Aims

The aim of this project is to explore whether early deficits in social cognition are associated with later substance abuse problems. Previous studies have shown that impairments of social cognition are common amongst individuals who abuse substances. For example, alcohol (1), opiate (2), and tobacco (3) use have all been associated with impaired recognition of facial emotional expression. Additionally, these impairments persist when smokers become abstinent (4) and when alcoholics are detoxified (5), suggesting addicted individuals' may rely upon substances to aid their social cognitive abilities. Furthermore, these deficits are sustained up to ~2 months into sobriety (6). This raises the question of whether it is substance abuse itself that cause these deficits, or whether these deficits lead to substance use (for example, to enhance certain aspects of social cognition).

The aim of the proposed study is to provide information regarding potential adverse outcomes associated with trauma exposure and posttraumatic stress symptoms (PTSS). Existing data suggest that youth trauma exposure and/or PTSS are associated with adverse outcomes in several domains including: substantially increased odds of objective physical disease states (Seng et al, 2004); poorer educational attainment (Hurt et al, 2000); engagement in substance use and other risky behaviours (Begle et al, 2011); and increased likelihood of antisocial behaviours/involvement in the youth juvenile justice system (Ford et al, 2010; Abram et al, 2004). However, existing studies are predominantly cross-sectional raising issues of cause versus consequence; or they have focused on specific populations or types of trauma, limiting the generalisability of the findings. The longitudinal data afforded by the ALSPAC cohort would allow for an analysis of whether youth trauma and PTSS contribute to later adverse outcomes, even once concurrent problem levels are taken account of.

Aims and hypothesis

Preliminary investigations have shown that average dietary zinc intakes in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort are below those recommended for children and this could be associated with deficits in long-term growth.

Exposure variables

The project will use the dietary data collected longitudinally from ALSPAC children from which nutrient intakes have been calculated. This will be combined with weight and height data collected at several time points throughout childhood. The project will investigate which foods and food groups contribute to zinc intakes in children age 1.5-13 years and whether this has an effect of height and body mass index at several time points throughout childhood.

Aims

Up to 25% of the global burden of disease is estimated to stem from preventable environmental exposures. Starting in utero, millions of children worldwide are exposed to toxic chemicals, including the metals lead, cadmium, and mercury, from natural and anthropogenic sources. Research clearly demonstrates that individually these toxic metals contribute to neurobehavioral deficits in children. It is also accepted that simultaneous exposure to multiple metals is the norm rather than an anomaly. Yet, surprisingly little is known about the combined effects of early exposure to multiple metals on child development and behaviour. Important research gaps, hinder our ability to set policies, create prevention or intervention measures, and care for affected individuals. First, except for select or specific population groups, the exposure to metals in the general population is likely to be of low magnitude. The patterns of exposure in the general population need to be established. Second, it is important to understand what sociodemographic factors are likely to predict exposures so that risk factors can be appropriately described and communicated. Most importantly, there is little understanding of the extent to which metals interact to produce deficits. Thus, the consequences, both in the short and the long-term, of multiple metal exposures need to be determined. The aim of this study is to 1) model the patterns of in utero exposure to three toxic metals (lead, cadmium and mercury), 2) compare sociodemographic factors/variables among groups of women with lowest and highest exposure patterns to identify salient predictors of exposure, and 3) examine the neurobehavioural consequences of exposure for the women's offspring using measures of early temperament and neurocognitive development.

Hypotheses

The central hypothesis is that women falling into the highest metal exposure pattern will have children with more difficult temperaments and lower developmental scores than women falling into the lowest exposure pattern.

Conduct problems (CP) in youth affect society in a wide and penetrating manner; the victimization and distress to individuals and impairment of life opportunities is substantial. The associated costs are thought to be especially severe for youth with an early onset (at or before the age of 10 years) of CP - these youth are often raised in high-risk environments (family, community); show abnormal neurocognitive development; and are at risk for a persistent pattern of offending (1-3).

