Genetic mechanisms of parenting
Viara R. Mileva-Seitz a,b,
⁎, Marian J. Bakermans-Kranenburg a
, Marinus H. van IJzendoorn a,c
a
Center for Child and Family Studies, Leiden University, PO Box 9555, 2300 RB Leiden, The Netherlands
b
Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, PO Box 2060, 3000 CB Rotterdam, The Netherlands
c
School of Pedagogical and Educational Sciences, Erasmus University Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands
a b s t r a c ta r t i c l e i n f o
Available online 23 June 2015
Keywords:
Parenting
Genetic mechanisms
Epigenetics
Intergenerational transmission
Twin studies
Candidate genes
Gene–environment interactions
Differential susceptibility
Maternal behavior
This article is part of a Special Issue “Parental Care”.
The complexities of parenting behavior in humans have been studied for decades. Only recently did we begin to
probe the genetic and epigenetic mechanisms underlying these complexities. Much of the research in this field
continues to be informed by animal studies, where genetic manipulations and invasive tools allow to peek into
and directly observe the brain during the expression of maternal behavior. In humans, studies of adult twins
who are parents can suggest dimensions of parenting that might be more amenable to a genetic influence.
Candidate gene studies can test specific genes in association with parental behavior based on prior knowledge
of those genes' function. Gene-by-environment interactions of a specific kind indicating differential susceptibility
to the environment might explain why some parents are more resilient and others are more vulnerable to stressful
life events. Epigenetic studies can provide the bridge often necessary to explain why some individuals behave
differently from others despite common genetic influences. There is a much-needed expansion in parenting research
to include not only mothers as the focus—as has been the case almost exclusively to date—but also fathers,
grandparents, and other caregivers.
© 2015 Elsevier Inc. All rights reserved.
Introduction: Mammalian mothering and its multiple influences
Colloquial references to a ‘maternal instinct’ or a ‘maternal drive’ are
common and reveal a general presupposition about mothers: that there
are innate rules shaped by the long course of evolutionary history and
hardwired into the DNA, which drive all mothers to respond to, nurture,
and protect their offspring (Rosenblatt, 1967). The focus of this review is
to explore the current evidence of such a genetic component to
mothering.
The evidence for intergenerational transmission of parental behavior
is clear: mothering begets mothering (Fleming et al., 2002). Both positive
and negative aspects of early experience being parented tend to
be repeated by the next generation, in humans and animals alike
(Belsky et al., 1989, 2005; Capaldi et al., 2003; Chen and Kaplan, 2001;
Chen et al., 2008; Gonzalez et al., 2001; Kovan et al., 2009;
Maestripieri, 2005; Maestripieri et al., 2007; Newcomb and Locke,
2001; Suomi, 1999; van IJzendoorn, 1992). Just how these behaviors
are transmitted across generations is as yet unclear. Does the transmission
stem from underlying similarities in genetic code, or are behaviors
repeated because environments are similar? The short answer based on
the evidence to date is: neither, and both.
Complex biological organisms function at the interface between
their genetic programming and the environment in which they dwell.
Myriad contextual or ‘external’ influences shape mothering, and much
work has been done in this area. A smaller but growing number of studies
have examined the heritable components of mothering and peered
deeper at the molecular level of genetic variation to ask how DNA
might shape parenting. Finally, we are beginning to understand the
bridge between environmental and genetic influences: epigenetic
changes. Epigenetic changes are more or less stable modifications of
gene regulatory machinery occurring outside the level of DNA sequences.
They might be the bridge or “physical point of connection”
(Boyce and Kobor, 2015) between genes and environment that can account
for some portion of the behavioral plasticity we see across an
individual's development. For instance, early neglect and abuse tends
to be repeated in the new generation, but not for everyone. Only
about 30–40% of mothers who were abused as children go on to abuse
their own children (Kaufman and Zigler, 1987; Sroufe et al., 2005),
and the complex associations between early life abuse and later abuse
toward one's own children might be in part owing to differential epigenetic
changes. The epigenome represents a way to introduce plasticity
in behavior, via plasticity in the expression of genetic products, despite
the underlying stability of structural DNA.
The mammalian order presents species with vast differences in the
types and quantities of parental care, from the simple licking and
grooming behavior of the mother rat to the highly complex parenting
behavior of humans. This review is aimed at the genetic underpinnings
Hormones and Behavior 77 (2016) 211–223
⁎ Corresponding author: Center for Child and Family Studies, Leiden University, PO Box
9555, 2300 RB Leiden, The Netherlands.
E-mail address: viara.mileva@gmail.com (V.R. Mileva-Seitz).
http://dx.doi.org/10.1016/j.yhbeh.2015.06.003
0018-506X/© 2015 Elsevier Inc. All rights reserved.
Contents lists available at ScienceDirect
Hormones and Behavior
journal homepage: www.elsevier.com/locate/yhbeh
of human mothering, but we will provide multiple examples from other
mammalian species used in parenting research (e.g., rats, sheep, voles,
monkeys). Even though there are basic features in human
parenting—including the provision of caretaking, ambulation, and
feeding—we see much fine-tuning or variation according to cultural or
environmental pressures (Bornstein, 1989; Bornstein et al., 1992,
2007; Harwood et al., 1999; Keller, 2004; Quinlan, 2007; Trehub et al.,
1993). For instance, mothers around the globe engage in face-to-face
communication, infant body contact/stimulation, and primary care
(e.g. nursing) (Mesman et al., 2012; Mileva-Seitz and Fleming, 2011).
Yet mothers can differ in their perception and processing of infant
cues, and in their motivation to attend to them (Barrett and Fleming,
2011; Leavitt, 1998, 1999; Mileva-Seitz and Fleming, 2011;
Mileva-Seitz et al., 2012a). When looking for genetic underpinnings of
parental behavior it might be helpful to start at the systems that
regulate these perceptual and motivational processes in the brain. In
the present review, we will consider studies of three broad dimensions
of ‘parenting’: (1) macro-analytic parental behaviors, such as the more
global scales of quality of parental interactions (e.g., sensitivity and
warmth); (2) micro-analytic parental behaviors, such as the quantity
(duration, frequencies) of discrete parental behaviors (e.g. frequency
of touch, orienting away from the infant); and (3) prenatal parenting effects,
such as the nutritional and hormonal prenatal environment a fetus
is exposed to. Before turning to specific genes of interest in parenting,
we review the evidence for a heritable component of parenting.
