Effect of bullying exposure on immune-system related gene expression: A longitudinal twin study

Epidemiological data indicate that an alarming number of youth report
experiences of bullying victimization (World Health Organization, 2016). The
deleterious consequences of bullying victimization include both mental health
(e.g., depressive symptoms, anxiety, suicidal though) as well physical health
(e.g., sleep problems, cardiovascular risk) outcomes and may extend well into
adulthood (e.g., McDougall & Vaillancourt, 2015; Takizawa et al., 2014).
Because bullying may have such pervasive and long-lasting consequences on
people*s lives, there is a need for a better understanding of the processes
underlying these deleterious effects. This knowledge is of critical importance
to properly inform prevention and intervention efforts aimed at reducing the
negative consequences of bullying exposure. A major next step to truly
integrate psychological with physiological underlying processes would be to
demonstrate that the long-lasting effects of bullying may be rooted in changes
occurring at the molecular level. Ground-breaking work in functional genomics
and human social genomics (Cole, 2014; Slavich & Cole, 2013) raises attention
to the possibility that such molecular pathways may in fact explain how
adversity (e.g., low socio-economic status; child abuse) could get biologically
embedded and have long-lasting effects on both mental and physical health
outcomes. Specifically, a number of studies using transcriptional profiling
have demonstrated that similar adversities may up-regulate the activity of
pro-inflammatory genes in leukocytes (i.e., immune systems cells) and, at the
same time, downregulate the activity of genes involved in antiviral and
antibody-related responses (e.g., Cole et al., 2015; Levine et al., 2017;
Powell et al., 2013). This pattern of gene expression (i.e., transcriptome
profile) has been labelled Conserved Transcriptional Response to Adversity
(CTRA) and it is hypothesized to represent an evolutionary maintained response
to deal with the microbial and physiological correlates of threat (Cole, 2014;
Slavich & Irwin, 2014). Hence, understanding whether bullying victimization is
associated with the CTRA gene expression profile represents a crucial step to
elucidate the molecular mechanisms through which bullying may pose risk for
poor health. The proposed study will be the first study to apply a genome-wide
gene expression approach to examine the effects of bullying on the CTRA
profile.

These associations will be examined in a sample of young adult twins, about
which information on bullying victimization exposure was previously collected
during early adolescence (10-12 years old). Examining these associations in
this population will substantially extend prior research on the CTRA in three
main ways. First, differences in individuals* genetic factors will be accounted
for. This is important given that: a) individuals with a different genetic
make-up are likely to show different patterns of gene activity (Slavich & Cole,
2013) and b) prior work has shown that bullying victimization experiences are
also influenced by genetic factors (Ball et al., 2008; Brendgen et al., 2011).
Thus, the association between bullying and the CTRA may be spurious because
variations in the genetic make-up contribute to both victimization as well as
gene expression. Notably, prior longitudinal twin studies examining the effects
of bullying on health indicated that, as compared to their non-bullied
co-twins, twins exposed to bully remained at increased risk for
psychopathology, (Arseneault et al., 2008; Silberg et al., 2016; Singham et
al., 2017; Schaefer et al., 2018). Second, a twin design will allow us to
quantify, for the very first time, genetic and environmental components of the
CTRA, and the extent to which these components are shared with bullying
victimization. This is crucial as the heritability of the CTRA remains unknown
and has rarely been taken into account in prior research examining
environmental effects. Finally, examining these associations in this specific
population will offer the unique opportunity to investigate the extent to which
the effects of adolescent bullying victimization on gene expression last over
time. If an elevated CTRA profile represents a possible pathway through which
exposure to bullying in adolescence increases the risk for negative health
outcomes, several years after bullying experiences terminated, these effects
should be evident also in (early) adulthood. There are strong theoretical
reasons to expect that the CTRA profile may get biologically embedded (Miller
et al., 2011; Slavich & Cole, 2013) and may therefore increase the risk for
mental health problems as well as physical health problems, which likely emerge
only later in life, during adulthood (Hostinar et al., 2018). This longitudinal
twin study will directly test whether the CTRA profile mediates the link
between bullying history and poor mental or physical health several years later
during adulthood, when some of the more severe health outcomes associated with
chronic up-regulation of inflammatory responses may begin to emerge (e.g.,
increased risk for cardiovascular diseases; Hostinar et al., 2018; Slavich &
Irwin, 2014).

Primary Objective:
1)To examine whether exposure to bullying victimization in adolescence is
associated with the CTRA transcriptome profile(increased pro-inflammatory
gene expression and decreased antiviral and antibody-related gene expression)
in early adulthood.
2)To quantify the genetic and environmental components of the CTRA gene
expression profile of di- and monozygotic twins and to explore the
genetic and environmental overlap between the CTRA profile and bullying
victimization.

Secondary Objective:
To investigate the CTRA gene expression profile as mediator in the link
between bullying victimization exposure during adolescence and poor mental
(anxiety, depression, burnout) and physical health (cardiovascular risk)
outcomes in early adulthood.

A classic twin design will be used. Specifically, early adult mono-and
dizygotic twins will be recruited from the Netherlands Twin Register (NTR).
We will make use of retrospective and newly collected data:
-Retrospective data on bullying victimization collected at age 10-12y
old will be used as inclusion criteria in this study, where focus will be on
the presence of the survey itself and not the absence of presence of bullying.
-After consent, participants will complete online questionnaires(e.g., on
bullying victimization, mental and physical health)and self-collect blood
drops at home for gene expression profiling.

In our opinion, there are no risks attached to joining the study and the
participant burden is low. The only disadvantage is thus time investment and
maybe minor short pain from the blood collection at home. As a member of the
Netherlands Twin Register, the participants receive already some benefits like
a newsletter.