Previous studies highlight that a poor diet (e.g., consumption of energy-dense foods that are high in saturated fat and low in unsaturated fat) in early life (i.e., in prenatal and early postnatal periods) can disturb child neurodevelopment and lead to cognitive, emotional and behavioural problems in later life (4-13). To date, however, no existing research has integrated - in a developmental context - nutrition (i.e., quantity and quality of dietary fat) and biological markers (genetic, epigenetic and metabolic) that can help to identify the mechanisms underlying the associations between poor nutrition from prenatal period through childhood and CP. For example, although epigenetic modifications have been associated with poor nutrition in general (14), further research is needed to examining the this is related to early onset of CP - and also the degree to which functional variation within genes that are involved in metabolism of the key macronutrients might moderate the associations between nutrition and DNA methylation in relation to CP (15, 16).

This application proposes a systematic examination of the impact of prenatal and postnatal nutrition and environmental risk exposure on CP in The Avon Longitudinal Study of Parents and Children (ALSPAC; UK). The developmental phenotype of CP trajectories between ages 4 and 13 years is available for the ALSPAC children (2). The sub-sample of ALSPAC children includes extensive measures of diet macronutrients using Food Frequency Questionnaire and dietary diary, and nutrition biomarkers available from a prenatal period through late-childhood; as well as whole-genome data for mothers and children; and DNA methylation status data available for children at birth, at ages 7 and 15-17 years.

The project aims to address the following research questions:

Aim 1: Does prenatal and/or early postnatal nutrition affect CP developmental trajectories?

Sub Aim 1a: Are these associations mediated by earlier neuro-cognitive development?

Sub Aim 1b: Are these associations affected by child stress exposures?

Aim 2: Are associations between nutrition and CP (partially) explained by DNA methylation?

Sub Aim 2: Are these associations moderated by child stress exposures?

Aim 3: Examine the role of SNPs involved in the metabolic pathways of key nutrients.

Aim 4: Examine causal associations using Mendelian Epigenetic Randomization.

Aims and hypotheses

Electronic-cigarettes (e-cigarettes) hold the potential to hugely reduce the harm caused by smoking, but it is important to determine the factors which lead to their use among young people. Previous cross-sectional research has investigated the prevalence of e-cigarette use among young people (1, 2), but to our knowledge, there have been no longitudinal studies investigating predictors of e-cigarette use.

ALSPAC has collected detailed information about substance use, in particular smoking behaviour. From these data, trajectories of smoking initiation during adolescence have been constructed (3). However, there is currently limited information regarding e-cigarette use. Identifying the pathways into e-cigarette use among young adults is key, given concerns regarding the potential of e-cigarettes to act as a 'gateway' to other, more harmful substances, such as conventional tobacco cigarettes (4). The ALSPAC young people are now between 22 and 23 years old. Therefore, this application is timely as data suggest that peak prevalence of e-cigarette use is in 16-24 and 25-34 year olds (5).

In this project, we aim to collect detailed information from the young people in ALSPAC regarding use of e-cigarettes; specifically frequency of use, demographics of users and dual use with tobacco cigarettes. Using this information, along with the rich data set already available within ALSPAC, we aim to answer the following questions:

1. What biological, social and environmental factors are associated with e-cigarette use in young people?

2. Are e-cigarettes likely to act as a 'gateway' to use of other, more harmful drugs among young people?

3. Is e-cigarette use an effective smoking cessation strategy among young people?

Study design

We will design questions on e-cigarette use to be included in the next annual questionnaire (2015/16) that will be sent to the ALSPAC young people. These data will be linked to previous ALSPAC data, allowing investigation of the biological, social and environmental factors associated with e-cigarette use. We are seeking funding for the data collection from Cancer Research UK (CRUK) have been asked to submit a full application by 22nd January 2015.

We will seek additional funding in the future to send follow up questionnaires, which will allow us to examine the long term implications of e-cigarette use. We would also like to extend this work to investigate e-cigarette use in the ALSPAC mothers and fathers.

