Neuroscience Research 102 (2016) 56–66

Contents lists available at ScienceDirect

Neuroscience Research
journal homepage: www.elsevier.com/locate/neures

Review article

Role of epigenetic factors in the development of mental illness

throughout life
Jerry Guintivano, Zachary A. Kaminsky ∗
The Mood Disorders Center, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

a r t ic l e in f o a b s t r a c t

Article history: Psychiatric disease is believed to result from a combination of genetic vulnerability and environmen-
Received 28 February 2014 tal influence. At the crux are epigenetic modifications, which mediate the influence of environment
Received in revised form 31 July 2014 on the genome. Twin and genome-wide association studies demonstrate a wide range of heritabilities
Accepted 4 August 2014
across psychiatric disorders, while epidemiological and animal models implicate distinct developmental
Available online 20 August 2014
windows where environmental factors may interact with genetic vulnerability to confer risk. Certain
developmental periods appear to be more prone to these influences including during gestation, in the
Keywords:
early postnatal period, and during periods of major hormonal rearrangement. Here we review the role of
Epigenetics
DNA methylation
environmental factors capable of epigenetic reprogramming during these periods and present evidence
Psychiatric disease for the link between these modifications and disease. The cross tissue relevance of environmentally
Heritability induced epigenetic change and its utility for identifying peripheral biomarkers is discussed.
Environmental influence © 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
1.1. Nature and nurture in psychiatric disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
1.2. Heritability in psychiatric disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
1.3. Epigenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
1.4. The possibility for epigenetic inheritance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
1.5. The intersection of epigenetics and the environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
2. Maternal diet and epigenetically mediated effects on neurodevelopment outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
2.1. Gestational consequences of maternal stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
2.2. Early life adversity mediated epigenetic reprogramming . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
2.3. The epigenetic intersect of gonadal hormonal fluctuation and mood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
2.4. Evidence for epigenetic associations in post mortem brain DNA methylation studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
2.5. The utility of epigenetic disease etiology: biomarkers and personalized medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
3. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

1. Introduction unknown, it is thought their onset is due to an underlying genetic

predisposition in combination with environmental insults. Many
Psychiatric disorders are complex diseases classified into clinical studies indicate that the genetic component for these disorders can
syndromes with little known etiology. Those who have psychiatric vary, with heritability ranges from 0.37 in major depression (MDD)
disorders live longer with the burden of their disease compared to to 0.81 in schizophrenia (SCZ) (Sullivan et al., 2012). Despite the
any other (Whiteford et al., 2013). While the etiologies of these are amount of information generated from genetic association studies,
recent studies have focused on the role of epigenetics, specifically
DNA methylation, and how it may contribute to disease risk. At the
∗ Corresponding author at: 720 Rutland Avenue Ross Research Building 1070 intersection of genes and environment, DNA methylation provides
Baltimore, MD 21205, USA. Tel.: +1 443 287 0093. a mechanism for different environmental factors to alter genetic
E-mail address: zkamins1@jhmi.edu (Z.A. Kaminsky). expression. In this paper, we discuss evidence for the contribution

http://dx.doi.org/10.1016/j.neures.2014.08.003
0168-0102/© 2014 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.
 J. Guintivano, Z.A. Kaminsky / Neuroscience Research 102 (2016) 56–66
Fig. 1. Developmental periods sensitive to epigenetic change. An individual’s risk to psychiatric disease may be modified by epigenetic changes induced by environmental
insults. Depicted here are three particularly vulnerable timepoints: gestation, early childhood development, and reproductive years.
of both genetic and environmental factors in the etiology of psychi-
atric disease across key developmental windows (gestation, early
childhood development, and during reproductive years) for epige-
netic reprogramming (Fig. 1).
1.1. Nature and nurture in psychiatric disease
Like most complex diseases, psychiatric diseases are believed
to result from the combined influences of ‘nature’ and ‘nurture’.
These two terms respectively refer to those inherited factors influ-
encing one’s development and later life outcomes as opposed to
those factors external to one’s self. In more modern terms, nature
refers to genetic factors while nurture refers to environmental
influences. Much of what is known about the degree to which these
two influences play a role in disease manifestation comes from the
employment of the classical twin design.
The classical twin design relies on a comparison of the concord-
ance rates for a given trait between monozygotic (MZ) to dizygotic
(DZ) twins. This design has long been regarded as one of the most
elegant systems through which to infer the influence of inherited
factors on a trait, as the degree of both genetic and environmental
variation occurring in both groups is known. MZ twins arise from
a single fertilized egg, while DZ twins result from two eggs being
fertilized by two separate sperm (Gringras and Chen, 2001). These
alternate origins result in MZ twins sharing approximately 100%
DNA sequence identity while DZ twins share about 50% of all seg-
regating DNA polymorphisms, on average (Boomsma et al., 2002;
Martin et al., 1997; Wong et al., 2005). Importantly, the degree of
shared environment in both MZ and DZ twins is high, so in the tra-
ditional model, if the DZ twin group is more variable for a trait, it
is said to be under the influence of heritable factors. Heritability
(Boomsma et al., 2002; Gottesman, 2004) is the degree to which
a trait is due to genetic differences, but does not indicate what
specific genetic factors are involved in influencing trait develop-
ment. Conversely, the remainder of the variation for a trait not
accounted for by heritability estimates is generally attributed to
the effects of non-shared environmental influence.