The early evidence for heritability in parenting: Behavioral genetics
The original way to explore genetic effects on human behavior was
through the use of ‘behavioral genetics’ studies, which employ multiple
types of families including twins and adoptive vs. biological siblings. In
twin studies, genetic contributions to behavior are inferred from
quantification of behavioral differences between monozygotic (MZ)
and dizygotic (DZ) twins. MZ and DZ twins differ in their genetic
similarity. The environment is shared when it makes them more similar
to one another, and unique or non-shared when it makes them more
different. Behavioral genetics makes it possible to differentiate between
the contribution of these three components—genetics, shared, and nonshared
environment—to a behavior or trait. Examining the heritability
of parenting, researchers have made use of twin studies that allow for
comparison of parenting behavior between adult parent twin-pairs
(parent-based in contrast to child-based designs, see BakermansKranenburg
and Van IJzendoorn, in press). Six parent-based behavioral
genetic studies that addressed the heritability of different dimensions
of parenting were meta-analyzed (Klahr and Burt, 2014). Non-shared
influences (experiences that are unique for each sibling) including
measurement error accounted for 63–90% of the variance in parenting.
For parental control the combined genetic estimate was zero, whereas
the combined genetic estimates for warmth and negativity were around
30% (Klahr and Burt, 2014). Twin studies however do not reveal the
genetic mechanisms underlying variation in phenotypes. A second
approach—the exploration of genetic variance at the molecular level of
the DNA—is therefore a useful and timely complement to behavioral
genetics efforts to gain a fuller understanding of genetic mechanisms
in parenting.
Molecular genetics, candidate genes
Molecular genetic studies in humans examine particular DNA
sequences that might be associated with traits of interest. Human maternal
responsiveness might be influenced by large networks of
interacting genes, in addition to the plethora of environmental influences.
Given such complexity and the sheer volume of potential candidates
for gene analysis, prior knowledge about function—of the genes,
proteins, and associated biochemical networks resulting from the
genes of interest—helps to narrow down the candidate genes. This is
the ‘hypothesis driven’ or ‘mechanistic’ approach (Dalziel et al., 2009;
Tabor et al., 2002). In accordance with this, genetic factors that regulate
key brain systems related to perceptual and motivational processes are
likely to also influence maternal behavior. The search for candidate
genes associated with human parenting has centered on three key
neurotransmitter systems (Bakermans-Kranenburg and van IJzendoorn,
in press) to which we turn next: dopamine, oxytocin, and serotonin.
Dopamine
Dopamine has a crucial role in regulating maternal care in rats. This
role can be better understood by considering the neural circuitry of the
maternal rat. This circuit consists of several major regions: the medial
preoptic area (MPOA), the ventral bed nucleus of the stria terminalis
(vBST), the nucleus accumbens (NA) and the medial and cortical
amygdala (MCA) (Numan, 2015). These regions either directly receive
dopaminergic innervation, or interact with other regions of the brain
that are under dopaminergic control. For instance, the MPOA stimulates
dopaminergic neurons via the ventral tegmental area to the NA, which
increases maternal responsiveness to pup stimuli (Numan, 2006). In
virgin rats, electrical or hormonal stimulation of the MPOA/vBST
induces maternal behavior (Numan et al., 2006), as does the application
of dopamine receptor agonists into the NA (Numan et al., 2005). Conversely,
lesions or the administration of dopamine receptor antagonists
either systemically or in the MPOA, VTA, and NA reduce the naturally
rewarding properties of pups in maternal rats (Lee et al., 2000), disrupt
normal maternal behaviors (e.g. pup approach and pup retrieval)
(Byrnes et al., 2002; Hansen et al., 1991; Keer and Stern, 1999; Li and
Fleming, 2003a,b; Li et al., 2004, 2005; Numan et al., 2005; Parada
et al., 2008), and block the consolidation of postpartum maternal experiences
(Li and Fleming, 2003a,b).
There are also natural differences between rat dams in the levels of
dopamine release into the NA: Those who are considered high-lickers
and groomers have a greater dopamine release than those who have
low levels of pup licking and grooming (Champagne et al., 2004). Postpartum
females have naturally suppressed dopamine baseline levels,
but these levels increase significantly when they are exposed to pups
(Afonso et al., 2009), or following reunion with pups after a separation
(Hansen et al., 1993). Pups are so rewarding that new rat mothers prefer
pups to cocaine until about day 8 postpartum (Mattson et al., 2001).
Even cycling (non-postpartum) females, for whom avoidance is the typical
response to pups, show a dopamine increase when exposed to pups
that is proportional to their prior pup exposure (Afonso et al., 2008). At
the genetic level, early evidence suggests that expression of dopamine
receptor genes D1 (DRD1) and D2 (DRD2) is upregulated during
pregnancy in the rat (Mann, 2014). Furthermore, there is upregulated
expression of dopamine receptor D4 (DRD4) and dopamine transporter
DAT1 mRNA in the MPOA following pup exposure, regardless of maternal
parity (Akbari et al., 2013). Taken together, this evidence suggests a
strong role of dopamine in rat maternal regulation. As Rosenblatt
(1967) already shown, pups may be partially responsible for the onset
and ongoing maintenance of maternal behavior, and the mechanism
might be the stimulation of gene expression in the mother. Natural
bursts of dopamine firing neurons in the mammalian striatum are said
to be crucial for the pup-regulated aspects of maternal care (i.e. maternal
care in response to pup-cues) (Robinson et al., 2011). However,
individual differences in dopamine gene function unrelated to pup
cues (e.g., from early rearing effects or underlying genetic variation)
might predict individual differences in maternal behavior. Other rodent
models have provided evidence for the dopamine-mothering link. For
instance, an interesting study of hypodopaminergic mice (mice genetically
engineered to express less dopamine) indicated that striatal
dopamine is crucial for ‘active’ maternal behaviors such as pupretrieval
and liking/grooming of pups, and not for ‘passive’ behaviors
such as nursing (Henschen et al., 2013). In voles, the effects of a dopamine
antagonist (haloperidol) had similar effects on parenting behavior
as are found in rats, generally reducing ‘active’ components of maternal
212 V.R. Mileva-Seitz et al. / Hormones and Behavior 77 (2016) 211–223
behavior (e.g. duration of licking), although species-specific differences
in the effects can be seen (Lonstein, 2002).
Dopamine and human mothering
Given dopamine's key role in mothering in rodents, it seems only
logical to explore genetic variants (polymorphisms) underlying dopamine
transmission (e.g. D'Souza and Craig, 2006) for their potential influences
on human maternal behavior. In humans, the non-genetic
evidence for dopamine's role in parental care is indirect. It comes chiefly
from a series of functional magnetic resonance imaging (fMRI) studies
in which mothers were exposed to infant vocalizations (Lorberbaum
et al., 2002; Sander et al., 2007; Seifritz et al., 2003), pictures (Barrett
et al., 2011; Bartels and Zeki, 2004; Leibenluft et al., 2004; Nitschke
et al., 2004; Strathearn et al., 2008), or video fragments (Noriuchi
et al., 2008; Ranote et al., 2004). These studies report activity in brain regions
occupied by the vBST and VTA, striatum, amygdala, cingulate cortex,
thalamus, medial prefrontal cortex, and right orbitofrontal cortex.
Most of these are either dopaminergic regions, or directly interact
with dopaminergic regions (Georges and Aston-Jones, 2002).
