There is substantial evidence that early environmental insults increase risk for psychiatric disorders,

especially those with strong neurodevelopmental origins. Thus, there is a need to reliably identify these

environmental factors, as well as whether higher exposure level during critical periods for

neurodevelopment are related to greater risk for psychiatric disorders. Moreover, while environmental

toxins have been reliably associated with early neurodevelopment, similar investigations into longer term

and psychiatric outcomes are scarce.

Current approaches use indirect measures of fetal exposure, such as chemical concentrations in maternal

blood and urine, which may not accurately reflect fetal uptake for many toxins due to variable partitioning

across the placenta (Smith et al., 2007). Thus, a direct marker of early exposure is needed to aid our

understanding of the etiology of psychiatric disorders, as well as to aid prevention.

The current study proposes to use a unique and well-characterized birth cohort: the Avon Longitudinal

Study of Parents and Children (ALSPAC) and applying an extensively developed and piloted method to

determine multi-toxin early exposure (Arora et al., 2006, 2011; 2012; 2013; Hare et al., 2011; Austin et

al., 2013). Human deciduous teeth undergo systematic mineralization commencing prenatally and are

composed of a collagen-based, lipid-containing, calcium-rich apatite matrix, which accumulates bone

seeking elements and organic compounds. The methodology combines detailed histological analysis and

associated analytical tools to establish a comprehensive record of weekly to monthly exposure history of

multiple chemicals and metals and history of infections from the second trimester through early

childhood.

Aims

The overall goal of this project is to determine the association of early life environmental metal and

chemical toxin and infection exposures with multiple psychiatric and neurological outcomes: psychotic

like experiences, depression, mild cognitive impairment and autstic-like traits. A detailed history of

exposure during prenatal and early childhood development will be established to distinguish between two

important aspects of the exposure profile:

1) Exposure timing: We will construct weekly to monthly exposure history over the prenatal and early

childhood periods in order to identify the developmental period(s) most strongly associated with risk for

poor psychiatric and neurological outcomes.

2) Exposure intensity: Cumulative exposure may be more important than exposure during any single

developmental window and our biomarker allows measurement of cumulative exposure from the prenatal

period to the time of tooth shedding, which occurs between ages 6 to 12 years.

This project is IEU research, linked with Laura Howe's MRC fellowship and the IEU stats theme. Analysis will be carried out by Sam Brilleman with supervision from Laura Howe and Kate Tilling.

Aim: to evaluate the use of Bayesian individual knot point models for modelling growth across childhood and adolescence and estimating age of puberty onset, and to compare these models with alternative approaches such as SITAR

Exposure: age

Outcome: height and weight

Confounding variables: gender

Project justification: Self-reported measures of pubertal status can be inaccurate and there is often lots of missing data due to participant embarrassment. Height-based indices of pubertal development offer an attractive alternative that may be both more accurate and result in less missing data. In this project, we will use all available height and weight data to estimate trajectories of growth across childhood and adolescence, using models that allow person-specific ages at which the rate of growth changes. The idea is that the timing of these knowpoints may be informative about pubertal growth spurts. The models will be compared with other approaches to identifying pubertal growth spurts from growth trajectories, e.g. superimposition by translation and rotation (SITAR), a method developed by Tim Cole.

Hypertension represents a major cause of cardiovascular morbidity and mortality, affecting one in three adults worldwide[1]. Intergenerational transmission of blood pressure characteristics has long been demonstrated[2, 3] and may be attributed to a variable combination of genetic and environmental factors[4-8].

Despite some studies demonstrating age-specific effects[9], tracking of cardiovascular traits, including blood pressure, has been shown to persist into adulthood[10]. There has been a suggestion that a stronger maternal-offspring association exists for some cardiovascular risk factors, including hypertension[11-13], although this has not been replicated in other studies[14-16], which has led to speculation that intrauterine influences may contribute to development of risk factors for adult diseases in the offspring[17].

Adolescent blood pressure increases with ageing and the rate of change has been shown to track into later adult life, being associated with higher systolic pressures and thus a greater risk of cardiovascular events[18, 19]. It has been postulated that adolescence provides a critical window for mediating the transition to adult hypertension[20], with the familial aggregation potentially increasing throughout this time[21]. However, there has been limited evidence to support screening and interventions in childhood to prevent later cardiovascular disease[22, 23]. Recent analysis of serial measurements in longitudinal studies have allowed calculation of adolescent blood pressure trajectories, which may facilitate a more accurate depiction of the associations between childhood blood pressure changes and later cardiovascular disease[24], allowing for better stratification of cardiovascular risk and interventions that are targeted[25] rather than population-based[26].

Arterial stiffness, measured non-invasively through pulse wave velocity[27] is independently associated with several cardiovascular risk factors in adults, including systolic hypertension[28, 29]. The main contributors to arterial stiffness are known to be time (age), heart rate and blood pressure[30] - pulse pressure is correlated with arterial stiffness and reflects age-related changes in systolic (increase) and diastolic (decrease) that occur with ageing. Such changes result from the reduced ability to repair damage to collagen and elastin fibres caused by constant expansion and relaxation and may be a reflection of age repair mechanisms more generally[31]. Arterial stiffness is related to ageing in other domains including cognition[32, 33] and thus parental vascular ageing may provide an indicator of an individual offspring's propensity to age across more than just cardiovascular traits, allowing for early interventions that minimise these effects.

The ALSPAC study provides an excellent resource to explore these issues further. In addition to investigating the relationships between blood pressure trajectories and vascular ageing in this study, the project will enable us to clean the existing PWV data. Due to occasional field worker errors and a software upgrade that changed the output fields, it will be first necessary to produce a clean research ready dataset with the arterial stiffness exposures that can subsequently be used by others.