1.2. Heritability in psychiatric disease
Using the classical twin design, relatively large ranges of her-
itabilities and environmental influences have been identified for
numerous psychiatric diseases (Wong et al., 2005). For example
SCZ and bipolar disorder (BP) exhibit relatively high levels of inher-
ited risk, between 60 and 80% (Bertelsen et al., 1977; Cardno and
Gottesman, 2000; Kieseppa et al., 2004; Lee et al., 2013a,b). An eval-
uation of 36 MZ and 53 DZ twins found panic disorder to be twice
57
as frequent in MZ twins than DZ twins (Torgersen, 1983) suggest-
ing that the disease is caused purely by genetic factors. Alzheimer’s
disease exhibits a high heritability (Kringlen, 1999), while neurode-
velopmental disorders such as autism spectrum disorder (ASD) and
attention deficit hyperactivity disorder (ADHD) exhibit high heri-
tabilities when assessed in childhood (Posthuma and Polderman,
2013). On the other end of the scale, MDD usually exhibits a gener-
ally low heritability around 30% (Bierut et al., 1999; Kendler et al.,
1993; McGuffin et al., 1991; Middeldorp et al., 2005; Sullivan et al.,
2000; Torgersen, 1986), while most reviewed heritability values for
suicidality range from 26 to 70% (Pedersen and Fiske, 2010). Other
psychiatric disorders such as anxiety, somatoform disorders, and
alcohol abuse exhibit lower heritabilities according to twin stud-
ies (Kringlen, 1999). The results and interpretation of such modern
twin studies have fueled the search for the implicated genetic and
environmental factors.
In recent years, this search has culminated in genetic screening
technologies that have enabled comprehensive investigations of
common genetic variation on the genome-wide level. The degree
to which the pool of genome-wide significant results from genome-
wide association studies (GWAS) has grown across psychiatric
diseases and has generally reflected initial heritability estimates
(Ripke et al., 2013); although it should be kept in mind that those
diseases with the highest heritabilities are currently also the best
powered to date (Ripke et al., 2013). The comparative deluge
of genome-wide significant results in MDD, however, stand as a
marked contrast to the results of SCZ and support the notion that
psychiatric diseases with low heritability estimates may therefore
be more under the control of environmental influences. What is
not attributed to genetics in heritability studies falls into the cat-
egory of non-shared environmental influence and, in the case of
MDD, this portion represents a relatively large (∼70%) piece of the
pie. In a recent review of the current state of genetic evidence
in MDD, Cohen-Woods et al. (2013) suggest that the conflicting
genetic results in MDD may be a consequence of a failure to account
for environmental influence.
A recent large scale analysis of available GWAS data across a
range of psychiatric diseases including SCZ, BP, MDD, ASD, ADHD,
among others demonstrates a striking overlap in the amount of
common genetic risk contributing across various combinations
of these disorders (Lee et al., 2013a,b). For example, SCZ was
most genetically similar to BP, but also shared genetic etiology
with MDD and to a much lesser extent, ASD. Cumulatively, the
data suggest that a common genetic etiology is shared across
a range of phenotypically distinct psychiatric disorders. GWAS
techniques have also enabled the quantification of heritability
based on genetic variation at single nucleotide polymorphisms
58 J. Guintivano, Z.A. Kaminsky / Neuroscience Research 102 (2016) 56–66
(SNP), known as “SNP heritability”. In the case of MDD, this value
estimated to be approximately 23%, which is lower than the 30%
suggested by classical twin studies (Lee et al., 2013a,b). These
specific types of “SNP heritability” speak only to the heritability
accounted for by the measured genetic polymorphisms, while twin
studies will identify the presence of all heritable factors indepen-
dent of their source. In general, the lower estimate when accounting
for a majority of common genetic variation suggests the intriguing
possibility that additional sources of non-genetic variation may be
affecting the measurement of heritability. Additionally, the data
suggest the possibility that risk to psychiatric disease is conferred
through the interaction of an inherited genetic susceptibility that
must interact with contributing environmental risk factors to result
in disease and that specific combinations of interactions may dis-
tinguish between disorders. This interpretation is consistent with
the observations of non-Mendelian features in psychiatric disease,
which include sexual dimorphism (Kaminsky et al., 2006), discor-
dance of identical twins (Kaminsky et al., 2009), and non-Mendelian
modes of inheritance (Petronis, 2001).
1.3. Epigenetics
Epigenetic factors include methylation and histone protein
modifications. In this review, we will primarily discuss DNA
methylation, as we focus mainly on human studies, which have
concentrated more on this epigenetic mark because of its stability
and relative ease of measurement relative to histone modifications.
In the mammalian genome, DNA methylation occurs on the 5′ car-
bon of the cytosine ring in cytosine-guanine dinucleotides (CpG).
DNA methylation is associated with a heterochromatic state that
can limit gene transcription as well as regulate numerous other
genomic functions (Brown, 1981; Dulac, 2010; Ehrlich and Wang,
1981; Razin and Riggs, 1980; Schwartz and Ast, 2010). Epigenetic
marks are stably inherited following cell division via DNA methyl-
transferase enzymes (Chen and Li, 2006), which can recognize the
hemi-methylated duplex strand of DNA following replication and
facilitate the addition of a methyl-group to the corresponding loca-
tion on the newly synthesized daughter strand. Importantly, this
inheritance refers to retaining the epigenetic code during mitotic
cell replication. Additionally, stochastic rearrangements, hormonal
influences (Kangaspeska et al., 2008) and environmental influences
(Jaenisch and Bird, 2003; Razin and Cedar, 1993; Riggs et al., 1998)
can result in a drift of these regulatory molecular signals over time.
