Associations Between Perinatal Exposures and Neonatal DNA Methylation Öffentlichkeit
Schroeder, James (2011)
Published
Abstract
Several perinatal exposures have been linked with adverse health
outcomes later in life.
Fetal exposure to maternal depression, symptoms and treatment are
associated with low
birth weight, fetal cardiac defects, and impaired cognitive and
emotional development.
Likewise, gestational age, often in the form of preterm delivery,
is associated with an
increased rate of neonatal mortality and development of cerebral
palsy, cognitive and
behavioral issues. In this study, we examined whether there was an
association between
these perinatal exposures and differential methylation in
>27,000 CpG loci in umbilical
cord blood DNA of neonates born to mothers participating in a
prospectively-
characterized psychiatric cohort. Contrary to previous reports, we
found no associations
between neonatal DNA methylation and any psychiatric diagnosis or
depressive symptom
measures taken during pregnancy. However, maternal exposure to any
antidepressant
during pregnancy was associated with differential methylation at
TNFRSF21 and
CHRNA2, though these findings were not associated with
individual antidepressant
classes. Gestational age was associated with differential
methylation at 41 CpG loci in
39 genes, including genes previously implicated in labor and
delivery (e.g., AVP, CRHBP
and ESR1) or that
may influence the risk for adverse health outcomes later in life
(e.g.
DUOX2, TMEM176A and CASP8). Twenty-six of
these loci in 25 genes were then
successfully replicated in an independent, non-psychiatric cohort.
These combined
findings will play an important role both in characterizing the
epigenetic dynamics
contributing to labor and delivery and in assessing potential
impacts of these perinatal
exposures on later-life health conditions.
Associations Between Perinatal Exposures and Neonatal DNA
Methylation
M.A., Texas A&M University, 2005
Advisors: Joseph Cubells, M.D., Ph.D.
Alicia Smith, Ph.D.
A dissertation submitted to the Faculty of the
James T. Laney School of Graduate Studies of Emory University
in partial fulfillment of the requirements for the degree of
Doctor of Philosophy
Graduate Division of Biological and Biomedical Sciences
Genetics and Molecular Biology
2011
Table of Contents
Table of Contents
Chapter 1: General Introduction 1
Epigenetics and DNA Methylation 2
Epigenetic Mechanisms During Fetal Development 4
Early-Life Impacts on Phenotypes in Later Life 6
Exposure to Maternal Mental Illness and Neonatal Health 7
Neonatal Risks of Antidepressant Exposure 8
Gestational Age and Health Outcomes 9
Animal Studies 10
Human Studies 13
Epigenetic Patterns Vary by Cell Type 14
Study Objective 15
References 20
Chapter 2: Technical Methodologies 26
Genome-wide Studies of Sequence Variation and DNA Methylation
27
Laboratory Approaches to Genomic-scale Analysis of DNA Methylation
28
Overview of the Infinium Protocol 30
Sample Preparation 31
Array Processing 31
Chip and Experiment Effects 33
HumanMethylation27 Probe Issues 35
Statistical Analysis 38
References 46
Chapter 3: DNA Methylation of Neonates Born to Women Receiving
49
Psychiatric Care
Introduction 50
Methods 51
Results 54
Discussion 56
References 62
Chapter 4: Neonatal DNA Methylation Patterns Associate with
65
Gestational Age
Introduction 66
Methods 67
Results 71
Discussion 72
References 83
Chapter 5: Summary and Conclusions 86
Figures and Tables
Chapter 1: General Introduction
Figure 1-1: Representative Model of Epigenetic Modifications
18
of Histone and DNA
Figure 1-2: Conversion of Cytosine to 5-Methyl Cytosine 19
Chapter 2: Technical Methodologies
Table 2-1: Prevalence of SNPs Under the HumanMethylation27 Probes
39
or at the Single Base Extension Nucleotide
Table 2-2: Prevalence of Flanking CpG Dinucleotides Under the
40
HumanMethylation27 Probes or at the Single Base
Extension Nucleotide
Figure 2-1: Model Depicting the HumanMethylation27 BeadChip
41
Extension Reaction
Figure 2-2: Bisulfite Conversion of Cytosine to Uracil 42
Figure 2-3: Chip Effects Shown by Average Sample Intensity 43
By BeadChip
Figure 2-4: Representative HumanMethylation27 Probe with 44
Mismatched Nucleotides
Figure 2-5: Scatterplots of Methylated vs. Unmethylated Signals
45
Chapter 3: DNA Methylation of Neonates Born to Women
Receiving
Psychiatric Care
Table 3-1: Demographic and Clinical Characteristics of 59
the WMHP Subjects
Figure 3-1: Methylation of Significant CpG Sites 61
Chapter 4: Neonatal DNA Methylation Patterns Associate with
Gestational Age
Table 4-1: Demographic and Clinical Characteristics of the
Discovery 76
and Replication Cohorts
Table 4-2: CpG Sites Reaching Experiment-wide Significance in the
77
Discovery Cohort Compared to the Replication Cohort Results
Table 4-3: Co-occuring Gene Ontology Results for the 41 79
Experiment-wide Significant Genes in the Discovery Cohort
Figure 4-1: Scatterplots of Representative CpG Sites Associated
with GA 80
with Regression Lines
Figure 4-2: Heat Map of Beta Values from Subjects with the Lowest
81
and Highest Gestational Ages from the Discovery Cohort
Figure 4-3: Samples in the Discovery Cohort that Used LMP to
82
Determine GA do not Significantly Differ From Those
Based on Obstetrician Report
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