Cardiometabolic disease (CMD) is a major public health problem. It is well known that CMD is caused by interactions between environmental and genetic factors. Additionally, recent studies on mechanism of CMDs have demonstrated that changes in molecular intermediates (e.g. levels of metabolites and DNA methylation) affect prevalence of CMDs. However, there has been limited evidence to suggest causal effect of dietary factors on CMDs, mediated by molecular intermediates. The aim of current study is to estimate relationship between dietary factors and cardiometabolic health, considering effect of molecular mediation including levels of metabolite and DNA methylation. This study can contribute to enhance an understanding of causal effect of dietary factors on CMDs and clarify the mechanism of diet-metabolome-genome-epigenome-health outcomes and contribute to prevent CMDs.

Unlike other conditions, there is no single test to establish a diagnosis of asthma. Instead a diagnosis is made by gathering information from an individual, and using that information to weigh up how likely they are to have asthma. Information can be gathered from the symptoms described, past or family history, findings from a physical examination, lung function and other clinical tests. In some cases, a diagnosis of asthma is clear from the information given and treatment can be started. However, for a large number of people, the diagnosis isn’t clear, and more information is needed before asthma can be ruled in or out.

The fact that asthma isn’t always straightforward to diagnose can lead to problems. Individuals can be wrongly diagnosed: being told they have asthma when in fact they don’t. Also known as over-diagnosis, the main consequences are unnecessary treatment, exposing patients to medicines with unhelpful long term effects and at a financially cost.

Improving the way in which asthma is diagnosed is very important. Identifying the most important aspects of information that can be gathered and using them to make a prediction score would help Doctors to weigh up the likelihood of asthma more easily and accurately.

Psychiatric disorders are a major health concern with numerous social and financial burdens (WHO, 2012). Disorders such as anxiety and depression are common all over the world and estimated lifetime prevalence rates range between 21%-29% (Kessler et al., 2005). Likewise, psychiatric disorders such as depression are associated with poorer physical health such as cardiovascular, metabolic and lung diseases, as well as being comorbid with other diseases such as anxiety (Bishop et al., 2004; Hessler, 2006). Understandably, there has been a great emphasis to try to understand the aetiology of these disorders in a bid to develop interventions and enhance existing treatments. Additionally, many psychiatric diseases that occur later in life (e.g., adolescence/early adulthood) originate from early life, and research has focussed on identifying potential risk factors with an end for developing treatments and interventions at an early stage (Bould et al., 2014). To date, much of the research on psychiatric disorders have used measures on depression, anxiety, temperament and wellbeing. Given the wealth of this type of data within ALSPAC, it seems rationale to concentrate on these phenotypes and build upon existing research.

There are many exposures that have been found to be associated with both immediate depression and depression at a later stage of life. Such exposures range from stress, relationships to job loss and financial difficulties (to name but a few). However, one important exposure for depression is the impact of neighbourhoods (Diez Roux and Mair, 2010; Mair et al., 2008; Matheson et al., 2006). To date, a wealth of longitudinal and cross-sectional data has investigated the impact of neighbourhoods on depression and mostly found that neighbourhoods are associated with increased depression (Graif et al., 2016; Kim, 2008). However, there is evidence that suggests that the neighbourhood may also protect against depression as well in certain contexts (Blair et al., 2014). Much of the research to date on neighbourhoods and depression has centred on certain aspects of the neighbourhood such as proximity to crime (Cutrona et al., 2005) or the urban environment (Gariepy et al., 2015). These are important stratifications to be made as it is still unclear how much these varying aspects like crime or urban build within an environment contribute to psychiatric disorders like depression. Nevertheless, it appears that the impact of the neighbourhood is important in the aetiology of depression and warrants further research. What remains unclear are the mechanisms that may underpin this association and what causal pathways lie on this association between neighbourhoods and depression.

Identifying causal pathways to disease are vital for developing effective treatments and interventions. Many cross-sectional studies suffer from confounding which make it hard to establish true effects along these pathways. However, through the use of longitudinal data, we can account for some of this confounding which can aid in understanding and identification of these causal pathways. A recent systematic review of the literature identified only 14 longitudinal studies investigating the association between neighbourhoods and depression (Blair et al., 2014). Many of these studies used small sample sizes are were mainly homogeneous to the USA. In order to fully understand the association between neighbourhoods and depression, more studies need to use longitudinal data that can incorporate confounding variables that can in turn detect true and meaningful effects.