1.4. The possibility for epigenetic inheritance
Until recently, no studies had investigated evidence for a her-
itable component to DNA methylation on the genomic scale. The
first such study was published in 2009 in Nature Genetics, whereby
a comparison of 20 pairs of MZ twins and to 20 same sex matched
DZ twin pairs from peripheral blood, and a similarly sized sam-
ple from buccal swab samples demonstrated significantly higher
DNA methylation variation between matched co-twins in the DZ
as opposed to the MZ group (Kaminsky et al., 2009). This finding
represented the first evidence for a heritable component to DNA
methylation in both the blood and buccal samples on the genomic
scale. This result has subsequently been replicated by numerous
additional studies performed by different laboratories (Bocklandt
et al., 2011; Boks et al., 2009; Gervin et al., 2011; Gordon et al.,
2011). Cumulatively, it appears that all epigenomic twin studies
performed to date are detecting at least some degree of a heritable
influence on DNA methylation patterns across tissues in humans,
the substrate of which may include both genetic and non-genetic
inheritance.
A larger degree of epigenetic variation in genetically non-
identical twins implies that epigenetic factors are, in part, under
genetic control. One such example observed in various human
leukemias (Boumber et al., 2008) is ‘methylation encroachment’,
which occurs when SNPs influencing transcription factor binding
result in the spreading of highly methylated CpG island shores into
relatively unmethylated CpG islands (Mummaneni et al., 1998).
Somatic mutations in the epigenetic modifiers may also influence
epigenetic patterns. For example, a SNP in the EZH2 gene result
in increased histone 3 lysine 27 (H3K27) tri-methylation marks in
other cancers (Yap et al., 2010). Genome-wide studies have shown a
majority of sequence associated epigenetic change occurs in cis and
are often referred to as allele specific methylation (ASM) (Bell et al.,
2010; Gertz et al., 2011; Numata et al., 2012; Schalkwyk et al., 2010;
Tycko, 2010). In one multigenerational study, ASM patterns were
consistent across six family members spanning three generations
(Gertz et al., 2011), suggesting that the inherited genetic template
may result in the passage of epigenetic signatures to subsequent
generations.
Importantly, as GWAS studies implicate a shared genetic eti-
ology across psychiatric disorders, these findings suggest the
possibility that deleterious contribution to disease etiology is on
the epigenetic level. For example, a portion of heritable DNA
methylation loci identified in one of the genome-wide heritabil-
ity twin studies of DNA methylation above were found to be
associated with genetic variations in cis (Boks et al., 2009). A
select list of top GWAS hits in BP were shown to be significantly
associated with cerebellar DNA methylation changes in proxi-
mal regions (Gamazon et al., 2013), while an alternative BP study
identified significant enrichment of ASM associated SNPs in gene
ontologies of gated channel and neurotransmitter receptor func-
tion (Chuang et al., 2013). These studies highlight the fact that
inherited genetic risk may provide a DNA template that is primed
for interacting with the environment in a dichotomous fashion,
promoting either a resilience or vulnerability in the face of envi-
ronmental insults mediated by the reprogramming of epigenetic
factors.
Beyond the influence of genetic factors resulting in inherited
epigenetic patterns, the possibility for a transgenerational pas-
sage of epigenetic signals, conventionally defined as an epigenetic
change that persists across three generations, would offer yet
another explanation to the high heritabilities observed in numer-
ous psychiatric diseases and the relatively low degree of identified
genetic findings. Can epigenetic inheritance account for this “Miss-
ing Heritability” as it has been termed (Manolio et al., 2009)?
It is conventionally believed that there is no passage of epige-
netic information from parent to offspring generations due to
the massive epigenetic rearrangements occurring during game-
togenesis and at fertilization (Allegrucci et al., 2005; Li, 2002;
Morgan et al., 2005; Santos and Dean, 2004; Santos et al., 2005),
including a global demethylation of DNA accompanied by mas-
sive histone modification rearrangement (Hajkova et al., 2008). In
mice; however, there are clear exceptions to this rule that often
involve the interaction of the parental generation with environ-
mental influences that result in epigenetically mediated inherited
phenotypes in the offspring (Morgan et al., 1999; Rakyan et al.,
2003). Other experiments demonstrate clear evidence for a direct
effect of the environment on the germline resulting in epigenetic
changes that may be transmitted to the next generation (Anway
et al., 2008; Dias and Ressler, 2014). Few examples of epigenetic
changes across generations exist in humans, possibly because it
is difficult to study. Critically, if the molecular mechanisms that
enable environmentally induced germline epigenetic reprogramm-
ing in mice to pass to the next generation are also seen in humans,
the implications for complex psychiatric disease is that a portion
of the heritability implicated by twin and family studies may,
in part, be influenced by environmental exposures in the parent
generation.
