .................................................................................................................... 61

4.2.3 Measures ................................................................................................................................ 61

4.2.2 Statistical Analysis ................................................................................................................. 62

4.2.3 High Dimensional Mediation Analysis .................................................................................. 63

4.2.4 Causal Mediation ................................................................................................................... 64

4.3 RESULTS .............................................................................................................................. 64

4.3.1 Characteristics of the study population .................................................................................. 64

4.3.2 Model 1: HDM of the Cumulative Morbidity Risk Score and Neonatal DNAm on BSID-III at 24 months ....... 65

4.3.3 Sensitivity Analysis: The Effect of Cerebral Palsy Adjustment on HDM Analysis of Model 1…………………... 66

4.3.4 Individual Mediation Analysis of Identified HDM Mediators of BSID-III at 24 months .............. 67

4.4 DISCUSSION ........................................................................................................................ 68

4.5 AIM 3 TABLES ..................................................................................................................... 72

4.6 AIM 3 FIGURES ................................................................................................................... 76

CHAPTER 5: Summary of Aims ............................................................................................... 83

REFERENCES ............................................................................................................................ 87

ADDITIONAL INFORMATION .............................................................................................. 98

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Genetics and Molecular Biology
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Health Sciences, Epidemiology Biology, Bioinformatics Biology, Genetics
Keyword	Neurodevelopment Prematurity Epigenetics Mediation DNA methylation Epidemiology Very preterm Bronchopulmonary Dysplasia
Committee Chair / Thesis Advisor	Todd M. Everson
Committee Members	T. Michael O'Shea, University of North Carolina Chapel Hill Anke Huels Karen N. Conneely Carmen J. Marsit

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