Genetic factors cannot exclusively explain the recent rapid increase in obesity; its aetiology is likely a multi-faceted and complex mix of genes and environment. A proposed mechanism is the establishment of epigenetic patterns early in development, known as developmental programming. One epigenetic modification, DNA methylation, can modulate gene expression and can be influenced by environment factors i.e. diet and lifestyle. Thereby there is potential for DNA methylation to be a mediating mechanism in a disease such as obesity. Life-course epidemiological data from three birth cohorts will be used to investigate if this epigenetic marker could mediate early life risk factors and obesity.

It is widely accepted that early life influences shape our development and health and behavioural outcomes across the lifecourse. Epigenetic mechanisms are increasingly implicated in these complex interactions and provide a key to understanding (i) what aspects of our environment impact upon gene regulation, (ii) how our environment and way of living become embodied in human biology, over what timeframe and with what degree of persistence and (iii) how social and biological inequality may influence development and health.

This project builds upon a substantial foundation of epigenetic research in richly characterised longitudinal cohort studies to explore these concepts of environment, embodiment and inequality. We will utilise the Avon Longitudinal Study of Parents and Children, which currently has the most extensive collection of longitudinal epigenetic data of any birth cohort study in the world, as a platform to address these concepts and through collaboration with seven other cohorts we will extend our investigations across the entire lifecourse to understand how different social and environmental experiences in early life operate to influence epigenetic signatures and downstream outcomes. We will extend these analyses by implementing causal analysis methods, including novel applications of Mendelian randomization, to strengthen causal inference in the associations we observe. Further, we will apply social constructs/theories to elaborate these interpretations.

Analysis of the role of epigenetic processes in linking the environment with development and health across the life.course requires the capacity to generate, analyse and interpret complex data. The high dimensional, dynamic characteristics of epigenetic data require advanced competencies in bioinformatics and statistical methods. We have invested considerable effort in generating epigenetic data, developing and refining informatics and statistical skills over recent years and through this project propose to apply them to the questions outlined above. The proposed work will extend current research activities, drawing together skills of social and biological scientists to apply recently developed methodologies to unresolved issues at the interface of epigenetics and social science. A major component of project activities will be the promotion of inter-disciplinary collaboration, training opportunities and widespread dissemination of both methods and scientific outputs. We will draw upon the expertise of our co-investigator team in bioinformatics, computational science, econometrics, education, epigenetics, lifecourse epidemiology, psychology, quantitative genetics, social science and statistics to execute the proposed project.

It is well known that people die more commonly during cold seasons of the year, especially of cardiovascular and respiratory disease. Several studies on older people have shown that blood pressure, and measures of infammation, tend to be higher in colder weather. We do not know however if these things actually cause people to die in winter. Also, we do not know if these patterns also exist in children. We wish to investigate the seasonal relationship between blood pressure and inflammatory factors with outdoor temperature at the time these measurements have been made in the ALSPAC children and mothers. We will look at changes in these markers on repeated measures of the participants, to see if these measures are particularly raised during cold weather spells. We will link temperature data from the Meteorological Office to the dates when participants were measured. We will also use information about the participants such as their age, sex and socioeconomic status, to see if this modifies their response to cold weather. In the same way, we will use data the participants have provided about their housing, to see whether certain types of house protect people better (for example, houses with central heating, or insulation).

How personality might contribute to the way people react to illness and personal change has been the subject of speculation for nearly 100 years but precious little empirical research. It is only with prospective longitudinal cohort studies that such issues can be addressed systematically. We will make use of a UK birth cohort (ALSAPC) to examine personality and other dispositional factors, measured during childhood and adolescence to see if these predict or shape the person's insight into later mental illness. In particular we will see if certain attitudes such as whether life is controllable and whether it is good to be consistent make it more difficult for people to accept they have an illness (if it strikes them later as an adult) and to accept treatment.

The speech of adults with psychotic disorders, including schizophrenia, is often abnormal. This may take the form of new words not generally understood by anyone other than the speaker and speech which is tangential and has loose associations. There is also some evidence that people with psychosis use less set phrases which are in common usage (such as 'I want to go') than healthy people. There is some evidence that children who later develop psychosis also use speech and language differently than people who do not later develop these problems, however this evidence is based on the child's parent's report of their speech and language and therefore may not be accurate. We would like to use recorded data of children actually speaking at ages 5 and 8 and code this for various measures of speech normality. If we find that the speech of children at these ages who later develop mental health problems is different from the speech of those that do not this would be a very useful finding for several professional groups, such as speech and language therapists, school teachers and mental health clinicians.

We intend to investigate the association between DNA methylation between parents and offspring in the ALSPAC cohort, as well as how the transmission of genetic variants impacts methylation and phenotypic expression.

The burden of overweight and obesity has reached epidemic levels globally. According to the World Health Organization in 2013, 42 million children under the age of 5 years were overweight or obese. Overweight and obesity are major risk factors for non-communicable diseases such as cardiovascular diseases or diabetes. These factors have also been linked with respiratory illness like asthma or sleep apnea in children. In addition, more recently, overweight and obesity have been longitudinally associated with decreased pulmonary function parameters during childhood and adolescence. However, previous studies are limited by a lack of repeated measures on lung function and by a lack of control for potential confounders, such as physical activity and diet. Also, to date, studies have used body mass index (BMI) as the main measure of overweight and obesity, although it has been recently suggested that body composition would be a better marker because of the potential different effects of fat mass and lean body mass on lung function. Fat mass has been shown to have a negative effect on lung function whereas lean mass positively influences respiratory function.

This project thus aims to longitudinally assess the association between body composition and lung function development up to 16 years of age.

Child maltreatment refers to the physical, emotional or sexual abuse and neglect of a child. In the UK, over 50,000 children have been identified as needing protection from abuse, a figure that is likely an underestimate. Abused children are at risk of severe health and social problems in later life, including depression and anxiety, substance misuse, unintended pregnancy, delinquency and crime and future perpetration of violence. Beyond this, child abuse has significant economic costs from medical treatment and long-term productivity losses. It is therefore a serious public health concern.

Despite these negative consequences, growing research has shown that some children achieve good developmental outcomes, suggesting that protective factors exist which moderate an individual’s reaction to stress and make them more resilient to abuse. Resilience is a developmental process involving the attainment of positive adaptation in the context of adversity (Cicchetti, 2010). Whilst various studies have identified factors promoting resilience, there are very few studies within the UK population, particularly relating to positive outcomes in adolescence.

Using mother-child data from the ALSPAC database, this study aims to identify the protective factors in the child, family and environment that enable maltreated children to develop good outcomes (high self-esteem and wellbeing scores) in adolescence. A better understanding of these protective factors and their interactions can help shape policy and focus interventions to reduce the negative impact of abuse and promote resilience in a greater number of vulnerable children.

References
Ciccetti, D. 2010. Resilience under conditions of extreme stress: a multilevel perspective. World Psychiatry, 9(3): 145–154

To evaluate the association of cord blood DNA methylation at over 450,000 methylation sites (CpG sites) across the genome with lung function, wheezing and asthma in children. This project will contribute epigenome-wide association study results to a meta-analysis as part of an ongoing large consortium.