INTERpreting epigenetic signatures in STudies of Early Life Adversity (InterStELA)

Lead Research Organisation: University of Bristol
Department Name: Social Medicine

Abstract

Early life adversity can have a significant and lasting effect on social, developmental, and health outcomes; various markers of early life adversity such as low socio-economic position (SEP); parental death, illness or divorce; separation from parents; parental mental health or addiction; lack of warmth and affection of parent-child relationships; residential instability, and physical, emotional and sexual abuse are associated with lower educational attainment, income and economic participation, as well as with adverse health behaviours and poorer mental and physical health outcomes. Reducing or potentially eliminating the harmful effects of early adversity is crucial for combating inequalities.
There is a large body of evidence documenting and describing the long-term consequences of early life adversity, but the pathways and mechanisms through which they occur remain uncertain. In order for early life adversity to influence later outcomes, biological systems must be affected. Epigenetics is a potential molecular mechanism linking early life adversity with later outcomes. DNA methylation is one type of epigenetic change. It is a chemical change to our DNA that influences the extent to which our genes are expressed. DNA methylation can respond to environmental factors in early life, which means it may be very useful to study early life adversity. Animal models have shown links between early life stress and altered methylation patterns, and more recently evidence from human studies has shown that low SEP and abuse are associated with differences in methylation patterns.
The aim of this project is to create a network of researchers working on the relationship between early life adversity and DNA methylation. Bringing together a team of social and biological researchers will enable the researchers to share data and expertise in order to drive the field forwards and speed up progress. The researchers will use existing high-quality data from studies where people have been followed across the life course in order to better understand how early life adversity affects changes in DNA methylation and whether there are other factors that alter these relationships.
In addition to carrying out specific research projects in this area, network members will meet at a series of workshops, in which the results from research will be discussed and future projects will be planned.

Planned Impact

The overarching goal of InterSTELA is to further understanding of the relationship between early life adversity and DNA methylation, and to expedite progress and methodological developments in this area. Thus the key groups we anticipate having an impact on are the public, social and health policy makers, and the scientific community.
The research carried out in InterSTELA will be of relevance to the general public, since it aims to further our understanding of the ways in which our lived experiences are embodied. We will ensure that our findings are communicated to the public through public engagement activities, as detailed in the Pathways to Impact section.
Social and health policy makers rely on high quality evidence to inform the design of policies and interventions. Our research will shed light on the potential reversibility of the long-term consequences of early life adversity, and the pathways through which such reversibility may occur. Our findings will thus be useful to inform the design of policies that aim to reduce or alleviate the harms caused by early life adversity, and to predict the potential benefits from such interventions. The inclusion of a wide range of biological and social researchers in the InterSTELA network, many of whom have experience of engaging policy makers and/or in intervention design, will facilitate dissemination to relevant parties.
As detailed in the academic beneficiaries section, our research is of relevance to a wide range of academics. Research findings will be published in high quality peer reviewed journals - both biological and social - and presented at a range of conferences. Methodological innovations will be published in a timely manner, including syntax for widely used statistical software (e.g. Stata or R) and new Stata commands/R packages. Links with other genetic and epigenetic consortia will facilitate our broad academic dissemination strategy, and a network website will advertise the existence of the website and provide a repository for workshop presentations and links to published papers. Another important form of dissemination to the academic community will be training. The School of Social and Community Medicine, University of Bristol hosts a programme of high-quality short courses. We will develop a course focused on early life adversity and epigenetics - this will be delivered internally within the University of Bristol and other partner organisations within the network, as well as being run as a satellite course to at least one major international meeting (funds are requested for this). Through the leadership of InterSTELA by a team of early- and mid-career researchers who are closer to the hands-on conduct of research than our senior colleagues, we aim to promote a strong inter-disciplinary culture and genuine multidisciplinary working (rather than linkage between separate projects run by academics from different disciplines).
 
Description 1. Associations between early life adversity and DNA methylation.
We have used two cohorts of women in mid-life (mothers in the ALSPAC cohort, and participants in the MRC National Survey of Health and Development, NSHD) to assess associations of socioeconomic position and a wide range of measures of early life adversity with DNA methylation age acceleration (Lawn et al. HMG 2018). Sexual abuse was strongly associated with age acceleration in ALSPAC (sexual abuse data were not available in NSHD), e.g. sexual abuse associated with a 3.41 years higher DNA methylation age at age 47 years (95% CI 1.53 to 5.29) after adjusting for childhood and adulthood SEP. No associations were observed between low SEP, any other psychosocial adversity measure or a cumulative psychosocial adversity score and age acceleration. The association between sexual abuse and DNA methylation age acceleration suggests a potential mechanism linking sexual abuse with adverse outcomes.

