Self-harm among adolescents and young adults is a widespread public health problem. Self-harm is often a maladaptive coping strategy used to alleviate severe emotion dysregulation following stressful events. Adolescence is a period of marked development in the realm of social relationships and socio-emotional competencies. However, the developmental associations between social stress and self-harm across the adolescent years are poorly understood. In particular, the mechanisms linking social stress and self-harm are largely understudied. Better knowledge about these processes is urgently needed, in order to identify promising targets for interventions designed to support adolescents with self-harm and help them cease from this self-destructive behavior.

Therefore, the aim of this project is to investigate how social stress and self-harm are interrelated between early adolescence and early adulthood. A particular focus will be on the mechanisms underlying these associations. Candidate mediators are a) biological manifestations of stress (e.g., inflammation) and b) physical health and health behaviors (e.g., sleep patterns). Potential gender differences will also be considered.

The findings will provide novel insights into the developmental precursors of adolescent self-harm and help improve intervention programs designed to reduce the enormous burden that self-harm can entail for individuals and society.

Social cognition, the ability to understand the mind of other people, is essential for successful social
interaction. Children with emotional and behavioural problems are more likely to have a history of poor
social cognition ability. However, the path from poor social cognition to emotional and behavioural problems
in childhood and adolescence is unclear. The possibility I will explore in this PhD project is that social
cognitive deficits increase stress (i.e., hypothalamus-pituitary-adrenal dysregulation and flattened cortisol
rhythm and/or chronic inflammation), leading to emotional and behavioural problems. Cortisol and
inflammatory cytokines are thought to be promising biomarkers of various stressed-related behavioural and,
particularly, emotional disorders, yet existing evidence in children and adolescents is little and mixed, and
is mostly about clinical disorders. Additionally, it is not known yet how cortisol and inflammatory cytokines
work when facing stress caused by social cognition deficits, especially in the general population. The aim
of the project is to explore the role of these biomarkers in the interplay mechanism of social cognition deficits
and emotional and behavioural problems in children and adolescents, using longitudinal data from a large
general population study, the Avon Longitudinal Study of Parents and Children. Analytically, the project will
explore three relationships: a) the longitudinal association between deficits in core aspects of social
cognition (emotion recognition & theory of mind) and emotional and behavioural problems, b) the role of
cortisol in explaining the association and c) and the role of inflammatory cytokines in explaining the
association. The relationship between inflammation and cortisol is complex so the final analysis exploring
the role of both will consider this complexity fully.

The World Health Organisation describes adverse childhood experiences (ACEs) including abuse, neglect, violence and other household dysfunction, as the commonest and most intense childhood stressors. About half of us experience at least one and those exposed to several are likely to experience more health problems later in life, including chronic pain. There is a strong relationship between exposure to multiple ACEs and social deprivation, and additional associations with having a young mother or being male. Although there is increasing evidence that ACEs contribute to health inequalities, there is no widespread screening to identify interventions. Reasons for this include the limited range of ACEs in existing methods of assessment and little consideration of other factors that may contribute to vulnerability.

CAPE will develop a thorough questionnaire for assessing ACEs to enrich large population cohort data. This information will be linked to prescribing, social care records, neuroimaging, genetics and tissue samples, enabling identification of biopsychosocial factors that create vulnerability to chronic pain and adverse responses to treatment.

Myopia (short-sightedness) is an eye condition in which distance vision is blurry. People with myopia need to wear glasses or contact lenses, or have laser refractive surgery, to achieve sharp distance vision. When people with myopia get older, they are at a higher-than-average risk of developing permanent sight problems such as macular disease. Myopia typically develops during school age. The reason it develops is not understood, however both genes and lifestyle factors are known to play a role. Children whose parents have myopia inherit a genetic predisposition to develop myopia themselves. In clinical studies, children who are randomly assigned to spend extra time outdoors each day have a lower incidence of myopia, suggesting that spending too little time outdoors is a risk factor. Individuals who spend more years at school also tend to develop a higher level of myopia. Around the world, the prevalence rate of myopia varies widely. This is thought to be related to the variation in the ‘intensity’ of school work and the pressure to do well at school. Myopia has also been linked to mental health problems such as depression and to levels of physical activity. However, for most of these links, it is unclear if myopia is a cause or a consequence of the association.

The ALSPAC cohort is unique in the scale and breadth of the information that has been collected about vision problems in childhood. This includes information about myopia development. In previous studies of ALSPAC participants, our research group has documented the time-course of myopia development and exposure to risk factors or protective factors such as time spent outdoors. For example, children from the ALSPAC cohort who spent relatively less time outdoors than their peers at age 7-years-old were found to have an increased risk of developing myopia by the age of 15. Here, we propose to build on our previous findings. Our primary aim is to discover if myopia is the cause or consequence of its associations with other lifestyle factors and health or wellbeing characteristics. To do this, we will use a technique called Mendelian randomisation, which uses random inheritance of subtle genetic features in a way similar to randomisation of participants in a clinical trial. Usually, Mendelian randomisation studies require very large cohorts of participants – larger than the ALSPAC cohort. However, myopia and many of the related conditions we plan to investigate are highly heritable, which means there is a good prospect of successfully answering our research questions using data collected in a sample the size of the ALSPAC cohort. Our secondary aims are extensions of the primary aim. We will compare the eye characteristics and lifestyle of children growing up in the UK with those of children elsewhere, to investigate if the risks for myopia are similar or different in countries with high or low prevalence rates of myopia. We will also extend our previous studies into the genetics of myopia. The exceptionally high level of detail that the ALSPAC research team has collected about genetics will allow us to test the role of specific genes in conferring a predisposition to myopia, and how this varies depending on the lifestyle risk factors that children are exposed to.

