Locus of control (LOC) refers to the connections individuals perceive between their behavior and what happens to them. If they perceive such connections they are internally controlled; but if they see their outcomes as due to luck, fate or chance they are externally controlled. Even though researchers have found an internal LOC to be related positively to important aspects of human life including academic achievement, business success, physical and mental health and, in a United Nations study of 84 countries, to happiness, little is known about how internal and external LOC develop, their stability over time or whether they can be changed. Such information is important because over the past 30 years the average locus of control score for adults and children has become more external. We need to know why, and how to change that negative trend. The data to be used in this project include measures of LOC of parents during pregnancy and 16 years later, and of their children at ages 8 and 18 on over 12000 families. It is the only large study in the world that includes multiple assessments of LOC for children and their parents linked to relevant outcome measures. Statistical analyses will provide crucial information on how to foster internality and hence develop interventions.

Hypotheses:

In utero particulate matter exposure has been linked to adverse pregnancy outcomes such as low birth weight and intrauterine growth retardation, which in turn have been linked to adult cardiovascular disease and metabolic abnormalities such as obesity, hypertension, insulin resistance and glucose intolerance. These findings suggest that adverse intrauterine conditions that promote reduced birthweight, such as air pollution exposure, may also promote lifelong susceptibility to cardiovascular diseases. Although it is becoming clear that in utero exposure to environmental stressors plays a role in fetal metabolic programming, the mechanisms are still unclear. The investigation of OMICS measurements at different molecular levels provides an insight into the biological pathways involved in the process linking in utero air pollution exposure to early life growth and cardiovascular development.

Aims:

The objective of this project is to derive a molecular pathway linking in utero air pollution exposure to fetal and childhood growth and to study potential consequences on the development of the cardiovascular system. I address four main objectives:

1) The investigation of prenatal and postnatal growth in association with in utero air pollution exposure.

2) The derivation of biomarkers (within in each OMICS level) linking prenatal air pollution exposure to growth trajectories in the first years of life.

3) The identification of common patterns across different OMICS levels (cross-omic analyses) in order to get an insight into the biological pathways involved in the association between in utero air pollution exposure and growth.

4) The investigation of the role of early life growth and the derived OMICS signature in the association between prenatal air pollution exposure and cardiovascular endpoints in childhood and early adulthood.

Higher blood pressure is associated with increased cardiovascular and renal disease and premature mortality. Although some of the biological pathways and disease endpoints linked to blood pressure changes are well understood, a large number of them remain unexplained. Higher blood pressure is associated with other risk factors for cardiovascular and renal disease, including dyslipideamia, hyperglycaemia and insulin resistance (referred to collectively as metabolites) and higher levels of inflammatory markers, which might mediate any causal effect of higher blood pressure on later disease. But associations with these other risk factors and their joint role in causing later disease could reflect several different alternatives:

1.Blood pressure causes variation in these other risk factors and via these effects causes later CVD and other diseases.

2.These other risk factors cause variation in blood pressure and the primary causal agents are the metabolites/inflammatory markers with blood pressure being more downstream and proximal to disease endpoints.

3.There is a bidirectional causal relationship between BP and metabolites/inflammatory markers

4.There is no causal relationship between blood pressure and metabolites/inflammatory markers, but rather the association is confounded, for example by socioeconomic position, lifestyle characteristics and obesity. .

In preliminary analyses, we have already identified a number of metabolites from the NMR platform that are strongly correlated with BP. We want to extend this work by using Mendelian randomization (MR) to determine whether the relationships are causal and if so which direction they are in (i.e. to distinguish which of the 3 alternatives listed above is most likely).

With UCLEB we can increase the number of available individuals to more than 30 000, all with blood pressure measurements, GWAS or other array genotyping, and NMR metabolites and inflammatory markers.

We will use the known BP genetic instruments to assess whether BP is causally related to the metabolites and inflammatory markers (alternative 1 or 3 above vs 4) and metabolite instruments from recent GWAS to test whether metabolites are causally related to BP (alternative 2 or 3 vs 4).

Aims:

The aim of the study is to investigate the trajectories of traumatic brain injury (TBI) from childhood into adolescence using the ALSPAC cohort. In particular the study will explore the impact that a single TBI event and recurrent TBI events will have on aspects of social cognition, risk behaviour engagement and general cognition. The control groups will include participants who have had a broken bone/fracture and also participants who have never had an injury. There will be exploratory analyses conducted to see whether the detrimental effects of recurrent TBI events are greater than for a single TBI event.