We have also studied the association between early life adversity and DNA methylation across the epigenome in the same two cohorts of mid-life women. This manuscript is currently under review. We assessed the association of seven adverse childhood experiences (ACEs: parental physical illness, parental mental illness, parental death, parental separation, suboptimal maternal bonding, childhood illness and child maltreatment) as well as their combination (ACE score) with genome-wide DNA methylation levels. No individual CpG sites replicated across cohorts. However, nine differentially methylated regions (DMRs) replicated across cohorts, respectively associated with the ACE score (one region), parental mental illness (two regions), parental physical illness (three regions) and parental death (three regions). These observations indicate that some adverse childhood experiences, notably those related to parental health, may leave imprints on peripheral DNA methylation that persist to mid-life.

Further work to examine the association of early life adversity and DNA methylation age acceleration in adolescence has been carried out in the ALSPAC young people. This manuscript is in preparation. We found that higher number of adverse childhood experiences (ACE score) was associated with greater DNA methylation age acceleration in females, but not males. There were no significant associations between any ACE and DNAm age acceleration in boys. In girls however, ACE count, emotional abuse, parent mental health problems, parent conviction, parent separation, physical abuse, physical illness and sexual abuse were each associated with DNAm age acceleration.

2. The gestational age epigenetic clock
We have highlighted some concerns with a recently published method to estimate gestational age at delivery from DNA methylation data. We conducted novel analyses to highlight the implications of different choices in study design and statistical methods for the prediction of phenotypes from methylation data (Simpkin et al. Clin Epigenetics, 2018). Subsequently, we investigated associations of sex, socioeconomic status, parental behaviours and characteristics and birth outcomes with gestational age acceleration (Khouja et al. Clinical Epigenetics 2018). Pre-pregnancy maternal overweight and obesity were associated with greater gestational age acceleration. Greater gestational age acceleration was associated with higher birthweight, birth length and head circumference of the child. There was evidence of an association between gestational age acceleration and mode of delivery (assisted versus unassisted delivery, odds ratio = 0.9 per week higher gestational age acceleration, 95% CI 0.7, 1.3 (p = .05); caesarean section versus unassisted delivery, odds ratio = 0.6, 95% CI 0.4 to 0.9 per week higher gestational age acceleration (p = .05)). There was no evidence of association for other parental and perinatal characteristics. The associations of higher maternal body mass index and larger birth size with greater gestational age acceleration may imply that maternal overweight and obesity is associated with more rapid development of the fetus in utero. The implications of gestational age acceleration for postnatal health warrant further investigation.

3. Networking and training activities
We have carried out a wide range of networking and training activities as part of this networking grant. Activities include, but are not limited to: training in epigenetics for social science and other researchers, interdisciplinary workshop for biological and social science PhD students, and workshops on statistics for epigenetics. Towards the end of the grant, we held a workshop for researchers working on adverse childhood experiences from a range of perspectives. As an output from this workshop, we are currently drafting a 'known unknowns' paper, discussing the recent policy focus on ACE and what needs to happen to drive change.

4. Adverse childhood experiences, health behaviours and educational attainment.
We have shown strong associations between adverse childhood experiences (ACE) - considered both individually and as a score of the number of ACE experienced - and health status and behaviours (depression, harmful alcohol consumption, smoking, obesity, drug use) and lower educational attainment. Using more detailed socioeconomic and family data than are available in many previous studies on this topic, we demonstrate that the associations are markedly reduced when these variables are adjusted for. We also demonstrate that low socioeconomic status of parents is responsible for more cases of obesity, smoking, harmful alcohol use, and low educational attainment compared with a high ACE score. These findings suggest that the current policy emphasis on ACE should also take the broader socioeconomic context into consideration. This manuscript is in preparation.