Finally, whilst research into the effects of neighbourhoods on depression have uncovered important findings, there are still a lot of unexplained variance in the data that has yet to be explained. One potential explanation for this is the role of genetics. It is well established that both genetics and the environment contribute to psychiatric disorders such as depression (Munafò, 2015). Recent research has identified a role for the genetics of schizophrenia predicting neighbourhood deprivation (Gage et al., 2016). Promisingly, findings conducted from a recent GWAS have identified genetics associated with depression and neuroticism (Obkay et al., 2016). In order to fully understand the effects of neighbourhoods on depression, it is important to establish if and how genetics can influence this relationship. This project will utilise data from the ALSPAC study to investigate the impact of the neighbourhood on depression whilst taking into account both genetic and environmental data.

Health literacy is the degree to which individuals can access, understand and use information in ways which promote and maintain good health. Inadequate health literacy is associated with low levels of education, poor health, increased use of health services, less use of preventative care, and increased mortality. Health literacy is an emerging and underfunded area and, to date, very little research has been done to address health literacy in childhood. The aim of the proposed project is to determine the factors in childhood that predict inadequate health literacy in young adults. The longer term objective is to use these factors to design community or public health interventions in childhood that improve health literacy early in life and continue to positively influence health throughout adult life. The proposed project will involve obtaining access to data from the existing ALSPAC study, from children aged 5-14 years and young adults aged 21-23 years. We have previously derived an indicator of health literacy from socio-demographic data in adults; we will use the same approach to assess health literacy in young adults, and investigate which factors in childhood predict a risk of inadequate health literacy in young adults. This innovative project will lay the foundations for developing future interventions in childhood that aim to improve health literacy in children which is crucial for life-long health and well-being.

Short summary
Adequate sleep is critical for wellbeing and physical health. Sleep disturbances are common in individuals with eczema (synonymous with atopic dermatitis), yet little is known about how eczema impacts sleep at different ages. Because eczema often occurs early in life and may wax and wane, it is important to better understand the impact on sleep over the course of the disease. We will use ALSPAC data to understand whether individuals with eczema have worse quality and quantity of sleep at each developmental stage, to understand how individual patterns of eczema disease activity relate to sleep over the long-term (i.e. do individuals with resolving eczema continue to have poor sleep in adolescence?), and to identify factors that may help to predict which patients are most likely to suffer from poor sleep so that they can receive targeted interventions.

Detailed summary
Research over the past decades has identified sleep as an important public health issue. Lack of sleep has been associated with an overall reduction in one’s quality of life, multiple health conditions, and even an increased risk of death. Adequate sleep during infancy and childhood may be especially important for brain development and the formation of long-lasting sleeping patterns. The teenage years are another critical period during which sleep disorders often arise.

Atopic dermatitis (eczema) typically begins in infancy or early childhood, and may persist into adulthood. Patients suffer from an intense sensation of itch, which is often worse at night, and leads to scratching and poor sleep. Studies from clinic populations suggest many children with eczema experience sleep disruptions, which may occur even when they don’t have active skin lesions. Little is known about how sleep loss affects eczema patients in the general population at different ages. Because the clinical course is heterogeneous and eczema waxes and wanes, it is especially important to study the relationship between eczema and sleep loss over time so that we can develop recommendations about which patients may need special treatment.

We will use data from over 14,000 people followed from infancy through adolescence to understand whether individuals with eczema have worse quality and quantity of sleep at each developmental stage, how individual patterns of eczema disease activity relate to sleep over the long-term (i.e. do individuals with resolving eczema continue to have poor sleep in adolescence?), and identify factors that may help to predict which patients are most likely to suffer from poor sleep so that they can receive targeted interventions. Our results will be used for future studies of targeted treatments and the impact of sleep on other outcomes like depression, ADHD, obesity and school achievement.

Patients with schizophrenia have shortened life expectancy, with mortality rates twice that of the general population. Causes for this extend beyond suicide, accidents and risk-taking behaviour. Research indicates that physical illnesses, including heart disease and type 2 diabetes mellitus (T2DM) account for a majority of the increased mortality risk. The prevalence of T2DM in schizophrenia is increased by around one-third compared with the general population.

There is a growing body of research to suggest that links between the two illnesses may go deeper than the previously assumed - related solely due to either a side-effect of medications used to treat schizophrenia, reduced access to healthcare in patients with schizophrenia, and poor diet/sedentary lifestyle. A recent meta-analysis in Lancet Psychiatry by the lead proposal author has shown that participants with first-episode psychosis (the first time a generally younger person goes to hospital with symptoms of schizophrenia) are more likely to have signs of early diabetes than healthy matched controls. All participants in the meta-analysis had very limited exposure to antipsychotic medication, reducing the impact of the potential confounder.

There is a growing body of work showing that both schizophrenia and diabetes may indeed feature an inflammatory component, and this may be shared. The inflammatory component in patients with a potentially earlier form of schizophrenia - termed 'psychotic experiences', has previously been examined in the ALSPAC cohort by one of the proposal authors, with positive findings.