Social cognition can be broadly conceived as the ability to understand other people through emotion perception and empathy and also by inferring the beliefs, intentions and feelings of others 1 Following a TBI event, many facets of social cognition have been shown to be impaired, such as the recognition of facial emotional expressions 1-4; however, current evidence is hampered by small, heterogeneous sample sizes 1.

Engagement in risky behaviour such as substance use has been implicated as an outcome of TBI 5-8. One large cohort study demonstrated that a TBI injury requiring hospitalisation between the ages of 0-5 years old increases the risk for adolescent substance use 5; while findings from another birth cohort indicate that drinking to intoxication is more common among 14 year olds who have experienced a TBI compared to those who have not 6. Ilie and colleagues 7 found that high school students who had experienced a TBI had higher odds of using illicit substances, were twice as likely to consume hazardous amounts of alcohol and were at greater risk for cannabis dependence. Likewise, in a group of incarcerated youths, those with a TBI history were found to be more likely to engage in risky alcohol and cannabis use as well as weekly use of another illicit drug prior to incarceration; this was also the case for participants reporting multiple TBI events9. In comparison to a single TBI event, individuals who have experience two or more TBI events have reported more frequent alcohol, tobacco and illicit drug use 8.

The sequelae of TBI is characterised by cognitive problems 10. Corrigan and colleagues 11 compared different characteristic profiles of TBI histories in persons with substance use disorders and found that a TBI event occurring between the ages of 6-10 may lead to slower processing speed and a greater number of cognitive complaints, while working memory was more impaired in those with a severe adult TBI, mild adolescent injury or multiple mild injuries. Elsewhere, processing speed has been found to be more impaired in participants with more than one TBI resulting in loss of consciousness than in participants who have had just one TBI 8.

Predictors of TBI from birth cohort studies include male gender 6,12, parental alcohol misuse 6, a punitive parenting style and the number of adverse life events experienced by the family 12. These will be controlled for in the proposed study.

Aims:

The study aims to investigate what interventions, services or policies could help prevent primary-school

children with conduct problems, living in high risk families, from developing antisocial and criminal

behaviour as they grow older. The study aims to take a broad view as to what could help and has therefore

been designed in two phases. Phase One is a qualitative longitudinal interview study with ten families to

build hypotheses about what might help. I would like to use ALSPAC data in Phase Two of the study. In

Phase Two the aim is to access longitudinal data on larger samples of similarly high need families that

include a child with behaviour problems to explore issues arising from the qualitative interviews. I aim to

explore possible modifiers (referred to as 'modifying factors') of the association between risk factors and

outcomes (antisocial and criminal behaviour in later adolescence). The aim is not to identify pre-existing

protective factors but to look at changes occurring between beginning primary school and adolescence

which appear to indicate a move onto a more positive trajectory. Outcomes will be compared for matched

groups of children who have or have not experienced the modifying factor/exposure. The matching will

be based on risk factors for the ultimate outcomes of interest, i.e.antisocial and criminal behaviour at ages

16+, and it is proposed that propensity score matching be used. This matching will make use of existing

knowledge about factors associated with resilience in an effort to control for these and isolate the impact

of later occurrences (e.g. Bowen, Heron, Steer, & El Comy, 2008). The method is imperfect for looking

at effectiveness of intervention but provides one route to addressing the possibly serious consequences of

prioritising easy-to-research interventions.

Socioeconomic status (SES), an individual's position in society, is defined by a number of interrelated individual, structural, and environmental factors (e.g., income, education, neighborhood). We have known for some time that an SES-health gradient exists (i.e., low SES associated with poor health, high SES associated with good health) but exactly what it is about SES that gets into the body to shape health is still unclear. Yet, understanding these biological mechanisms will be critical for minimizing the costs of low SES for health as well as maximizing the benefits of high SES for health. This lack of clarity may reflect variations in the measurement of SES, a lack of recognition of factors that influence for whom the SES-health gradient will hold and, until recently, limited availability of epigenetic data. We contend that in order to clarify how SES might get into the body to influence health we should first, determine which indictor(s) of SES, and in which combinations, might work to influence biological mechanisms and second, we should consider whether there might be specific factors that influence for whom SES might get into the body to influence mental and physical health. We believe that psychological well-being is an excellent candidate. The key biological mechanism that we will focus on in these relationships is DNA methylation.

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