Only a handful of candidate gene studies have explored dopamine
gene polymorphisms in relation with individual differences in human
parenting (Table 1). For instance, polymorphisms of DRD4 and COMT
(coding for catechol-O-methyltransferase, a dopamine deactivating enzyme)
genes interact with maternal daily hassles to predict differences
in maternal sensitive responding to toddlers (van IJzendoorn et al.,
2008). Polymorphic variation on DAT1 is associated with more negative
maternal behaviors and commands to their 5-year-old children (Lee
et al., 2008). Furthermore, polymorphisms on both DRD1 and
DRD2—key receptors in rat maternal regulation—are also associated
with differences in observed maternal care in humans: DRD1 polymorphisms
associate with how often mothers turn away from their 6month
old infants during a 20-min free-play episode; and DRD2 polymorphisms
associate with how long mothers vocalize (talk and sing)
to these infants (Mileva-Seitz et al., 2012b). Not all studies find significant
associations, however. Mills-Koonce et al. (2007) failed to find an
association between maternal genotype at another dopamine-related
polymorphism (on the gene ANKK1, close to DRD2) and observed
maternal sensitivity. Among the notable strengths of these studies is
that they used observed measures of parenting. Nonetheless, in the
absence of knowledge about the specific function of these genetic polymorphisms,
further replication is necessary before their role in the regulation
of maternal sensitivity and maternal behavior is clear.
Oxytocin/vasopressin
Another neurotransmitter important to mothering is the nineamino
acid peptide oxytocin (or alpha-hypophamine). Oxytocin is
synthesized mostly in the hypothalamus (Lee et al., 2009) and oxytocin
neurons in rats project to brain regions important for social and maternal
behavior regulation, including the MPOA and NA (Carter, 2014;
Francis et al., 2000; Numan, 2015). In addition to its crucial peripheral
(hormonal) role during labor and delivery and lactation, in many
non-primate mammalian species oxytocin is also key to regulating
(the onset of) maternal behavior (Fahrbach et al., 1985; Kendrick,
2000; Numan, 2015; Pedersen et al., 1994). Oxytocin receptor binding
is higher in rat dams who are naturally high-lickers and groomers
(Francis et al., 2000). Accordingly, oxytocin receptor antagonist infusions
into the VTA and MPOA immediately postpartum inhibit maternal
behavior onset (Pedersen et al., 1994), whereas antagonist infusion into
the cerebral ventricles inhibits the expression of maternal behavior in
rats (van Leengoed et al., 1987). Individual differences in centrally inducible
oxytocin receptors predict natural differences in rat maternal
behavior (Champagne et al., 2001). Oxytocin may also mediate maternal
behavior in rat dams indirectly, by altering the dam's anxiety levels,
which themselves relate to maternal behavior (Bosch, 2010). Other species
also provide evidence of the importance of oxytocin in mothering:
in sheep, oxytocin administration results in maternal behavior toward
foreign lambs (Keverne and Kendrick, 1992) and decreases the aggression
and aversion to newborn lambs (Insel and Young, 2001). In mutant
mice lacking the oxytocin receptor gene, maternal behavior is impaired
(Takayanagi et al., 2005).
In primates, oxytocin is not essential for the establishment of maternal
care, but it is important in post-parturition bonding and maternal
behavior (Broad et al., 2006; Saltzman and Maestripieri, 2010).
Pregnancy hormones prime the mesolimbic dopamine projections to
the NA and up-regulate oxytocin receptors in the brain. These modulations
of the reward system facilitate mother–infant bonds at birth
(Broad et al., 2006). Additionally, peripheral administration of an
oxytocin receptor blocker in rhesus macaques reduces interest in the
infant (e.g. lip-smacking, approaching, touching) (Boccia et al., 2007).
Furthermore, whereas cerebrospinal levels of oxytocin in multiparous
rhesus macaque females do not correlate with mother-infant interaction
(Cooke et al., 1997), plasma levels of oxytocin are highly correlated
with ‘maternal warmth’ (Maestripieri et al., 2009). The behavioral and
physiological evidence from both rodents and primates gives reason
to examine genetic variation in the oxytocin system in human
parenting.
Oxytocin and human mothering
In humans, an increase in plasma oxytocin level from early to midlate
pregnancy correlates with higher scores on ratings of attachment
to the fetus (Levine et al., 2007). Thus oxytocin might be important for
bonding even before the infant has been born. In the postpartum period,
maternal and infant salivary oxytocin levels are correlated with each
other and with mother-infant affect synchrony (Feldman et al.,
2010b); and high levels of plasma oxytocin predict high levels of affectionate
touch toward infants (Feldman et al., 2010a). Increased oxytocin
levels are found in mothers who recently touched or interacted with
their infants (Light et al., 2000). Thus, oxytocin is important for
human parenting (Galbally et al., 2011), and this is not limited to parturition
and breastfeeding but rather extends to the expression of behavioral
responses toward infants. Among the limitations of this research is
that oxytocin levels are difficult to quantify. This is for several reasons:
oxytocin has a multiple-site release, many functions, and a diurnal
rhythm in the cerebrospinal fluid but not peripherally (Amico et al.,
1983). Moreover, because oxytocin does not cross the blood–brain barrier
in adult animals (Saltzman and Maestripieri, 2010), plasma and cerebrospinal
fluid levels may not be identical. However, plasma and
cerebrospinal fluid oxytocin levels have been found strongly correlated
(Carson et al., 2014).
A next step has been to determine whether genetic variation in the
human oxytocin genes is associated with differences in maternal behavior
or related functions. The first study of this kind showed a significant
association between the rs53576 polymorphism on the oxytocin receptor
gene (OXTR) and parental sensitive responsiveness in a sample of
mothers with toddlers (Bakermans-Kranenburg and van IJzendoorn,
2008). A later study in 500 families with twins indicated that maternal
genotype at this site is also associated with maternal warmth (Klahr
et al., 2014). This same polymorphism has since been associated with
differences in positive parenting and with differences in neural activation
of brain regions previously associated with positive parenting in a
longitudinal study spanning 15 years (Michalska et al., 2014). The
OXTR rs53576 SNP also appears to be associated with cardiac reactivity
to infant cries: Non-mothers with the GG genotype had greater heart
rate responses to infant cries, but only when they had low depression
scores (Riem et al., 2011). This genetic polymorphism is likely one of
many other variants involved in cardiac reactivity to infant distress. In
fact, a twin study indicates that nearly half of variance in adults' cardiac
reactivity to infant cry stimuli is explained by genetic factors (Out et al.,
2010). However, as with dopamine polymorphisms, one of the difficulties
with the use of polymorphisms in association studies is the lack of
clear evidence of a functional impact. Although the OXTR rs53576 SNP
has been suggested to influence oxytocin function (Meyer-Lindenberg
213V.R. Mileva-Seitz et al. / Hormones and Behavior 77 (2016) 211–223
Table 1
Candidate gene studies in parenting.