5. Creating a shareable resource of adversity variables for the ALSPAC cohort.
We have done extensive data cleaning and preparation on the early life adversity variables within the ALSPAC cohort. This has created a resource that can be widely used by other researchers.
Exploitation Route 1. Associations between early life adversity and DNA methylation
Our work here is likely to stimulate other activities within this research area. Our results suggest that DNA methylation age acceleration may be a more promising avenue for exploring the embodiment of adversity than epigenome wide association studies.
2. The gestational age epigenetic clock
Our analysis here has both highlighted some guidance for researchers wishing to develop and use epigenetic clocks, and generated some interesting findings about the ways in which maternal size could potentially affect the offspring.
3. Networking and training activities
We have trained a number of social science and health researchers in epigenetics, and have brought together researchers from different fields to facilitate collaborations. I am currently involved in a Health Integration Team for Adverse Childhood Experiences, which is addressing the local policy and health sector responses to ACE, and my work on this grant is directly feeding into this.
4. Adverse childhood experiences, health behaviours and educational attainment.
Our findings suggest that the policy focus on ACE should not be at the expense of broader socioeconomic considerations. We have presented these findings to our local Health Integration Team (NHS, local government, academia) on ACE, and have submitted them to the Lancet Public Health conference. We feel that these results are of high policy relevance and are keen to ensure their wide dissemination.
5. Creating a shareable resource of adversity variables for the ALSPAC cohort.
We are publishing a 'Data Note' in Wellcome Open Research (in preparation) to publicise the availability of the adversity data in ALSPAC and increase its use by other researchers.
Sectors Education,Healthcare,Government, Democracy and Justice

 
Description Interstela Project: Bristol and Cardiff Collaboration 
Organisation Cardiff University
Country United Kingdom 
Sector Academic/University 
PI Contribution Epidemiology expertise, inequalities, statistical methods (Laura Howe), bioinformatics and epigenetics (Matt Suderman), Statistics (Andrew Simpkin), bioinformatics (Tom Gaunt), epigenetic epidemiology (Caroline Relton) and epidemiology (George Davey Smith).
Collaborator Contribution Professor Rosalind John from Cardiff University brings expertise in biomedicine and epigenetics.
Impact Epigenetics and Social Science Network (ESSN) Launch event at M Shed, Bristol. Epigenetics and Social Science Network (ESSN) website. Professor Rosalind John has contributed to meetings and has research in progress.
Start Year 2016
 
Description Interstela Project: Bristol and Edinburgh Collaboration 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution Epidemiology expertise, inequalities, statistical methods (Laura Howe), bioinformatics and epigenetics (Matt Suderman), Statistics (Andrew Simpkin), bioinformatics (Tom Gaunt), epigenetic epidemiology (Caroline Relton) and epidemiology (George Davey Smith).
Collaborator Contribution Dr Riccardo Marioni brings expertise in epigenetics.
Impact 'Epigenetic Epidemiology' Workshop Miami. Epigenetics and Social Science Network (ESSN) website. 'Statistical approaches for epigenetics' workshop Bristol. Epigenetics and Social Science Network (ESSN) Launch event at M Shed, Bristol. Dr Riccardo Marioni contributes frequently to meetings and has ongoing research as part of this project.
Start Year 2016
 
Description Interstela Project: Bristol and Exeter Collaboration 
Organisation University of Exeter
Country United Kingdom 
Sector Academic/University 
PI Contribution Epidemiology expertise, inequalities, statistical methods (Laura Howe), bioinformatics and epigenetics (Matt Suderman), Statistics (Andrew Simpkin), bioinformatics (Tom Gaunt), epigenetic epidemiology (Caroline Relton) and epidemiology (George Davey Smith).
Collaborator Contribution Jonathan Mill from the University of Exeter contributes expertise in epigenetics.
Impact Research is in progress. Epigenetics and Social Science Network (ESSN) Launch event at M Shed, Bristol.
Start Year 2016
 
Description Interstela Project: Bristol and KCL Collaboration 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Epidemiology expertise, inequalities, statistical methods (Laura Howe), bioinformatics and epigenetics (Matt Suderman), Statistics (Andrew Simpkin), bioinformatics (Tom Gaunt), epigenetic epidemiology (Caroline Relton) and epidemiology (George Davey Smith).
Collaborator Contribution Dr Chloe Wong from King's College London brings expertise in epigenetics and Dr Helen Fisher brings expertise in psychology.
Impact Epigenetics and Social Science Network (ESSN) website. Epigenetics and Social Science Network (ESSN) Launch event at M Shed, Bristol. Dr Helen Fisher has contributed to meetings and actively engaged in the post doctoral researcher's (Dr Lotte Houtepen) work here at Bristol.
Start Year 2016
 
Description Interstela Project: Bristol and UCL Collaboration 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Epidemiology expertise, inequalities, statistical methods (Laura Howe), bioinformatics and epigenetics (Matt Suderman), Statistics (Andrew Simpkin), bioinformatics (Tom Gaunt), epigenetic epidemiology (Caroline Relton) and epidemiology (George Davey Smith).
Collaborator Contribution Dr Gabriella Conti from UCL brings expertise in economics, Dr John Jerrim provides expertise in educational and social statistics and Professor Rebecca Hardy provides expertise in population and lifelong health research.
Impact Epigenetics and Social Science Network (ESSN) website. Epigenetics and Social Science Network (ESSN) Launch event at M Shed, Bristol. Professor Rebecca Hardy is closely involved in the ongoing research.
Start Year 2016
 