Children with precocious puberty are defined as girls with breast development before age 8 years and boys with testicular enlargement before age 9 years (which corresponds to minus 2 standard deviations (SD) compared to the average age of these changes in both sexes). Earlier age at pubertal start has been associated with earlier age at first vaginal bleeding (menarche) in girls and earlier age at voice change in boys, and with long-term consequences, including shorter adult height and psychosocial adverse effects. Although more frequent in certain ethnicities, the prevalence of precocious puberty in girls is constantly increasing worldwide, following the increase in cases of pediatric obesity. Most children with precocious puberty do not present any endocrine, metabolic, neurologic or neurosurgical condition explaining their earlier pubertal start (these cases are defined as “idiopathic” precocious puberty), but extensive work up (including specific hormone measurements and radiological exams) is routinely performed to eliminate such conditions. An important portion of children with precocious puberty will be considered for treatment with puberty-blocking pharmacological agents, without clear evidence that these treatments will increase their adult height.
Late puberty is defined as an absence of breast development by age 13 in girls (or absence of menarche by age 15), and an absence of testicular enlargement before age 14 in boys. This phenomenon is more frequent in boys, in most of which no pathological cause is detected, and these children will end up developing a spontaneous puberty and achieve a normal adult height. Nonetheless, these children are often referred for endocrine evaluation and investigated to eliminate an underlying medical condition.
Given that age at pubertal start in the population follows a Gaussian distribution, 2.3% of normal healthy children will start their puberty at and age below 2 SD below the mean for each sex, and another 2.3% will start their puberty above 2SD above this mean. Defining which children with precocious or late puberty correspond to these 2.3% of the general population is important, since this would avoid unnecessary investigations and treatment in these patients.
Pubertal traits (age at breast development and menarche in girls, testicular enlargement and voice change in boys, age at pubertal growth spurt in both sexes), have a polygenic nature, and an overlapping genetic architecture in boys and girls. It has been estimated that about 50% of variation in age at menarche can be attributed to genetics. Polygenic risk scores (PRS) have been demonstrated to have an improving ability to identify individuals at significantly high/low predisposition towards complex diseases. Therefore, it has become possible to identify individuals who will lie at the extreme distribution of a trait, such as age at menarche in girls or age at voice change in boys.
Therefore, we posit that PRS for age at menarche in girls or age at voice change in boys, in combination with clinical risk factors (such as increased body mass index) may be able to effectively predict children diagnosed as having idiopathic precocious puberty and in which no further investigation or treatment would be required to achieve a normal adult height (within their parental target height). Also, the same scores could identify children in the opposite extreme of the normal distribution, ie children with late puberty.

Certain behavioural (e.g. diet, smoking, physical activity) and physiological (e.g. obesity, cholesterol, glycaemic control, blood pressure) risk factors have long been known to increase risk of atherosclerotic CVD in later life. Although clinical events rarely occur prior to middle-age, our group have previously shown that early signs of damage to the vasculature can be detectable from as early as childhood (Charakida et al 2012 JACC; Dangardt et al 2019 Lancet Child and Adolescent Health; Chiesa et al JACC Imaging 2019), and that cumulative exposure to this damage across the lifespan likely represents one of the biggest causes of later-life events.

Intriguingly, recent research strongly suggests that these modifiable health behaviours and risk factors may also contribute to another of the world's most pressing global health crises – dementia. A wealth of recent research supports the concept that the development and progression of cognitive decline and eventual dementia can be slowed or perhaps even prevented by addressing various risk factors more commonly linked to CVD (Livingstone et al 2020 Lancet). The implementation of early-life prevention strategies to improve heart health may therefore also provide dual benefits for long-term brain health.

Our group and others have recently contributed to accumulating evidence suggesting that it is exposure to these CV risk factors earlier in the lifespan which appear to relate most strongly to risk of cerebral (i.e. brain) disease risk in later life. These findings suggest that although dementia diagnoses are almost exclusively made in older age, they may in fact represent the end result of cumulative damage to brain tissues which have been sustained over decades previously. However, how early this damage starts and what factors are responsible for its appearance is currently unknown, as very few populations are available in which detailed brain scans have been carried out on a young population with wide-ranging CVD risk factors.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic condition of childhood, but remains a relatively rare condition. Whilst there is growing knowledge about JIA disease management, we have very limited knowledge about the wider impacts of the condition, particularly in adolescence and adult life. For example observational data suggests that JIA patients have adverse educational attainment levels and employment outcomes. There is also growing concern about wider health implications of JIA such as cardiovascular disease risk, similar to that seen for adult rheumatoid arthritis patients, although long term follow-up data of JIA patients into adulthood is very limited. Within this PhD a range of different techniques are being used to explore causes and effects of JIA across the life course using observational and ‘omic data. Our earlier work has shown associations between JIA and a number of other health outcomes, however outcome datasets have all derived from older adult populations. Building on earlier work, this project aims to examine the association between the level of the genetic risk of JIA (using polygenic risk scoring) and a range of clinical (e.g. cardiovascular risk factors), biological (e.g. circulating CRP levels), metabolic (eg circulating lipids) and molecular (e.g. changes to DNA methylation) outcomes during childhood and early adulthood. This will allow us to identify potential JIA associated comorbidity earlier in disease to a) allow earlier risk stratification of patients and b) allow underlying mechanisms of comorbidity to be explored.