Aims and hypothesis

The impact of rare copy number variants (CNVs) has almost exclusively been evaluated using clinical cohorts; it is thus unclear how these variants affect health in the general population. Our aim is to assess the genome-wide burden of rare CNVs on carriers' health and life quality in general population. We have conducted genotype and phenotype analyses of a random sample of 7877 adult individuals from the population biobank of Estonia (Estonian Genome Center, University of Tartu; Tartu, Estonia). Using this set we generated a genome-wide map of rare autosomal CNVs and identified 10.5% of the screened adult general population (n=831) as carriers of CNVs >=250kb with frequency <=0.05%. We found that when compared to the population, carriers of deletions >=250kb and duplications >=1Mb show lower education achievements (a proxy for intelligence) and a greater prevalence of intellectual disability. These effects are associated with the number and functions of contained genes, e.g. rare deletions are significantly enriched for genes with a role in neurogenesis, cognition, learning, memory and behavior. Interestingly, the effect on education attainment was more pronounced in female carriers of rare deletions in general population, who were also overrepresented amongst carriers.

Our results suggesting that rare CNVs contribute to a substantial portion of the population variance of educational attainment need to be replicated in a geographically independent cohort. The ALSPAC cohort of mothers and children would provide us, in collaboration with group of Dr. Nicholas Timpson, a valuable result as (i) ethnically unrelated to the discovery cohort; (ii) sufficient sample size of individuals with CNVs calls; (iii) the cognitive information of children is unbiased by preselection; (iii) large number of uniformly recruited females provides a possibility to validate the female effect of rare CNVs.

Background

Maternal early- / pre-pregnancy BMI and gestational weight gain have been shown to be positively associated with offspring greater adiposity in later life in numerous prospective cohort studies, including in previous publications from ALSPAC. However, the extent to which this association is causal or due to bias (including publication bias, where studies that show a positive association are more likely to be published) is unclear.

We want to explore this by undertaking an individual participant meta-analysis in all birth cohorts (globally) that we can identify and that have relevant data. Our aim is that this should allow us to obtain precise estimates that are less likely to be influenced by publication bias than undertaking a systematic reivew and meta-analysis of published studies.

Further we want to compare association of maternal exposures with offspring outcomes to the same associations in fathers in order to determine whether there is evidence of specific maternal associations, which would support a intrauterine causal effect.

Aims and objectives

1. To undertake an independent participant data meta-analysis of the association of maternal pre-pregnancy BMI and gestational weight gain with offspring adiposity and body composition.

2. To compare associations of maternal exposures with offspring outcomes to the same associations of paternal exposures to explore whether associations in mothers are likely to represent intrauterine causal mechanisms

3. To explore the extent to which any associations might be mediated by birth characterists and later offspring activity and energy intake

Background: There is increasing evidence that childhood cancer is more likely to occur in children that were relatively large at birth, and unpublished information indicates that this is particularly true of non-leukaemic cancers occurring after 3 years of age [1]. The risk is lowest among children born small-for-dates and tends to increase linearly with increasing birth-weight. The evidence indicates that the birth-weight association with leukaemia relates to excessive growth in utero [2,3]. This raises the question as to whether there are features that increase the growth of the fetus that are responsible for increases in the risk of cancer. Although many high quality studies have focused on the aetiology of growth retardation, little attention has been paid to the high end of the birth-weight distribution.

Hypothesis and objectives: This study is designed to identify factors that influence fetal growth in order to develop coherent hypotheses as to ways in which the unexplained link with childhood cancer may be explained. We hypothesise that features of the environment including diet and lifestyle, genetics and epigenetics may play important parts. We have already shown an excess in birth-weight if the non-smoking mother was exposed in utero to her own grandmother's smoke [4], which indicates a possible epigenetic influence; additionally our unpublished data have shown an association with maternal prenatal intake of paracetamol (acetaminophen). Thus our hypotheses concern the likely complexity of factors that influence excessive fetal growth.

The objectives are to determine features of the life-course of each parent, and grandparent, to determine associations with increased fetal growth using an 'exposome' approach [as in B2190]. Where appropriate, linkage to genetic variants and methylation patterns will be used to determine biological pathways which may be associated with childhood cancer.