Description Interstela Project: Bristol and Ulster Collaboration 
Organisation Ulster University
Country United Kingdom 
Sector Academic/University 
PI Contribution Epidemiology expertise, inequalities, statistical methods (Laura Howe), bioinformatics and epigenetics (Matt Suderman), Statistics (Andrew Simpkin), bioinformatics (Tom Gaunt), epigenetic epidemiology (Caroline Relton) and epidemiology (George Davey Smith).
Collaborator Contribution Professor Colum Walsh and his team bring expertise in biomedical sciences.
Impact Epigenetics and Social Science Network (ESSN) website. Collaborative research visit to Bristol - Ulster University. Epigenetics and Social Science Network (ESSN) Launch event at M Shed, Bristol.
Start Year 2016
 
Description Interstela Project: Interstela and E4 Collaboration 
Organisation University of Bristol
Department E4 Project: Epigenetics: Environment, Embodiment and Equality
Country United Kingdom 
Sector Academic/University 
PI Contribution Epidemiology expertise, inequalities, statistical methods (Laura Howe), bioinformatics and epigenetics (Matt Suderman), Statistics (Andrew Simpkin), bioinformatics (Tom Gaunt), epigenetic epidemiology (Caroline Relton) and epidemiology (George Davey Smith).
Collaborator Contribution Professor Caroline Relton and her team bring expertise epigenetic epidemiology.
Impact The E4 and Interstela projects, both within the University of Bristol, work closely, share expertise, collaborate on a training programme and have ongoing research. Engagement activities include: Epigenetics and Social Science Network (ESSN) website. Collaborative research visit to Bristol - Ulster University. Epigenetics and Social Science Network (ESSN) Launch event at M Shed, Bristol. 'Statistical approaches for epigenetics' workshop Bristol.
Start Year 2016
 
Description Interstela Project: Interstela and Epigenetics and Social Science Network (ESSN) Collaboration 
Organisation University of Bristol
Department Epigenetics and Social Science Network
Country United Kingdom 
Sector Academic/University 
PI Contribution Epidemiology expertise, inequalities, statistical methods (Laura Howe), bioinformatics and epigenetics (Matt Suderman), Statistics (Andrew Simpkin), bioinformatics (Tom Gaunt), epigenetic epidemiology (Caroline Relton) and epidemiology (George Davey Smith).
Collaborator Contribution The ESSN consists of a network of 8 projects/networks UK wide comprising of biological and social scientists from many disciplines to facilitate collaboration and communication within the epigenetics community.
Impact The network have contributed to joint meetings and there are research collaborations within the network supported by a joint website. Engagement activities involved in: 'Statistical approaches for epigenetics' workshop Bristol, Epigenetics and Social Science Network (ESSN) website, Epigenetics and Social Science Network (ESSN) Launch event at M Shed, Bristol.
Start Year 2016
 
Description 'Epigenetic Epidemiology' Workshop Miami 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Matthew Suderman, Riccardo Marioni and Andrew Simpkin represented the Interstela project by leading a workshop for approximately 50 people at the 2016 Congress of the Americas conference. Feedback was captured using Turning Point throughout the workshop with very positive results. Attendees engaged with the speakers throughout the workshop with many discussing their own epigenetic or social and behavioural modelling studies and discussed plans for future collaborations.
Year(s) Of Engagement Activity 2016
URL http://www.bristol.ac.uk/integrative-epidemiology/epigenetics-social-science-network/news/2016/epige...
 
Description 'Mediation Analysis' workshop Bristol 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact A workshop organised for approximately 70 delegates outlining the challenges of traditional methods for mediation analysis and some of the novel approaches based on counterfactual theory or instrumental variable methods (with examples from epigenetic epidemiology) including Mendelian Randomisation.
Year(s) Of Engagement Activity 2016
URL http://www.bristol.ac.uk/integrative-epidemiology/epigenetics-social-science-network/news/2016/media...
 