 J. Guintivano, Z.A. Kaminsky / Neuroscience Research 102 (2016) 56–66
1.5. The intersection of epigenetics and the environment
Epigenetic signatures are transmitted through cell division to
daughter cells; however, several environmental factors can change
epigenetic patterns in nonspecific ways across the genome, or
at specific sites, which may result in altered phenotypes. In this
way, changes to epigenetic patterns represent a molecular medium
through which the environment can interact with genetic predispo-
sition and influence phenotype. Numerous environmental factors
have been associated with psychiatric disease risk. For example,
SCZ onset has been linked to prenatal risk factors including, mater-
nal infection and malnutrition, and advanced paternal age. Other
risk factors associated with SCZ include migrant status, growing up
in an urban setting, parental loss, substance abuse, and adverse life
events (Bratlien et al., 2014; McDonald and Murray, 2000; McGrath,
2011; Oher et al., 2014; Sorensen et al., 2014). Environmental risks
for MDD include both low as well as high birth weight relative to
gestational age (Grissom and Reyes, 2013; Tamashiro and Moran,
2010) early life adversity, trauma, or sexual abuse (Klengel and
Binder, 2013), hormonal fluctuation (Kessler et al., 1993, 1995;
Weissman and Olfson, 1995), and stress (Stankiewicz et al., 2013).
The development of ASD has been linked to early developmental
environmental factors such as maternal weight gain but not preg-
nancy BMI (Bilder et al., 2013), maternal migrant status (Lehti et al.,
2013), advanced maternal age (35 years or older), low birth weight,
multiple gestation, gestational age at birth, breech presentation,
prolonged labor, low Apgar score at 5 min, hypoxia, and parental
psychiatric status (Larsson et al., 2005; Maramara et al., 2014).
Each of the environmental risk factors above are associated
with specific developmental time periods where their effects can
be most influential. During these periods, environmental expo-
sures alone or in combination may lead to epigenetic changes that
can reprogram key genes, altering developmental trajectories and
increasing the risk for psychiatric disease. Over the course of devel-
opment these subtle changes may lead to a greater vulnerability to
stress and culminate in disease, all mediated by epigenetic mech-
anisms. The sections below highlight the influence of different
developmental risk factors relevant to epigenetic change.
2. Maternal diet and epigenetically mediated effects on
neurodevelopment outcomes
The environmental exposures during gestation represent the
earliest non-genetically mediated source of variation potentially
conferring risk to disease. The mother’s womb is meant to direct
and support early fetal development, with maternal diet influ-
encing developmental outcome of her offspring. One of the first
studies introducing the idea of maternal diet and in utero pro-
gramming of offspring found a significant increase in BMI in female
offspring who were exposed during gestation to the Dutch famine
of 1945–1955 (Ravelli et al., 1999). While this example relates
specifically to obesity, it illustrates the effect of stress on mater-
nal environment on offspring. Also, it should be noted that there
is a high comorbidity between MDD and obesity (Levitan et al.,
2012), and that being in the bottom tenth percentile or upper tenth
percentile of gestational weight is associated with obesity, MDD,
and other psychiatric disorders (Grissom and Reyes, 2013). Infants
born into the bottom tenth percentile are referred to as small for
gestational age (SGA), while those in the top tenth are large for
gestational age (LGA)(ibid). Low maternal nutrition and restricted
blood flow to the placenta give rise to cases of SGA (Godfrey et al.,
2011; Grissom and Reyes, 2013; Resnick et al., 1982), while LGA
is seen in mothers with obesity and increased weight gain during
pregnancy (Drake and Reynolds, 2010). In addition, maternal obe-
sity can restrict development of the placenta, which can alter how
59
the developing fetus is protected from stress hormones and inhibit
the delivery of serotonin, brain derived neurotrophic factor (BDNF),
and leptin, which play important roles in fetal brain development
(Grissom and Reyes, 2013).
SGA has been implicated as a risk factor for a number of psy-
chiatric disorders. A comparison of a 4650 SCZ cases across three
population-based registries identified an increased SCZ incidence
ratio associating with cases of SGA (Nielsen et al., 2013). A com-
parison to case-sibling registries confirmed this effect was due
primarily to gestational factors and not other factors shared across
siblings, such as genetic or postnatal environmental factors. An
investigation of 724 BP cases and 1147 controls from the Finnish
Prenatal Study of Bipolar Disorders identified a significant associa-
tion of Caesarian section with BP (Chudal et al., 2014). A significant
association of SGA was found with ASD in an analysis of the New
Jersey Population (Maramara et al., 2014), while an MRI based study
of brain morphology demonstrated an association of low in birth
weight with cortical surface area and reductions in cognitive per-
formance (Haukvik et al., 2014).
Dysregulated cell proliferation in the hypothalamus is a con-
sequence of both SGA and LGA, which affects nutrient sensing
pathways in the developing organism and may be due, in part,
to the restricted placental hormone delivery mentioned previ-
ously. In animal models, fetal hypothalamic neuronal progenitor
cells exposed to leptin showed a neuronal cell fate commitment,
while insulin had a similar effect driving to glial cell fate commit-
ment as a function of DNA methylation changes (Desai et al., 2011;
Hirabayashi and Gotoh, 2010). Both leptin and insulin also medi-
ate development of the ventral tegmental area (VTA), the origin of
dopaminergic neurons in the mesocorticolimbic reward pathway.
The VTA drives hedonic feeding behavior (Grissom and Reyes, 2013;
Narayanan et al., 2010) and may be responsible for obesity changes
seen in the Dutch famine offspring mentioned previously (Ravelli
et al., 1999). Animal models also support the mechanism of altered
BDNF signaling in the brain and placenta of SGA and LGA offspring
(Wang and Xu, 2007), which may be linked with observed deficits
in spatial learning and memory that are associated with reduced
hippocampal volumes (Ranade et al., 2008).