Neurobiological
system
Gene Parental
polymorphisma
Moderatorb
Outcomec
Sample size Child age Reference
Dopamine Dopamine Receptor D1
(DRD1)
rs265981
rs5326
rs4532
rs686
rs265976
– Sensitivity (M)
Vocalization duration (M)
Orienting away from infants frequency (M)
187 Caucasian 6 mo (healthy) Mileva-Seitz et al., 2012a
Dopamine receptor D2
(DRD2)
rs1799978
rs1799732
rs6277
– Sensitivity (M)
Vocalization duration (M)
Orienting away from infants frequency (M)
187 Caucasian 6 mo (healthy) Mileva-Seitz et al., 2012a
Dopamine receptor D4
(DRD4)
Exon III
7-repeat
Daily hassles
COMT genotype
Daily hassles ×
COMT genotype
Sensitivity (M) 176 Caucasian 23 mo (at risk) Van IJzendoorn et al.,
2008
Dopamine transporter
(DAT1)
10-repeat Disruptive child
behavior
Positive parenting (M)
Negative parenting (M)
Number of commands (M)
259 Mixed ethnicity 3.8–7.0 years (ADHD
cases & controls)
Lee et al., 2008
Ankyrin repeat and kinase
domain containing 1
(ANKK1)
Taq1A Child genotype Sensitivity (M) 172 Mixed ethnicity 6–12 mo (healthy) Mills-Koonce et al., 2007
Catechol-O-methyltransferase
(COMT)
Val158met Daily hassles
DRD4 genotype
Daily hassles ×
DRD4 genotype
Sensitivity (M) 176 Caucasian 23 mo (at risk) Van IJzendoorn et al.,
2008
Oxytocin Oxytocin receptor (OXTR) rs53576 5HTT genotype Sensitivity (M) 159 Caucasian 2 years (at risk) Bakermans-Kranenburg
and van IJzendoorn, 2008
Oxytocin receptor (OXRT) rs53576 – Warmth (M, F)
Control (M, F)
Negativitiy (M, F)
500 Mixed ethnicity 6–10 years (healthy) Klahr et al., 2014
Oxytocin receptor (OXTR) rs53576
rs1042778
– Positive parenting (M)
Negative parenting (M)
Hemodynamic responses to child stimuli in
orbitofrontal cortex, anterior cingulate cortex, and
hippocampus
34 Mixed ethnicity 4–6 years (at risk) Michalska et al., 2014
214V.R.Mileva-Seitzetal./HormonesandBehavior77(2016)211–223
Oxytocin receptor (OXTR) rs53576 Depression Cardiac reactivity to infant cries (N) 40 Caucasian – Riem et al., 2011
Oxytocin receptor (OXTR) rs2254298
rs1042778
Plasma oxytocin Parental Gaze (B)
Parent–infant gaze synchrony (B)
Parental Touch (B)
272 Caucasian 4–6 mo (healthy) Feldman et al., 2012
Oxytocin receptor (OXTR) rs237885 Early life
adversity
Breastfeeding duration 201 Mixed ethnicity + 151
Mixed ethnicity (replication
sample)
0–12 mo (healthy) Jonas et al., 2013
Oxytocin receptor (OXTR) rs237885 Early care
quality
Sensitivity (M)
Orienting away from infant frequency (M)
Infant-directed vocalizing duration (M)
Instrumental care (M)
187 Caucasian 6 mo (healthy) Mileva-Seitz et al., 2013
Oxytocin (OXT) rs2740210
rs4813627
Early care
quality
Sensitivity (M)
Orienting away from infant frequency (M)
Infant-directed vocalizing duration (M)
Instrumental care (M)
187 Caucasian 6 mo (healthy) Mileva-Seitz et al., 2013
Oxytocin (OXT)
rs4813627
rs2740210 Early life
adversity
Breastfeeding duration 201 Mixed ethnicity + 151
Mixed ethnicity (replication
sample)
0–12 mo (healthy) Jonas et al., 2013
Cluster of differentiation 38
(CD38)
rs3796863 Plasma
oxytocin
Parental Gaze (B)
Parent-infant gaze synchrony (B)
Parental Touch (B)
272 Caucasian 4–6 mo (healthy) Feldman et al., 2012
Vasopressin Arginine Vasopressin
Receptor 1A (AVPR1A)
RS3
microsatellite
rs1042615
rs7298346
Early life
adversity
Sensitivity (M) 151 Caucasian 18 mo (healthy) Bisceglia et al., 2012
Arginine Vasopressin
Receptor 1A (AVPR1A)
RS3
microsatellite
- Positive parenting (M)
Controlling behavior (M)
Focused support (M)
135 Caucasian 3.5 years (healthy) Avinun et al., 2012
Serotonin Serotonin transporter (5HTT) 5HTTLPR OXTR genotype Sensitivity (M) 159 Caucasian 2 years (at risk) Bakermans-Kranenburg
and van IJzendoorn, 2008
Serotonin transporter (5HTT) 5HTTLPR +
rs25531
Early care
quality
Sensitivity (M)
Orienting away from infant frequency (M)
Perceived attachment to infant (M)
166 Caucasian 6 mo (healthy) Mileva-Seitz et al., 2011
Serotonin transporter (5HTT) 5HTTLPR Observed
fearfulness
Sensitivity (M) 767 Caucasian 14 mo, 36 mo, 48 mo
(repeated measures)
(healthy)
Cents et al., 2014
Serotonin transporter (5HTT) 5HTTLPR Child sex Positive parenting (M) 228 Caucasian 3.5 years (healthy) Pener-Tessler et al., 2013
a
Bolded values indicate a main effect of genotype and/or interaction effect (genotype × moderator) on the outcome.
b
Bolded values indicate a significant interactive effect between the moderator and the genotype.
c
M indicates this variable was measured for mothers; F indicates fathers; B indicates a mixed report of fathers and mothers; and N indicates a non-parent sample; bolded values indicate a significant effect on the outcome.
215V.R.Mileva-Seitzetal./HormonesandBehavior77(2016)211–223
et al., 2011), a meta-analysis of 48 studies (combined N = 17,559) using
this polymorphism found no significant combined effect sizes for five
domains of outcomes (biology, personality, social behavior, psychopathology,
and autism) (Bakermans-Kranenburg and van IJzendoorn,
2014).
Other SNPs in OXTR-related genes have also been explored in
relation to differences in human parenting. For instance, an Israeli
study examined three SNPs (OXTRrs2254298 and rs1042778, and
CD38 rs3796863) in association with parent-infant gaze synchrony
and parental touch (Feldman et al., 2012). Parents with the CD38 CC
genotype and the OXTR rs1042778 TT genotype touched their infants
less frequently than parents with other genotypes, whereas no genetic
associations were found for gaze synchrony (Feldman et al., 2012).
This is an interesting finding as CD38 regulates oxytocin release and
has been found related to autism spectrum disorders (Munesue et al.,
2010). Mice-knockouts for the CD38 gene exhibit reduced oxytocin
levels and deficits in social and maternal behavior (Jin et al., 2007).
