Pathways to self-harm: Biological mechanisms and genetic contribution

Self-harm in young people is a major problem. As many as 1-in-6 teenagers have self-harmed at some point in their lives, and self-harm is particularly common between the ages of 10 and 16 years. Young people who self-harm seem to be more likely to do poorly in a number of ways in early adulthood, including being more likely to have a mental health problem, and to use substances like alcohol and drugs. It is also the strongest known risk factor for suicide. Although self-harm is very common in young people, we know little about what causes it. A better understanding of the things that increase the risk for self-harm, and how they work could help us to develop more effective ways to prevent self-harm and support young people when they need it.

Research shows that facing bad experiences early in life (such as physical and sexual abuse, and emotional neglect) increases the chances that a young person will self-harm. However we do not yet understand how this works. We know that the social environment (including the occurrence of adversity) can have an impact on the body's internal working, such as inflammation, changes to chemicals around genes, and hormones, and that these things in turn are involved in suicide and self-harm. In this study, we aim to investigate whether early bad experiences are associated with three different biological processes (inflammation, alterations to DNA, and puberty (stage and timing)) and explore whether these factors are, in turn, associated with self-harm in adolescence. Our research will also investigate whether associations between inflammation, alterations to DNA, puberty and self-harm are real, or whether they might be explained by other factors. This research could help to identify potential markers of future self-harm risk, as well as possible targets for treatment for young people who self-harm.

We also plan to increase understanding about whether there are clearly distinct types of self-harm. Some researchers have proposed that it may be useful to classify self-harm according to whether or not the person has suicidal ideas, and has self-harmed with the intention of ending their life. However, it can be difficult to judge the extent to which someone wants to end their life and so we are not sure how useful it is to try and judge this in clinical practice. We plan to study whether the genes of young people who self-harm differ according to whether or not they have harmed with suicidal intent. This work will inform future research studies of self-harm, and could help practitioners working with young people who self-harm.

In order to take the research forward, we have assembled a team of outstanding scientists from two universities. The proposed research will use data from the Avon Longitudinal Study of Parents and Children (ALSPAC). ALSPAC is a long term study of over 13,000 children born in Bristol and the surrounding area in 1991-1992 who have been followed up since birth with regular questionnaires and research clinics. There are very few studies that have such a large number of people with such detailed questions that were collected in real time. This is important as people's experience can be a strong influence on what they remember. It is also unusual for this kind of study to also have the biological samples that we need to answer the questions about genes, and the body's internal biological processes.

Self-harm is common in adolescence with community studies indicating a prevalence of between 13% and 18%. Self-harm is associated with a range of adverse outcomes, including an increased risk of suicide. Yet we know little about the aetiology of this behaviour. A history of early life adversity (ELA) is one of the strongest risk factors for self-harm. Long-term health conditions typically result from a complex interplay between social environment and biology. Our research will examine the role of three key biological mechanisms (inflammation, DNA methylation, and puberty (status and timing)) in the pathway between ELA and later self-harm. This work will advance knowledge of the aetiology of self-harm, and could lead to novel approaches for risk detection, treatment and prevention.
Most existing studies have focused on suicide attempts yet only a third of adolescents have harmed themselves with suicidal intent. There is increasing interest in non-suicidal self-harm, however it is uncertain whether self-harm with and without suicidal intent are different clinical entities, or part of a continuum of risk. Research has begun to explore differences in psychosocial risk factors for these behaviours, but our understanding of potential differences in their genetic architecture is limited. This work will inform future research studies of self-harm.
We propose investigating these key issues for the self-harm field in the ALSPAC cohort; an on-going study of over 13,000 children followed prospectively from birth into adulthood. Participants completed a detailed self-harm questionnaire at age 16 years (N= ~5,000, self-harm prevalence 18.8%). No other cohort has such detailed life-course phenotypic information, along with genetic, epigenetic, biological, and environmental data. To address our research questions we will use appropriate statistical techniques including structural equation models, Mendelian randomisation, polygenic score analysis, and genomic-REML analysis.

1) Scientific advancement and impact upon the research community:
The research will lead to new knowledge concerning the aetiology and classification of self-harm, by providing evidence regarding the importance of distinguishing between self-harm with and without suicidal intent. This will guide researchers in future studies of self-harm and inform revisions of the Diagnostic and Statistical Manual (DSM) and the International Classification of Diseases (ICD).

Our research will use summary data from publicly available genome-wide association studies (GWAS) in a two-sample Mendelian Randomisation (MR) approach. Our use of this emerging method will serve as an exemplar for other researchers seeking to answer similarly difficult questions about causal inference.

2) Service users and families:
Contributing to increased public awareness about self-harm and its biological underpinnings will benefit patients and their families by reducing the stigma associated with self-harm, and increasing the likelihood that individuals will seek help.

3) Clinical community:
Our findings could also lead to the identification of potential biomarkers of self-harm risk. This would aid the early identification of young people who are at increased risk of self-harm, and enable more efficient targeting of resources to those who are most in need, and most likely to benefit from early intervention. In addition, a better understanding of the biological mechanisms underlying the development of self-harm could lead to novel approaches to assessment and treatment. Our work using MR approaches will also help to establish whether associations between i) inflammation, ii) DNA methylation, and iii) puberty (status and timing) and self-harm are causal, thus paving the way for the development of successful intervention strategies.

4) Development of capacity and capability:
If funded, the project will support the career development of a talented new PI in the field of self-harm research (Dr Mars). Our proposal brings together an outstanding multidisciplinary team of academic experts who will be supporting Dr Mars throughout the project. Such a partnership is extremely rare, and the infrastructural funding underpinning this partnership will potentially allow our team to develop further competitive proposals tackling the issue of self-harm.

In addition, the two researchers employed on the study will develop skills through their analysis, write-up and presentation of study findings that will be invaluable in terms of their career development.