Changes in neuronal development seen in SGA and LGA offspring
may be a result of epigenetic alterations in the brain due to mater-
nal diet. Using animal models, Vucetic et al. (2010) reported that
in the nucleus accumbens (NAc) and hypothalamus of offspring
maternal high fat diet reduced DNA methylation in the promoter of
genes involved in the mesocorticolimbic reward pathway, includ-
ing the dopamine reuptake transporter (DAT), !-opioid receptor
(MOR), and preproenkephalin (PENK) genes. Subsequently, Carlin
et al. (2013) reported that supplementing the maternal diet with
methyl-donors reversed the observed high fat diet induced changes
in DNA global hypomethylation and the associated weight gain.
In humans, maternal diet induced alterations to DNA methyla-
tion may result in MDD associated VTA hyperactivity observed
in neuroimaging studies (Kumar et al., 2008; Rive et al., 2013).
Further evidence that epigenetic patterns may be affected by pro-
cesses affecting gestational growth come from the aforementioned
twin studies identifying epigenetic heritability. A second consis-
tently replicated finding from those works was twins that share a
placenta, known as monochorionic twins, have significantly more
epigenetic variation than those with separate placentas, or dichori-
onic twins. Sharing a placenta between twins results in unequal
blood flow between the developing siblings. In extreme cases, this
can result in a condition known as twin-to-twin transfusion syn-
drome (TTTS), whereby one twin is essentially nutritionally starved
during development (Lopriore et al., 2011). This suggests that ges-
tational inequality can induce epigenetic disruption and has the
potential to affect key systems leading to the development of psy-
chiatric outcomes. Importantly, approximately 70% of twin pairs
60 J. Guintivano, Z.A. Kaminsky / Neuroscience Research 102 (2016) 56–66
are monochorionic and are likely to have experienced some degree
of gestational inequality (Hall, 2003). While few epigenomic twin
studies are available in the psychiatric literature, the handful of
those performed to date demonstrate evidence for epigenetic drift
between genetically identical yet discordant co-twins. Peripheral
blood DNA methylation was assessed genome-wide in a sample
of twins discordant for BP and SCZ, resulting in the identification
of over 100 CpG dinucleotides differentially methylated between
affected and unaffected MZ twins (Dempster et al., 2011). Pathway
analysis identified enrichment of DNA methylation changes asso-
ciated with genes related to ‘psychological disorders’, ‘dopamine
receptor signaling’, and ‘nervous system development and func-
tion’. Another genome-wide investigation of DNA methylation in
MDD discordant twins identified a higher epigenetic variation in
affected co-twins relative to their unaffected siblings (Byrne et al.,
2013), leading the authors to posit that affected twins may be
subjected to environmentally induced epigenetic instability. Taken
together, the results suggest that variations in maternal diet may
alter the developmental trajectories through epigenetic mecha-
nisms, potentially leading to psychiatric disease.
2.1. Gestational consequences of maternal stress
Along with the epigenetic alterations induced by maternal diet
on the neural development of offspring, there is mounting evidence
that suggest offspring of women suffering from depression during
pregnancy are at a greater risk for various negative outcomes and
future psychiatric illness. In a comprehensive review examining
the outcomes of antenatal depression on offspring, Davalos et al.
(2012) states that both maternal depression during pregnancy and
negative offspring outcomes are highly prevalent yet understudied.
Research in this field is limited, in part, by a lack of consideration of
antidepressant treatment during the antenatal period. For example,
maternal but not paternal depression was significantly associated
with the incidence of ASD in a sample of 4429 individuals with
autism and 43,277 matched controls (Rai et al., 2013); however, it
is unclear from this study how much of the effect was mediated
by prenatal antidepressant use. For this reason, the most informa-
tive studies limit their inclusion criteria to treatment naïve cases
of antenatal depression and the subsequent offspring effects. In
the Davalos et al. (2012) review, only 14 studies meet this crite-
rion. From these, numerous observations of low birth weight and
preterm birth associate with offspring of treatment naïve mothers
who were antenatally depressed. In some cases, these metrics were
correlated with maternal cortisol during pregnancy. Cumulatively,
these studies propose that risk for psychiatric disease later in life
could begin in utero, via maternal anxiety and depression during
pregnancy leading to altered HPA-axis function and development
of brain structures related to emotional procession.
There is growing evidence that maternal affective changes
coincide with hormonal alterations that cross the placenta and
mediate epigenetic reprogramming of the offspring hypothalamic–
pituitary–adrenal (HPA) axis (Dulawa, 2014). Stressful life events
during pregnancy, thought to be moderated by anxiety levels, were
moderately associated with elevated risk of psychosis in offspring
at 12 years (Dorrington et al., 2014). Maternal depression antena-
tally, measured by the Edinburgh Postnatal Depression Scale (EPDS)
was associated with microstructure changes in the right amygdala
of their offspring (Rifkin-Graboi et al., 2013). Some studies have
identified higher cortisol and stress behaviors in neonates born to
mothers with antenatal depression. While increased maternal anx-
iety was associated with decreased dopamine and norepinephrin
levels in offspring (Field et al., 2003), both of which may be
downstream consequences of placental alteration in estrogen and
cortisol (Shansky and Lipps, 2013). Hompes et al. report that
maternal anxiety and serum cortisol measurements taken during
pregnancy associate with DNA methylation levels in the cord blood
of offspring at the low affinity glucocorticoid receptor (GR) gene,
NR3C1, which is activated by the binding of cortisol. Similarly,
Bromer et al. (2012) demonstrate a significant association between
placental NR3C1 DNA methylation and NICU Network Neurobehav-
ioral Scales (NNNS), an indicator of early neurobehavioral outcome.