It would therefore be of great interest to examine whether any possible disease link begins earlier than the 'first psychotic episode', by examining patients suffering 'psychotic experiences'. With the noted possible inflammatory disease links between diabetes and schizophrenia, it would be of great interest to examine whether those with psychotic experiences and abnormal inflammatory profiles also have abnormal glycaemic indices.

Finally, it would be interesting to examine whether markers of early diabetes can predict the onset of psychotic experiences.

Self-harm in young people is a major public health concern. Recent community studies indicate that up to 1 in 6 adolescents have self-harmed at some point in their lives, with the incidence rising rapidly between 10 and 16 years of age. Self-harm is distressing for individuals, their friends, families, and carers, and is associated with a range of poor outcomes in early adulthood. It is also the strongest known risk factor for suicide. Although self-harm is very common in adolescence, we know little about what causes this behaviour. A better understanding of the factors that increase the risk for self-harm, and the mechanisms through which they operate is important in order to develop more effective treatments.
Many previous studies have identified early life adversity (such as physical abuse, sexual abuse, and emotional neglect) as an important risk factor for self-harm. However we don’t yet understand how exposure to adversity can trigger later self-harm behaviour. It is known that the social environment can have an impact on internal biological processes. This is of interest as there is growing evidence to suggest that biological factors are involved in suicide and self-harm. We aim to study whether experiences of early adversity are associated with three different biological processes (inflammation, onset of puberty, and DNA methylation) and explore whether these factors are, in turn, associated with self-harm in adolescence. This work can provide a model whereby early adversity can lead to self-harm through biological pathways. This could lead to identification of potential markers of future self-harm risk, as well as possible targets for treatment, and interventions to prevent people from developing self-harm. In order to investigate these pathways, it is necessary to establish the order in which events occur. To do this requires a large sample with information collected at multiple time points from childhood to adolescence. Our research will also investigate whether associations between inflammation, puberty, DNA methylation and self-harm are causal, or whether they might be explained by other factors (known as confounding).
To date, most studies of self-harm in adolescence have been based on small clinical samples – these are highly select groups, already known to medical services. In addition, existing studies have tended to focus only on suicide attempts, but only one quarter of self-harm episodes are carried out with expressed suicidal intent. An important question is whether suicidal and non-suicidal self-harm are distinct behaviours, or part of a continuum of risk. Previous studies have explored whether there are differences in risk-factors and outcomes for these behaviours. We aim to extend this work by providing new information about whether there are differences in their genetic architecture. This work will inform future research studies of self-harm, and help to inform decisions on how self-harm should be defined.

Dyslipidemia is a common disorder associated with abnormal lipid levels, usually elevated, commonly associated with the risk of a cardiovascular event. Our understanding of the genetics of the disease relies mainly on common polymorphisms affecting the levels of proteins involved in lipids metabolism. In contrast, changes in the areas of the genome containing the information for the building blocks of proteins can alter the structure and function of these proteins. These DNA changes tend to be less common in the genome and currently we are only aware of a small number of them associated with lipids associated disorders, some of them severe.

The largest consortium of scientists working on the genetics of plasma lipids, the Global Lipids Genetic Consortium (GLGC), has recently used more than 300,000 individuals to study these protein changing mutations and identified a number of them both in novel and previously reported areas of the genome as associated with one or more of the four main measured lipids traits: high density lipoprotein (HDL), low density lipoprotein (LDL), triglycerides and total cholesterol levels. These four commonly measured lipids traits though, are groupings of other lipids subfractions that can have very different compositions and properties not evident in the overall grouping, thus making the understanding of the specific action of the gene of interest difficult. Although we can sometimes infer the action of the genes through model organisms or laboratory experiments, these are not always accurate representations of how things work in the human body.

Prevalence estimate of the autism spectrum disorders (ASD) has significantly increased over the decades. Maternal body mass index (BMI) prior to pregnancy and gestational weight gain (GWG) have attracted attention as potential risk factors for offspring ASD, given noticeable increase in the prevalence of prepregnancy obesity and high prevalence of inappropriate GWG in recent years.

The project will examine the effects of maternal prepregnancy BMI and GWG on ASD among offspring, and explore the underlying mechanism. Our hypotheses are that prepregnancy obesity and inadequate/excessive GWG are associated with increased risk for offspring ASD and that adverse obstetric outcomes account for part of these effects.

If our hypotheses are supported, this project will shed light into the environmental base of ASD and aid in the development of preventative strategies. Moreover, with underlying pathways understood, interventions can be applied on the modifiable mediators.