Finally, two recent studies indicate that polymorphic variation in the
vasopressin receptor 1A gene associates with differences in maternal
sensitivity (Bisceglia et al., 2012) and structuring and support (Avinun
et al., 2012) toward their children. Vasopressin has structural similarity
to oxytocin and there is mounting evidence for its implication, too, in
the regulation of social behavior (Ebstein et al., 2012; Heinrichs and
Domes, 2008; Meyer-Lindenberg et al., 2011). More work is needed to
establish a potential role for vasopressin in human mothering.
In prairie voles, oxytocin and vasopressin dynamics during pregnancy
are primarily regulated not by the receptors for these peptides (which
remain fairly stable in the brain throughout pregnancy), but instead by
the synthesis and release of the peptides themselves (Ophir et al., 2013).
Thus polymorphisms on the peptide-coding genes, rather than on the
receptor-coding genes, might prove useful to study, also in human
parenting. In this vein, a longitudinal study on Maternal Adversity,
Vulnerability, and Neurodevelopment (MAVAN) examined two SNPs
in the oxytocin peptide gene (OXT rs2740210 and OXT rs4813627)
and one polymorphism in the oxytocin receptor gene (OXTR
rs237885) in association with several dimensions of observed maternal
behavior (Mileva-Seitz et al., 2013). The two OXT SNPs were significantly
associated with differences in maternal vocalizing to the infant, but
not maternal ‘sensitivity’ (a more global measure of parental quality;
Ainsworth et al., 1978). That SNPs associate with some but not other
maternal behavior outcomes could indicate that the multiple dimensions
of parental behavior have differential genetic regulation. A subsequent
study in the same sample revealed that the OXT rs2740210
genotype was also related to breastfeeding duration, with replication
in an independent sample (Jonas et al., 2013). The OXTRrs237885 genotype
was not related to either vocalizing or maternal sensitivity or
breastfeeding. Oxytocin has an undisputed role in parenting, and yet
the evidence for a significant association between genetic variants in
oxytocin genes and human parental behavior is not conclusive. OXTR
genotypes have been suggested as an important direction in parenting
research (Taylor, 2008), but the results from human studies are less
consistent than might be expected on the basis of animal research.
The lack of functional knowledge about many of these SNPs limits the
conclusions that can be drawn. Once more, replications and functional
studies of the oxytocin and vasopressin genes are necessary.
Serotonin
Serotonin (5-hydroxytryptophan; 5-HT) is another monoamine
with major function in the brain. It is involved in regulating mood, emotion,
cognition, and vital functions like sleep, appetite, and sexuality. Animal
studies provide evidence that 5-HT plays at least an indirect role in
parental behavior. For instance, juvenile rats have higher levels of 5-HT
in the MPOA and lower levels of dopamine in the NA than adults, correlating
with a shorter time to spontaneous maternal behavior (1–3 days)
than in adult rats (5–7 days) (Olazábal et al., 2004). The underlying differences
in dopamine and 5-HT levels between juvenile and adult brains
may explain differences in neophobia towards pups (Olazábal et al.,
2004). Early work inducing lesions in the rat median raphe, a region responsible
for the primary serotonin production, showed resulting deficits
in pup retrieval and increased pup cannibalism (Barofsky et al.,
1983). Serotonin reuptake inhibition with fluoxetine increases the appetitive
aspects of rat maternal behavior (Johns et al., 2005). Finally administration
of clozapine results in impairments in rat maternal
behavior and due to the pharmacology of the drug, specifically implicates
the 5-HT2 serotonin receptor in this process and in interaction
with the dopamine system (Zhao and Li, 2009). In primates, 5-HT is implicated
in anxiety arousal of mothers (Maestripieri, 2010). Infants of
abusive or restrictive mothers have lower levels of 5-HT metabolites
(5-HIAA)(Maestripieri et al., 2006). Conversely, monkeys with lower
CSF 5-HIAA levels are more restrictive and rejecting (Maestripieri
et al., 2007). Together this evidence suggests the serotonin system is
an important modulator of parental behavior, either directly or when
acting in concert with the dopamine and oxytocin systems. Moreover,
the serotonin system might indirectly impact parenting through its regulation
of related processes like mood and emotion, both of which are
important to parenting.
Serotonin and human mothering
In humans, dysregulations in brain 5-HT levels are associated with
increased aggressive behaviors, and with the development of psychopathologies,
particularly in the affective spectrum (Lucki, 1998). A single
study assessing the effects of SSRI use on maternal behavior in women
with postpartum depression found an increase in maternal reported appreciation
of motherhood, but no accompanying differences in mother–
infant interactions at 8 weeks postpartum (Logsdon et al., 2009). A
handful of candidate gene studies have explored genetic variants on serotonin
genes in association with differences in parenting behavior. For
instance, a first study reported that the short allele on the serotonin
transporter gene 5HTT was related to lower maternal sensitive responsiveness
(Bakermans-Kranenburg and van IJzendoorn, 2008). A subsequent
study showed the opposite: mothers with the short allele were
more sensitive during interactions with their 6-month old infants, and
less often oriented away from their infants (Mileva-Seitz et al., 2011).
Mileva-Seitz et al. speculated that the discrepant findings in those first
two studies of the short 5HTT allele were owing to methodological
differences: if it can be assumed that carriers of the short allele are
more responsive to environments, both good and bad, then a less stressful
experimental protocol (as in the Mileva-Seitz et al. study involving
home visits) might be associated with greater parental sensitivity than
a more stressful experimental protocol (as in the BakermansKranenburg
and Van IJzendoorn study involving structured laboratory
tasks and children with high levels of externalizing behavior). The findings
initially reported by Mileva-Seitz et al. (2011) were later replicated
in a large cohort using repeated measures of observed maternal
sensitivity (Cents et al., 2014). A twin study revealed a gender effect in
the association between the short allele and parenting: for mothers of
boys, positive parenting decreased with the number of maternal short
alleles, whereas for mothers of girls positive parenting was not associated
with the number of short alleles (Pener-Tessler et al., 2013). These
findings emphasize the importance of study design and covariates in
the search for replication.
Other genetic pathways
There is considerable overlap in both region of expression and functional
significance of the three neurotransmitter systems described
above—oxytocin, dopamine, and serotonin—and interactions between
these systems could influence social behavior (Baskerville and
Douglas, 2010; Emiliano et al., 2007; Skuse and Gallagher, 2011). In
rats, an interaction between oxytocin and dopamine helps regulate maternal
behavior (Shahrokh et al., 2010). However, almost nothing else is
known about the potential overlap between these three systems in the
expression of maternal care. Additional closely related systems might
216 V.R. Mileva-Seitz et al. / Hormones and Behavior 77 (2016) 211–223
also be involved. For instance, variation in the mu opioid receptor gene,
OPRM1, is associated with maternal attachment to infants in freeranging
rhesus macaques (Higham et al., 2011). Mu opioid receptor
genes are good candidate genes for study in human parenting for several
reasons: they are implicated in social reward processing in the NA of
the rat (Trezza et al., 2011) and are regulated by both the dopamine and
oxytocin systems in the brain (Gigliucci et al., 2014). Finally, the SNP on
the OPRM1 gene in rhesus macaques has a functionally similar ortholog
in humans (Bond et al., 1998; Miller et al., 2004).