In addition, placental epigenetic changes at the 11"-HSD2 gene
are also associated with altered NNNS (Marsit et al., 2012). This
finding was replicated in a prenatal stress rat model where similar
changes to placental 11"-HSD2 were observed and were correlated
with methylation changes in the cortex of offspring at the same
gene (Jensen Pena et al., 2012). The stress-exposed offspring were
shown to have elevations in cortical DNMT1, which may regulate
changes observed in 11"-HSD2 DNA methylation (ibid). The role of
11"-HSD2 is to metabolize maternal cortisol in the placenta to limit
fetal exposure, further supporting the hypothesis that neurobehav-
ioral outcomes in the offspring may be mediated through hormone
induced epigenetic reprogramming. Other studies suggest that ges-
tational factors influence adult depression-like behavior through
methylation of the #CGRP gene (Jiao et al., 2012).
The above mechanisms represent a means for epigenetic change
to be transmitted from one generation to another. Those offspring
exposed to maternal cortisol in utero may in turn subject their own
offspring to increased levels of cortisol when they are pregnant.
The epigenetic foundations of cortisol dysregulation laid down dur-
ing pregnancy in offspring may be perpetuated. But this epigenetic
mechanism along with diet-associated changes in DNA methyla-
tion may affect how the results of previous heritability studies have
guided research into psychiatry over the past 30 years. These trans-
generational epigenetic changes can be viewed as a component of
heritability outside of pure genetic component, though the mech-
anisms presented here only represent a portion of the potential
risks for developing psychiatric disorders. While the current data
supporting these hypotheses is limited, future work should be
aimed at studying the relationship between maternal stress during
gestation and offspring outcomes.
2.2. Early life adversity mediated epigenetic reprogramming
Following birth the brain continues to undergo rapid and
dynamic change as neurodevelopment continues (Knickmeyer
et al., 2008), however environmental factors have been thought
to increase risk for the development of psychiatric illness such as
SCZ (Rapoport et al., 2012; Stachowiak et al., 2013) ASD (O’Hearn
et al., 2008), and affective disorders (Ansorge et al., 2007; North
et al., 2013; Sigurdsson et al., 1999). More specifically, environmen-
tal influences such as mothering behavior and early life traumas
can alter trajectories of cognitive development and stress response
later on in life (Odgers and Jaffee, 2013). It is not only widely stud-
ied and associated with extreme events like childhood sexual abuse
or assault that convey risk for disease, but also chronic and more
common stressors such as familial hostility, financial and food inse-
curity, and under-resourced schools and neighborhoods (Odgers
and Jaffee, 2013). Epigenetic changes, such as DNA methylation
reprogramming in the brain, represent the “molecular medium”
through which these environmental stressors may alter genetic
pathways. Weaver et al. (2004) published the seminal study that
demonstrates how maternal care can impact epigenetic patterns.
They showed that differences in arched back nursing and groom-
ing of rat pups altered DNA methylation in the NGFI-A transcription
factor-binding site of the NR3C1 gene. These changes to the DNA
methylation led to an altered stress response in the offspring rats
later in life. Similarly in mice, early life stress has demonstrated
an increase in arginine vasopressin gene transcription driven by
a decrease in DNA methylation within hypothalamic paraven-
tricular nucleus neurons, a critical region in the regulation of
 J. Guintivano, Z.A. Kaminsky / Neuroscience Research 102 (2016) 56–66
neuroendocrine stress response (Murgatroyd et al., 2009).
McGowan et al. showed that in humans epigenetic variation at the
exon 1F promoter of NR3C1 in post mortem hippocampal tissue from
suicide victims, syntenic to the Weaver et al. locus, associated with
early life trauma in the form of abuse. Using genome-wide microar-
rays, Mehta et al., identified distinct epigenetic profiles associated
with gene transcription changes in blood from those with PTSD
coinciding with childhood abuse status (Mehta et al., 2013). Path-
way analysis of the DNA methylation induced gene changes suggest
an alteration in “central nervous system”, “tolerance induction”,
and “apoptosis and growth rate” pathways between those with
childhood trauma and those without. Importantly, this study shows
that early childhood trauma can result in persistent changes in DNA
methylation and that these early environmental influences are both
widespread and detectable across tissues.
One implication of these findings is that the passage of HPA axis
sensitivity and GR mediated stress response phenotypes associ-
ated with psychiatric disease risks could be influenced by mood
disorders affecting the early postnatal period, such as postpartum
depression (PPD). Only a handful of heritability studies have been
performed in PPD; however, a systematic review of the literature
suggests that treatment of PPD is insufficient to affect the long-
term outcomes in child health (Gunlicks and Weissman, 2008). This
finding could be related to either an underlying genetic susceptibil-
ity or to risk conferred from the above intrauterine environmental
mechanisms that are likely to be comorbid with PPD risk.
2.3. The epigenetic intersect of gonadal hormonal fluctuation and
mood
The reproductive years have been shown to be a time of
increased vulnerability to psychiatric illness, potentially due to
the effects of gonadal hormones and their role in psychiatric risk.
During the reproductive years, there are varying degrees of sexual
dimorphism among psychiatric diseases, an observable phenotypic
difference between the sexes, including SCZ, Alzheimer’s disease,
anxiety disorders, ASD, and alcohol dependence (Aleman et al.,
2003; Menger et al., 2010; Petronis, 2001; Seeman, 1997). However,
sex differences among those disorders have been understudied.
The best examples of sex differences are widely observed in MDD.
