Epigenetic trajectories of biological response to adolescent psychosocial stress: A novel longitudinal study of discordant monozygotic twins

Stress is a normal, adaptive response to stressors (e.g. events that make a person feel threatened or upset) in our environment. However extensive research on the biology of stress now shows that healthy development can be derailed by excessive or prolonged activation of stress response systems in the body especially during important developmental periods in life such as adolescence. Exposure to severe stress during early life unfortunately is not uncommon. A World Health Organization survey reported that nearly 40% of adults experienced some form of severe stress during childhood and adolescence. Exposure to severe stress may have immediate or long lasting damaging effects on learning, behavior, and health. Therefore, it is imperative that we develop a better understanding of how exposure to psychosocial stress during adolescence gets under the skin to leave lasting biological imprints.

There is now increasing evidence to show that one of the ways in which severe psychosocial stress exposure can lead to physical and emotional problems is by getting underneath the skin and influencing the degree to which genes are turned on and off. This regulation of gene expression is known as epigenetics and often occurs through changes in DNA methylation. Initial studies have shown that individuals exposed to severe psychosocial stress have different patterns of DNA methylation (epigenetic 'signatures') compared to individuals exposed to no/minimal stressful life events. However limited conclusions can be drawn from these studies as they often do not fully account for factors that are important in one's reactivity to stress including age, sex and genetic difference between individuals.

Taking advantage of an established longitudinal twin study, our team of biological and social science experts will investigate epigenetic differences within 100 genetically identical twin pairs that exposed to different level of severe psychosocial stress during adolescence. In particular, all of these carefully selected twin pairs were not exposed to any major psychosocial stressors during childhood but in adolescence one twin is exposed to severe psychosocial stress while the co-twin is not. Severe psychosocial stress includes being physically attacked, beaten by parent, frequently bullied, sexually assaulted, persistently harassed on the internet or via a mobile phone, witnessing domestic violence, having a serious illness and being involved in an accident (e.g., a car accident). The use of genetically identical twins who essentially have the same genes and family experiences as well as age and sex will allow us to ascertain the 'purer' impact of psychosocial stress on the epigenetic signatures. Utilising repeated assessments over time (i.e. before and after exposure to stress) is a powerful design as it enables exploration of changes that occur within the same child rather than simply comparing one child to another. We will also investigate whether these stress-associated epigenetic signatures are similar or different in DNA extracted from cheek swabs and blood as this will help us to know whether these 'signatures' can be detected using minimally invasive procedures. The findings from this study will shed light on how biological systems operate under environmental challenge with the potential to ultimately advance understanding of how to sustain lifelong health and wellbeing and prevent health inequalities through early detection of the biological impact of psychosocial stress exposure which will aid prevention efforts. In addition, our multidisciplinary team is highly committed to increase awareness about epigenetics and how the environment may influence the way our genes are expressed and ultimately impact upon cognition and behaviour. This will be achieved through our team's ongoing public engagement with schools and science open days, as well as hosting workshops for university students across London.

Who will benefit? The findings from this project will be of interest to and benefit biological and social scientists, PhD, A-Level and school students, and the wider public. It will also have an impact on the early career researchers leading the project and the postdoctoral scientist employed by the grant.

How will they benefit? Biological and social scientists anywhere in the world will benefit by being able to utilise the DNA methylation profiles from the 800 samples this project will generate for their own research or to contribute to a meta-analysis by downloading the de-identified dataset from the Gene Expression Omnibus (GEO) repository. They will also be able to download from the internet the new analytical pipeline we develop in R for longitudinal genome-wide epigenetic data to apply when analysing their own data. Moreover, the potential for cross-disciplinary working will be enhanced through our publication during this project of integrative opinion pieces outlining how biological and social scientists can work together to advance understanding of stress biology.

This project will directly impact on the two early career-researchers leading this biosocial project as it will provide them with a unique opportunity to enhance their project, people and financial management skills as well as increase their multidisciplinary skills through collaborating to deliver this biosocial project. The postdoctoral scientist employed by the grant will develop new skills in conducting longitudinal epigenetic analysis, integrating social and biological data and media engagement which s/he will be able to utilise in future academic or industrial employment. S/he will also receive training in early career development and mentorship from the investigators to develop a fellowship application thus contributing to his/future career prospects.

One of the key objectives of this project is to build and enhance capability for adopting cross-disciplinary approaches to research. This will be achieved through our proposed two 3-day multidisciplinary workshops for biological and science PhD students across the London ESRC Doctoral Training Centre Network. The slides and audio captures from these sessions will be made available on the internal e-learning platform for all King's PhD students to view as well as on the University website to maximise the information available to the wider public. Dr Fisher will also run workshops for PhD students on the bio-psycho-social consequences of stress exposure to accompany a theatre production of the Pelican. Additionally, she will present the findings generated through this project at the national British Psychological Society Student events to encourage A-level students to pursue a career in research. Dr Wong will deliver science sessions to secondary school children, in collaboration with teachers, around epigenetics and explain how the environment may influence the way our genes are expressed and impact upon cognition and behaviour. In addition, this study will benefit the wider public by stimulating discussions about epigenetics and increasing awareness of how psychosocial stress gets under our skin to influence how our genes function and ultimately impact on health and well-being across the life-course. This impact will be realised through the project team communicating key findings to the public via science open days at King's, national science festivals, press releases, TV and radio appearances, media articles, newsletters to study participants, and discussions with a community audience following a theatre production. These activities will be facilitated and supported by the Institute of Psychiatry Psychology & Neuroscience's Public Relations Officer and Press Office. In the longer-term the findings from this project could enable the early detection of the biological impact of psychosocial stress exposure which would aid prevention efforts and subsequently improve lifelong health and well-being.