Another useful strategy for identifying genes and pathways involved
in parenting has been to identify sexually dimorphic genes: that is,
genes that are expressed at different levels in females and males.
Subsequently their expression can be experimentally disrupted to
detect resulting changes in parental behavior. This approach has led to
the successful identification of several other genes without which
normal maternal behaviors (e.g. retrieval of pups to the nest and aggression
toward intruders) are disturbed (Xu et al., 2012). An early study in
mice indicated that the deletion of the paternally imprinted Peg3 gene
leads to impairments of maternal behavior so severe they often led to
the death of the offspring (Li et al., 1999). Maternal memory and learning
in the mouse appears to be partially dependent on the estrogen
receptor-β (Esr2) and oxytocin, and appears to require stable changes
in gene expression to maintain heightened maternal responsiveness
for long durations (Stolzenberg et al., 2014). Subsequent studies have
shown that compared with virgin mice, postpartum mice exhibit
enrichment in the expression of hundreds of genes involved in reward
and addiction (Zhao et al., 2014). This suggests that the shift to parenting
is intricately tied to changes in the reward-processing mechanisms
in the brain. Studies comparing wide-scale gene expression in postpartum
and virgin rats, specifically in brain regions thought to be involved
in parenting (e.g. MPOA, medial prefrontal cortex), support the notion
that subsets of genes regulating maternal behavior and maternal memory
are also implicated in psychopathologies like social disorders, depression,
psychosis, and bipolar disorder (Driessen et al., 2014;
Eisinger et al., 2014; Zhao et al., 2014). Thus the neural plasticity required
during the normal shift to parenting also puts mothers at risk
for mental health disorders often associated with the postpartum
period.
Limitations of the candidate gene approach
Though candidate gene studies have reported thousands of genetic
variants associated with a range of complex phenotypes, such studies
suffer from a general lack of replication among a suite of other limitations
(e.g., neglecting the importance of the environment; Rutter,
2005). On the one hand, such studies often use invalid measure for complex
traits (Ebstein, 2006) and small sample sizes with insufficient
power to detect true effects (false negatives). On the other hand, an inconsistent
use of correction for multiple testing often results in spurious
effects (false positives). Moreover, even when effects can be replicated,
meta-analyses often reveal non-significant combined effects after taking
into account multiple studies conducted in a variety of environments
and populations, reporting findings in the opposite directions.
Finally, the functional significance of most of these variants—even
some of the most widely studied (e.g. DRD4 Exon III 7-repeat)—is still
unclear (Pappa et al., in preparation).
The role of genes as moderators of environmental influences on
parenting (G × E)
Main effects of genetic variants on parenting might represent only a
small part of the genetic influences on parental behavior. In fact the
most important genetic effects in shaping parenting may reside in the
interaction of genes with the environment. In the words of Urie
Bronfenbrenner (1979): main effects are to be found in interactions.
Gene-by-environment interactions may explain why some parents are
more and others less impacted by disadvantageous childhoods or
concurrent daily stresses in parenting their offspring. For example, in
the MAVAN study mentioned before, OXTR rs2740210 moderated the
effect of early life experiences on depressive feelings, which in turn affected
breastfeeding. In mothers with the CC genotype childhood
abuse experiences were related to lower maternal mood at 6 months
postpartum, which was associated with reduced breastfeeding duration
across the first year (Jonas et al., 2013).
Parents may be differentially susceptible to environmental influences
for better and for worse. In a study with Israeli mothers of twins,
mothers with the DRD4 7-repeat allele who experienced more stress
around child birth (e.g., low gestational age, low birth weight, and
prolonged stay at the neonatal intensive care unit) were less sensitive
in the interaction with their children at age 3.5 than other mothers,
whereas mothers with the DRD4 7-repeat allele whose children had
few complications around birth showed the highest levels of parental
sensitivity (Fortuna et al., 2011). Mothers without the 7-repeat allele
seemed less affected by the perinatal strains and stresses in their
parenting interactions with the toddlers. In another G × E study on
parenting not only DRD4, but also the COMT gene polymorphisms
were included. Mothers and toddlers were observed in a series of
problem-solving tasks, and parents reported on their daily hassles
(van IJzendoorn et al., 2008). The two dopamine-related genes moderated
the negative influence of daily hassles on sensitive parenting behavior
to their offspring. In parents with the combination of genes
leading to the least efficient dopaminergic system functioning
(COMTval allele, DRD4 7-repeat allele), more daily hassles were associated
with less sensitive parenting, but in this group lower levels of daily
hassles were associated with more sensitive parenting. The other combinations
of COMT and DRD4 polymorphisms did not show significant
associations between daily hassles and maternal sensitivity.
In a large cohort (the Fragile Families and Child Wellbeing Study) of
American children born between 1998 and 2000, and going through the
Great Recession of 2007 to 2009, Lee et al. (2013) examined the effects
of economic hardships on harsh parenting, and explored whether this
association was moderated by dopamine-related genes. Harsh parenting
was assessed at three time-points throughout the first 10 years
after birth using a selection of items from the Conflict Tactics Scales
(Straus et al., 1998). More than 2600 mothers were genotyped, and
the researchers focused on Taq1A rs1800497 of the DRD2-related
gene ANKK1, because in previous work it had been related to the number
of D2 dopamine receptors in the brain and seemed associated with
being more or less susceptible to aggression. The authors found support
for the differential susceptibility theory. For mothers with a T allele,
harsh parenting increased as macroeconomic conditions worsened but
decreased as conditions improved. By contrast, for mothers with the
CC genotype, harsh parenting did not change in response to changes
in macroeconomic conditions. Thus, parenting of the T allele carriers
was more susceptible than those with the CC genotype to environmental
changes, for better and for worse.
In these G × E studies for carriers of dopamine-related genes similar
patterns of results emerge: Parents with the DRD4 7-repeat allele,
Taq1A T-allele, or a COMT val allele were more affected by socioemotional
stressors than parents without these susceptible genotypes.
Under conditions of stress, they are among the least sensitive parents,
but lower levels of stress are accompanied by an increase in caregiving
sensitivity, much stronger so than for parents without this genotype.
The role of DRD4 and other dopamine genes as susceptibility markers
may thus not be limited to children, where these markers were discovered
first (Bakermans-kranenburg and van IJzendoorn, 2006), but
rather might extend to parents (Bakermans-Kranenburg and van
IJzendoorn, 2015). Differential susceptibility theory suggests that the
same genotype that make individuals vulnerable to adversity may also
make them disproportionately likely to benefit from contextual support
(Belsky et al., 2007). The differential susceptibility hypothesis proposes
that in positive environments ‘vulnerable’ individuals, the so-called
‘orchids’, may flourish even more than their peers who are less
217V.R. Mileva-Seitz et al. / Hormones and Behavior 77 (2016) 211–223
susceptible, the so-called ‘dandelions’ (Bakermans-Kranenburg and van
IJzendoorn, 2007; Belsky et al., 2007; Ellis et al., 2011). The model's
evolutionary foundation implies that certain genotypes must be called
susceptibility alleles instead of risk alleles as was common in the traditional
diathesis-stress or cumulative risk models of the past three decades
(Bakermans-Kranenburg and van IJzendoorn, 2015).