Prior to puberty and the onset of gonadal hormones, the preva-
lence for MDD is equal between the sexes. Following puberty,
however, the rate of MDD more than doubles in females com-
pared with males (Nolen-Hoeksema and Girgus, 1994; Wade et al.,
2002), suggesting that an interaction of genetic susceptibility with
major hormonal changes may contribute to the manifestation of the
psychiatric phenotype. This sex difference appears in twin studies
where proband-wise MZ concordance for MDD differs by gender
with 31% for male-MZ twins and 48% for female-MZ twins (Kendler
and Prescott, 1999), suggesting an increased heritability of depres-
sion risk in the female population. Similarly, an analysis of 6265
twin pairs from the Netherlands Twin Registry demonstrated a
higher heritability for thoughts of self harm and suicidality for
females (H = 0.74) as compared to males (H = 0.45) (Althoff et al.,
2012). The divergent amounts of circulating hormones between
the sexes are thought to contribute to the manifestation of psychi-
atric phenotypes. It is known that androgens and estrogens have
differential effects on neural development, affecting programmed
cell death, cellular migration, synaptogenesis and axonal migra-
tion, and formation of sexually distinct neuronal circuits (Simerly,
2002, 2005). While perhaps an over simplification of our current
understanding of hormonal effects on the developing brain, var-
ious studies have shown that androgens are related to neurite
arborization and neuronal survival, while estrogens are responsi-
ble for synapse formation and initiation of cellular communication
(Brandt et al., 2013; Hamson et al., 2013; Lustig, 1994; Ottem et al.,
61
2013; Zhou et al., 2014). Post mortem studies have shown that there
may be sex-specific influences driving DNA methylation differences
seen in SCZ and BP (Mill et al., 2008).
For women, the reproductive years are punctuated with periods
of hormonal fluctuation that coincide with increased incidences of
psychiatric disease. Specifically, estrogen fluctuations are thought
to contribute to times of psychiatric risk given estrogen’s role as an
antidepressant, anxiolytic, and neuroprotectant (Galea et al., 2001;
Romano-Torres and Fernandez-Guasti, 2010). Estrogen, like other
steroid hormones, binds to and activates its respective hormone
receptors which have been shown to alter chromatin structure and
DNA methylation through various interacting protein partners (Fu
et al., 2003, 2004; Kaminsky et al., 2006; Kangaspeska et al., 2008;
Metivier et al., 2003, 2008). A combination of these sex and tissue
specific epigenetic differences, along with underlying genetic pre-
disposition, has been suggested to influence the level of response
to gonadal hormone. Major changes in the hormonal milieu may
induce epigenetic changes in vulnerable women resulting in phe-
notypic changes such as premenstrual dysphoric disorder (PMDD),
premenstrual syndrome (PMS), perimenapausal depression, PPD
(Payne et al., 2009), and an increased probability in hospitalization
for women with SCZ during the leuteal phase of their menstrual
cycle (Riecher-Rossler and Hafner, 2000). Further, the role of estro-
gen in psychiatric risk is supported by work done by Joinson et al.
(2012) where they found depressive symptoms among girls during
adolescence were more strongly influenced by breast development
stage, rather than timing of menarche. This suggests that the onset
of depression during puberty may be due to increasing levels of
estrogen and may account for the sex differences seen in depression
rates during the reproductive years.
PPD represents a psychiatric phenotype typifying the poten-
tial intersection between epigenetics and gonadal hormones. PPD
occurs following parturition, when there is a rapid withdrawal of
estrogen and progesterone. Importantly, numerous studies have
demonstrated that levels of these hormones do not vary between
PPD and non-PPD women (Studd, 2011). Numerous studies have
implicated that risk is conferred through an increased sensitiv-
ity to estrogen (Bloch et al., 2000; Mehta et al., 2014; Mitsushima
et al., 2003), and more recently, that risk is conferred through an
increased sensitivity to estrogen induced DNA methylation change
in the hippocampus (Guintivano et al., 2013a). While extensive
evidence implicates the hippocampus as the site for estrogen’s
anxiolytic and antidepressant effects on mood (Green and Galea,
2008; MacLusky et al., 2005; Suda et al., 2008; ter Horst, 2010;
Walf et al., 2008), altered sensitivity to estrogen may also result in
down stream alterations in HPA-axis function and vulnerability to
stress (Bloch et al., 2000, 2005; Mehta et al., 2014; Mitsushima et al.,
2003; Shansky and Lipps, 2013; Skalkidou et al., 2012; Tarantino
et al., 2011). Shansky and Lipps (2013) posit that estrogen may
exacerbate the effects of stress on glucocorticoid release, which is
consistent with higher cortisol response in PPD cases observed dur-
ing simulated pregnancy (Skalkidou et al., 2012). Finally, women
with PPD have been shown to have exacerbated stress-induced cor-
tisol and corticotropin releasing hormone (CRH) responses during
pregnancy (Nierop et al., 2006; Yim et al., 2009), which results in
reductions following childbirth (Skalkidou et al., 2012; Tsigos and
Chrousos, 2002), a period already characterized by decreased HPA-
axis function (Groer and Morgan, 2007; Harris et al., 1996; Jolley
et al., 2007; Taylor et al., 2009).