Description 'Statistical approaches for epigenetics' workshop Bristol 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact 31 academics from across the UK attended this event. There were 5 talks, each followed by discussion: Methods for multiple imputation of missing data in epigenetic datasets (Professor Kate Tilling) Principal Component Informed Dimensionality Reduction Approach for 450K Mehtylation data (Tom Richardson) Modelling epigenetic change (Dr Andrew Simpkin and Dr Riccardo Marioni) Enrichment Analysis in Epigenome Wide Association Studies (Dr Benjamin Lehne) Prediction modelling using epigenetic data (Dr Matthew Suderman and Ryan Langdon). There followed an interactive quick fire 3 minute discussion point session where all academics were able to discuss and share their ideas and expertise and make plans for the future.
Year(s) Of Engagement Activity 2016
URL http://bristol.ac.uk/integrative-epidemiology/epigenetics-social-science-network/news/2016/statistic...
 
Description Collaborative research visit to Bristol - Ulster University 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Three members from Ulster University (Professor Colum Walsh, Rachelle Irwin and Sarah-Jayne Mackin) visited our research unit in Bristol for a collaborative research visit. We all presented our work and looked for synergy within the projects in order for us to share research strategies for the future.
Year(s) Of Engagement Activity 2016
 
Description Epigenetics and Social Science Network (ESSN) Launch event at M Shed, Bristol 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact This event was to launch the ESRC and BBSRC Epigenetics Initiative, which has subsequently became known as the Epigenetics and Social Science Network (ESSN). Approximately 54 people attended the launch event, including academics in a variety of fields, as well as ESRC and BBSRC representatives in order to share information about the 8 projects which make up the network. All eight research projects were presented, and discussion followed regarding how the ESRC and BBSRC epigenetics community might provide mutual support including through data sharing, a shared calendar of events, resource sharing, networking opportunities for early career researchers and effective communication within the group. Following the event research collaborations have been established and a network website has been produced which allows the group to have a central method of communication.
Year(s) Of Engagement Activity 2015
URL http://www.bristol.ac.uk/integrative-epidemiology/epigenetics-social-science-network/news/2016/epige...
 
Description Epigenetics and Social Science Network (ESSN) website 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact We have designed and established a website for the epigenetics community within the Epigenetics and Social Science Network (ESSN) as a means of communication between researchers within the network, as well as providing insight into our work to other users and the general public. The website reaches over 100 unique users per month and provides an overview of each of the eight projects/networks within the ESSN. It also provides a means to communicate research outputs, publicise events related to the network, job opportunities linked to the network and post news stories of relevance. The website has provided a central means of communication within the network and all eight projects have contributed to it.
Year(s) Of Engagement Activity 2016
URL http://www.bristol.ac.uk/essn
 
Description KCL PhD student workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Joint interdisciplinary PhD student workshop with C Wong from KCL, explaining key biology concepts to social science PhD students, and key social science concepts to biology PhD students
Year(s) Of Engagement Activity 2017
 
Description Oral presentation at CLOSER conference - R Lawn 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact R Lawn presented paper on early life adversity and DNA methylation as an oral presentation at the CLOSER conference, London
Year(s) Of Engagement Activity 2017
 
Description Pint of science - public engagement 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact L Houtepen gave a 'pint of science' talk about epigenetics
Year(s) Of Engagement Activity 2017
 
Description Poster presentation Lawn et al Canada 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Poster presentation at the 2016 Human Behaviour and Evolution Society conference in Canada: 'Associations between psychosocial adversity and epigenetic ageing: Avon Longitudinal Study of Parents and Children' Authors: R Lawn, EL Anderson, M Suderman, AJ Simpkin, C Relton, I Penton-Voak, LD Howe.
Rebecca Lawn represented the Interstela project at the 2016 Human Behaviour and Evolution Society conference in Vancouver, Canada by presenting this poster.
Year(s) Of Engagement Activity 2016
URL http://www.bristol.ac.uk/integrative-epidemiology/epigenetics-social-science-network/research-output...
 
Description Poverty Safari 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Public engagement event to discuss poverty and its consequences
Year(s) Of Engagement Activity 2018
 
Description Two poster presentations - DOHAD 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact J Khouja and L Houtepen presented two posters at the DOHAD conference - on eoigenetic gestational age, and on early life adversity in ALSPAC
Year(s) Of Engagement Activity 2017
 
Description Workshop - epigenetic clocks 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Workshop to discuss the epigenetic clock, as used across multiple disciplines. Common statistical and theoretical issues discussed.
Year(s) Of Engagement Activity 2017
 
Description Workshop: Education in our genes? 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Workshop to explore various interdisciplinary aspects of educational attainment - social mobility, causal links with outcomes, known genetic variants, epigenetic associations
Year(s) Of Engagement Activity 2017
 
Description Workshop: child maltreatment: resilience and embodiment 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Interdisciplinary workshop discussing various perspectives on child maltreatment
Year(s) Of Engagement Activity 2018