The mechanism of environmental mediation: Epigenetics
In the past behavioral and molecular genetics assumed that the genetic
make-up of every individual was invariable, originating from conception
to remain basically the same across the whole life-span, except
in rare cases of mutations through radiation or other toxic influences.
This assumption is valid as far as it pertains to the fixed sequence of
the DNA base-pairs. But the expression of genes is (partly) regulated
by epigenetic influences, and epigenetic changes through methylation,
acetylation or other pathways affect the functional significance of structurally
identical genotypes (Brookes and Shi, 2014; Kundakovic and
Champagne, 2014; Meaney, 2010). The most widely studied epigenetic
mechanisms is methylation, which is simply put the blocking of gene
expression through the linking of a methyl (CH3) molecule to one of
the bases, cytosine, at a CpG site located in a gene-promoter region.
Methylation might be loosely compared to a cork on a bottle of champagne,
down-regulating the escape of bubbles (messenger RNA) and
thus modulating the level of protein and enzyme production encoded
for by the specific gene (van IJzendoorn et al., 2011).
Ironically, dandelions are a prime example of the power of epigenetics
because they show flexible adaptation despite asexual reproduction
(apomicts). The plants that grow from the mother plant's seeds are
structurally genetic clones, identical to the mother plant, but they nevertheless
adapt to a large variety of conditions. Their epigenetic patterns
might be responsible for this adaptation as these patterns vary strongly
in response to environmental conditions, and, moreover, epigenetic features
seem to be transmitted across generations and thus become determinants
of ‘parenting’ (Verhoeven et al., 2010). In an experiment with
various nutrient conditions (sufficient food versus shortage of food)
Verhoeven et al. (2010) demonstrated that compared to control plants
growing in a high-nutrient environment, dandelions exposed to food
shortage produced much less offspring shoot—which is an indicator of
fitness. Moreover the offspring of the deprived dandelions adapted
well to deprived circumstances, because they seemed to be preprogrammed
for hardship, whereas the offspring of controls fared poorly
in nutrient shortage. This difference in adaptation persisted into the
third generation and was associated with differences in epigenetic characteristics
in DNA methylation-sensitive regions of the dandelion
genome.
Epigenetic studies of rodents (e.g., Meaney, 2010; Szyf et al., 2005)
have made clear that the caregiving environment – for example the
amount of licking and grooming and arch-back nursing that parents
provide—may radically alter epigenetic patterns and consequently
gene expression in the pups, and not only in the pups exposed to sensitive
parenting themselves (or deprived thereof) but even in these pups'
offspring. They carry on to be sensitive or insensitive parents
themselves depending on the epigenetic changes they ‘inherited’ from
their parents (Meaney, 2010). In particular altered methylation of the
glucocorticoid receptor gene seems to induce long-term changes in response
to stress, affecting the next generation (Weaver et al., 2004;
Zhang and Meaney, 2010; Zhang et al., 2013). One of the first epigenetic
studies on human behavioral development was also conducted by
Meaney's team (McGowan et al., 2009). They examined the brains of
deceased young males stored in the Quebec Suicide Brain Bank,
matching suicide victims with and without a history of abuse, and comparing
these two groups with age- and gender-matched victims of fatal
accidents. They found that through methylation, glucocorticoid receptor
(GR) gene expression in the hippocampus of the suicide victims was decreased
but only when they had experienced child abuse. Hippocampal
glucocorticoid receptors play a crucial role in down-regulating the
HPA-axis that is responsible for the level of the stress hormone cortisol.
In other studies similar epigenetic alterations have been found as a
result of child maltreatment (Perroud et al., 2014) or structural neglect
in orphanages (Naumova et al., 2012).
Even monozygotic twins with identical DNA structures may grow
apart in gene expression. They may develop radically different parenting
patterns because of changes in the epigenome that influences and
regulates the expression of genes. Fraga et al. (2005) found for example
that a 3-year-old monozygotic twin pair had about 1000 genes with differential
gene expression, whereas a 50-year-old monozygotic twin pair
showed more than 5000 differently expressed genes. Differences in the
epigenome increase with age and with non-shared environmental influences,
implying that they are larger when twins have spent more
time in separate environments. In a sample of monozygotic twin pairs
aged 18 to 89 years Talens et al. (2012) confirmed that with increasing
age significantly more epigenetic changes of the differentially methylated
region (DMR, representing an entire stretch of DNA rich in methylation
sites and which exhibits a different methylation pattern among
different samples) of the insulin-like growth factor 2 (IGF2) within
these twin pairs could be observed.
Prenatal parenting
Parenting starts before birth, for example when pregnant mothers
decide to continue or quit smoking or the use of SSRIs, or when they
observe the moving fetus in the womb through ultrasound recordings
and respond to these movements by gentle touch or vocalizations.
Severe prenatal parental stress may also exert substantial influence on
the fetus, continuing after birth, and methylation may be one of the
mechanisms through which prenatal parenting is transmitted to the
fetus. For instance, in pregnant rats, multiple genes are up- or downregulated
in the hypothalamus, including genes encoding for dopamine
receptors, prolactin, and a number of cholinergic receptors (Mann,
2014). In humans, differential methylation may play a crucial role in intergenerational
transmission of the Dutch Hunger Winter effects on
birth weight and somatic issues (obesity, cardiovascular risks), and
maybe also on patterns of parental behavior. In the harsh winter of
1944–1945 the Western and Northern part of the Netherlands were
still occupied by the German forces who rationed food supply for the civilian
population to a bare minimum of about 600 calories per day.
Offspring conceived at the height of this Hunger Winter were born
with a normal weight but they had elevated risk for obesity in adulthood,
and their offspring (grandchildren of the pregnant women in
the Hunger Winter) were born with higher weight. In contrast, offspring
conceived a few months prior to the famine were born with lower
weight but they did not develop obesity and their offspring (third generation)
had normal birth weight (Roseboom et al., 2006). The first trimester
in utero seemed to be critical. Heijmans et al. (2008) showed
that IGF2 methylation might be the epigenetic mediating mechanism.
Offspring exposed to the famine just after conception had about 5%
lower methylation in the IGF2 region compared to their siblings conceived
earlier or later, even 60 years after the Hunger Winter. In a recent
study of the same sample, Heijmans and colleagues (Tobi et al., 2014)
showed that methylation differences were not restricted to IGF2. They
found six prenatal malnutrition related differentially methylated regions
(p-DMRs), one of which was significantly associated with cholesterol
levels in adulthood.