2.4. Evidence for epigenetic associations in post mortem brain
DNA methylation studies
One of the challenges in the study of psychiatric epigenetics
is that DNA methylation is tissue and cell type specific, meaning
that to understand the role of epigenetic variation in the brain,
62 J. Guintivano, Z.A. Kaminsky / Neuroscience Research 102 (2016) 56–66
one must study the brain. This fact has limited psychiatric studies
in humans to post mortem studies, which confer numerous chal-
lenges including a difficulty to assess the cause vs. effect nature
of any identified changes and to exclude the influence of various
confounders such as disease specific differences in psychiatric med-
ication, post mortem interval, brain pH, and neuronal relative to
glial proportions. Variation in the detailed recording of medication
history and other substances complicates findings. Until recently,
no methods were available to account for cellular heterogeneity
without the separation of neuronal and glial nuclei by fluorescence
activated sorting (Jiang et al., 2008). More recently, Guintivano
et al. (2013b) developed the first bioinformatic methods to con-
trol for cellular heterogeneity based on DNA methylation proxies
in genome-wide data after which various other methods have been
developed (Jaffe and Irizarry, 2014). As analytical methods improve
to make the study of post mortem tissues easier and more devoid
of confounding factors, it is possible that novel epigenetic associa-
tions will be discovered with the analysis of new brain samples or
the re-analysis of existing data using novel methods. Unfortunately,
the availability of post mortem brains are rare relative to what is
available from peripheral tissues. The ability to assess and iden-
tify epigenetic associations in peripheral blood would open up vast
opportunities for biomarker discovery and personalized medicine
and greatly add to the statistical power available for psychiatric
epigenetic studies.
2.5. The utility of epigenetic disease etiology: biomarkers and
personalized medicine
The degree to which peripheral tissues like blood or saliva
may contain brain relevant epigenetic signatures is a topic of con-
tinued study and has been reviewed extensively by Gladkevich
et al. (2004). Some initial reports in small sample sizes have
investigated this issue (Davies et al., 2012). Davies et al. performed
MeDIP sequencing on blood, prefrontal cortex, and cerebellum
from the same post mortem individuals and identified numerous
regions of tissue specific epigenetic variation; however, they noted
that some inter-individual variation was reflected across brain
and blood. These inter-individual associations across tissues were
observed between blood, which is composed of multiple cell types
each of which may have unique changes in DNA methylation, and
brain, which may undergo varying degrees of active demethyla-
tion in addition to methylation events (Gavin et al., 2013). In the
case of these cross tissue findings, what factors might mediate an
agreement of epigenetic patterns in a systemic manner? Petronis
has suggested that a shared developmental origin prior to major
tissue differentiation, such that inherited or early developmentally
acquired epimutations may be reflected across primary germ layers
(Petronis, 2006). In these cases, developmentally acquired epige-
netic change in response to intrauterine environmental factors like
maternal anxiety or diet may initiate such early epimutations that
are propagated across germ layers. Due to the epigenetic repro-
gramming inherent in the differentiation process, it follows that
inherited or developmentally acquired epimutations would stand
the best chance of being detected in regions not responsible for
differentiation.
Alternative mechanisms may be responsible for cross tissue
correlations of epigenetic patterns such as those observed above
in PPD where the implicated risk for disease involves a response
to systemic hormone exposure capable of reprogramming epige-
netic patterns. Peripheral detection of disease specific epigenetic
variation in peripheral blood is therefore a proxy marker of the
deleterious hormonal influences on the brain in the disease group.
Importantly, in our own work we identified an increased sensitiv-
ity of estrogen induced epigenetic change in PPD above were able
to prospectively predict PPD status using epigenetic biomarkers in
blood (Guintivano et al., 2013a). This altered sensitivity to estrogen
could be due to changes in DNA methylation of the estrogen recep-
tors. The first month of postnatal development is associated with
increased methylation of the estrogen receptor alpha promoter
(Westberry et al., 2010; Westberry and Wilson, 2012). Alterations
to this normal developmental process, such as differences in rear-
ing (Edelmann and Auger, 2011; Pena et al., 2013), may result in
DNA methylation changes that persist into adulthood and affect the
downstream signaling of estrogen. Could similar scenarios be pos-
sible in response to systemic exposure to other hormones? While
potentially all hormones may be candidates for such a mechanism,
a good example is the stress hormone cortisol because dysregu-
lated HPA axis function is a common feature to many psychiatric
diseases. Etiological insults resulting in altered cortisol response
such as those observed in MDD may be expected to leave proxy
epigenetic reprogramming in peripheral tissues to some degree
mirroring patterns that might be expected in the brain. In the
above developmental time points reviewed in this paper, systemic
influences of diet and hormonal factors are generally implicated in
epigenetic reprogramming. Such early environmental influences
may therefore leave early yet stable epigenetic proxies of brain
related deleterious gene regulation. These epigenetic biomarkers
may then be used to develop better prospective diagnostics for
disease and allow for the testing of prophylactic psychiatric treat-
ments as well as pharmacoepigenetic status, allowing treatments
to be tailored to the response profile of the individual.
3. Summary
Risk to psychiatric disease is likely mediated by the complex
interaction between underlying genetic susceptibility, environ-
mental exposures, and their downstream epigenetic consequences
to mediate long lasting changes in gene regulation. Twin studies
implicate a range of evidence for the contribution of inherited fac-
tors and environmental influences across numerous psychiatric
disorders. Distinct developmental windows during gestation, in
the early postnatal environment, and during periods of major hor-
monal rearrangement may result in epigenetic changes that confer
risk to disease. The system wide nature of the majority of these
influences, be it dietary or hormonal, leave the potential for cross
tissue epigenetic reprogramming. Such an epigenetic record of past
environmental influences opens the door for the use of peripheral
tissues such as blood to study psychiatric phenotypes.
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