In the Generation R study, a large cohort study of about 10,000 children
and their families in the Netherlands (Jaddoe et al., 2012) the question
was addressed why smoking during pregnancy would lead to lower
birth weight. Smoking was assessed at three time-points during the
three trimesters of pregnancy and methylation of IGF2 DMR was analyzed
in cord blood. A quarter of the pregnant mothers continued
smoking, and smoking was indeed related to lower birth weight. Most
importantly, smoking was associated with lower IGF2DMR methylation
levels in a dose–response manner, also after controlling for potential
218 V.R. Mileva-Seitz et al. / Hormones and Behavior 77 (2016) 211–223
confounders such as socioeconomic status. IGF2 methylation mediated
the effects of smoking on birth weight (Bouwland-Both et al., in
preparation). Moreover, prenatal adversities impacting on the mothers
were examined, including negative life-events, symptoms of depression
and anxiety, conflicts between the partners, and social issues such as
financial problems. The global risk factor was associated with level of
problem behaviors of the children at 6 years of age. An Epigenome
Wide Association Study (EWAS) showed several suggestive hits and
one significant DMR on chromosome 20, covering 3 CpGs for which
the functional meaning still has to be explored (Rijlaarsdam, in
preparation). Although the sample (more than 900 newborns) was
much larger than the average sample used in behavioral epigenetics,
these preliminary findings have to be replicated before drawing firm
conclusions.
A moderated mediation model of the (epi)genetics of parenting
There is a dearth of studies on the (epi)genetics of parenting, in particular
on human parenting, in contrast to epigenetic studies on human
diseases like cancer (Brookes and Shi, 2014). This is surprising because
parenting is an all-pervasive phenomenon with high impact on
everyone's life. But it is also a complex phenotype without consensus
about how to measure parenting in the most reliable and valid way.
Therefore, cooperation of large cohort studies needed to unravel the
(epi)genetics of parenting on the molecular level has proven to be complicated,
and most of the current findings are in need of replication. Nevertheless
we brought together several strands of genetically informed
research on parenting, with results from behavioral genetics,
candidate-gene studies, G × E research, and epigenetics. We speculate
that the various strands might be combined in a model in which there
is room for main effects of genes, interactions between genes and environment,
environmental main effects, and mediating effects of epigenetics
in shaping parenting (see Fig. 1). The transmission of epigenetic
marks to the next generation of parents may be just one of the many
ways of non-genetic intergenerational transmission. Parentingrelevant
information can be carried across generations by hormones, cytokines,
and even microorganisms, without the involvement of the
gametes (Toth, 2015). In fact, it is still unclear whether and how epigenetic
signatures are transmitted across generations in humans.
In the model we have outlined, the parental epigenome mediates
the influence of grandparenting on parental behavior. Abusive grandparental
behavior may change methylation patterns of the OXTR, 5HTTLPR
or GR genotypes in the offspring, and may thus change set-points for the
oxytocin, serotonin, or cortisol levels which in turn might lead to insensitive
or abusive parenting in adulthood. Parental susceptibility genes
such as DRD4 and DRD2 may moderate this mediation as well as the influence
of the parental environment on parental behavior. For example,
stressful life-events and adverse conditions might have more impact on
parents with susceptible genetic variants, and these parents might also
have been more open to epigenetic changes in childhood. Parents inherit
their susceptibility genes from the grandparents, which is of course a
genetic main effect. Lastly, genes might be associated with the parental
environment through passive or active gene–environment correlations
as documented by twin studies. Parents with less efficient oxytocin
genes might be less inclined to seek the stimulating and rewarding affective
interactions and touch with their offspring, which might result
in a downward spiral of ever more insensitive and disharmonious
parent–child interactions.
The future of genetic parenting research
Despite the neural and behavioral differences between rodents and
humans, animal models will continue to inform the field of human parenting
at all levels, from the genetic, through the environmental, to the
epigenetic. Mammals share an ancient evolutionary drive for parental
responsiveness and appear to exhibit a general overlap in the neural regions
dedicated to parental and other motivated behaviors, with some
species-specific differences and exceptions. Human parenting seems
more complex than rodent parenting, and yet what we have learned
about the regulation of rodent maternal behavior has driven much of
the work on the genetic influences in human parents (e.g. MilevaSeitz
et al., 2012b).
Far less explored in this field are the genetic mechanisms underlying
caregivers other than the mother, including fathers. This is remarkable
considering the fact that almost half a century ago Rosenblatt (1967)
already had shown that ‘there is a basic maternal responsiveness in
rats which is not dependent upon hormones or sex for its arousal’ and
can be triggered solely by the exposure to pups, in female as well as
male rats. Because across animal species and even across human
Fig. 1. The genetics of parenting: a mediated moderation model. Note: The parental epigenome mediates the influence of grandparenting on parental behavior but parental susceptibility
genes may moderate this mediation as well as the influence of the parental environment (e.g. stress) on parental behavior.
219V.R. Mileva-Seitz et al. / Hormones and Behavior 77 (2016) 211–223
cultures fathers often play differing roles in the raising of their offspring,
fatherhood and its biological underpinnings have been put on the
backburner and sometimes even ignored. A meta-analysis on twin
studies of parenting indicated that heritability estimates are in fact
similar for both fathers and mothers (Klahr and Burt, 2014). This suggests
that the study of genetic mechanisms underlying fathers might
be just as fruitful as the study of mothering. The ‘father of mothering’
(Fleming et al., 2009) would have applauded such an approach.
Finally, if we are to acknowledge that human parenting is infinitely
more complex than rodent parenting, we must address the likelihood
that diverse mechanisms regulate what parents think and do. We
might begin to ‘think smaller’ when hypothesizing biological underpinnings
to behavior, by examining sub-phenotypes of discrete, quantifiable
behaviors. Behavioral microanalysis can untangle phenotypic
complexities: the frequencies, durations, and contingencies with
which parents perform behaviors X, Y, and Z, likely represent intricate
layers of the overarching ‘parental quality’ phenotype obtained from
macroanalysis. A neural mechanism and its biological regulators
(genetic or epigenetic marker) might more readily associate with a discrete
micro-phenotype than with an overarching macro-phenotype. Or
perhaps not, if the dyadic organization of discrete interactive behaviors
is the hallmark of parenting (Sroufe and Waters, 1977; Feldman, 2007).
This is a question that remains to be addressed.
Conflict of interest
None.
Acknowledgments
Grant support during the writing of this paper was provided by the
Netherlands Organization for Scientific Research (NWO): RUBICON
prize (446-11-023) to V.R.M.-S., an NWO VICI grant (453-09-003) to
M.B.-K., and an NWO SPINOZA prize to M.H.v.IJ. Additional funding to
M.H.v.IJ. and M.B.-K. was provided by The Consortium on Individual
Development (CID), funded through the Gravitation program of the
Dutch Ministry of Education, Culture, and Science and the Netherlands
Organization for Scientific Research (NWO grant number 024.001.003).
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