Introduction

The social context in which biomedical research occurs is constantly changing, eg. social media is reshaping views and expectations about individual privacy; understandings of health are constantly evolving. At the same time, new research technologies are becoming available with increasing rapidity, eg. new 'omics tools for analysis. Any change in society or technology may raise new ethical questions for studies such as ALSPAC and may have implications for the policies used to govern these studies.

New policy issues emerge relatively frequently but not necessarily in predictable patterns. Recently emerging issues of concern to cohort studies and biobanks internationally have included: return of incidental findings, recall by genotype, commercial funding in research and data sharing. Legislation proscribes some actions related to these emerging issues, (eg. EU Directive 95/46/EC: 'Protection of personal data', 2012), funder policy provides broad guidelines for policy (eg. MRC/Wellcome Trust 'Framework on the feedback of health-related findings in research', 2014), and individual studies produce in house policy (ALSPAC 'Disclosure of biomedical information to participants', 2011).

Transparency of study policies and practice, especially as new issues emerge, is axiomatic to building and maintaining trust. For longitudinal studies maintaining trust with their participants is crucial to the establishment and maintenance of the long term relationships that characterise these studies; relationships that are realised in participant retention. But extant trust is not enough. Policies must also continue to be sensitive to and aligned with participant (social) values and norms. One way to achieve this is to ensure meaningful engagement of participants in the issues that impact them. Children of the 90s has always been keen to involve participants in the research and ethical decisions made about the study. As part of that commitment the Data to Knowledge Research Group, University of Bristol, will undertake a series of qualitative studies to explore, in depth, the views and perspectives of participants on key emerging research/ethical issues. Drawing from the findings of these qualitative studies ALSPAC will then invite the wider cohort to become involved in engagement activities to assess the views of the broader constituency.

This programme of work will address key issues as they arise over the duration of the current strategic award funding (2014-2019). In the first instance these will include return of incidental findings, recall by genotype, commercial funding in research. In each case the aims and objectives of the research will take the form:

Aim

To gain a better understanding of Children of the 90s participants' perspectives on the issue under study.

Objectives

1. To assess the attitudes of participants to the issue and to understand whether these attitudes may change over time.

2. To understand the potential impact of the issue on Children of the 90s participants.

3. To help inform the policy on the issue in Children of the 90s.

Proposed methods

Background:

Economists and psychologists have established that non-cognitive traits, such as persistence and motivation, are more strongly associated with educational, labour market and risky behaviour outcomes than cognitive measures such as IQ (1-3). This observation has been used to motivate substantial government investments in early years interventions, such as Head Start in the US and Sure Start in the UK. These programs are partly designed to develop children's non-cognitive skills and ultimately improve their outcomes as adults (4). Yet, despite the increasing enthusiasm for these initiatives amongst policy makers, there are still major unresolved questions about whether the associations of non-cognitive skills and later outcomes are due to underlying causal relationships.

The evidence about the importance of non-cognitive skills is largely based on observational studies, both cross sectional and longitudinal. It is very difficult to infer causation in these studies, because of the challenge in sufficiently accounting for all the potential differences between individuals. This may be one reason why, in practice, experimental and quasi-experimental studies have found that the success of early interventions has been mixed (5). Additionally, we do not know the extent to which the associations between non-cognitive skills and educational and labour market outcomes are driven by common genetic and environment factors. The progress in genome-wide data and statistical tools such as GCTA mean it is now possible to estimate both the contribution of common genetic variation to these traits and the proportions of the associations of non-cognitive skills and outcomes which are due to a shared genetic aetiology. Finally, we can use these methods to show how common genetic variation influences these traits across the life course (6).

Aims:

We will use Genome-wide Complex Trait Analysis to investigate the genetic architecture underlying cognitive and non-cognitive skills.

Aims and objectives

Within this project, we aim to enhance the understanding of genetic and epigenetic factors driving the development of human language, and how these factors impact on later child development. We will 1) investigate the genetic architecture of early linguistic abilities, especially expressive language, with respect to common and moderately rare genetic variation, exploiting detailed information from UK10K(http://www.uk10k.org/) and 1000Genomes(http://www.1000genomes.org/)1.

Aim I: Search for single variant genetic effects through a genome-wide meta-analysis of early linguistic skills

Aim II: DNA-based heritability estimations for early language skills using genome-wide data

Aim III: Identification of pleiotropic effects between early linguistic skills and intellectual and developmental outcomes in middle/late childhood

Furthermore, epigenomic variation at birth is likely to harbour a large proportion of cumulative environmental changes during early prenatal development2.

Aim IV: Search for links between epigenetic changes in newborns and early linguistic skills

Background:

There is a growing recognition that adverse experiences such as abuse, neglect and domestic violence in early life may have implications for cardiometabolic health later in life. But whilst a substantial body of evidence has examined the long term consequences of parental divorce on mental health, the potential implications for physical health including cardiometabolic health have received far less attention. Limited evidence suggests that children who experience parent divorce are at increased risk of obesity, poor self-rated health, asthma, cancer[1], and more recently, CVD mortality[2] and stroke[3]. Early life socio economic position is probably a main confounder of the association of interest. Cross cohort comparisons (here between ALSPAC, Pelotas and APCAPS) allow us to examine an association of interest in different settings, with differing confounding structures (e.g. in high and low income countries). The assumption is that if an association is consistent in both settings, it is less likely to be driven by residual confounding[4]. In addition, the role of age at parental divorce and the degree of conflict in the household prior to the parental separation as potential effect modifiers of the association between parental divorce and cardiometabolic health will be explored. Finally, a range of social, behavioural, and biosychosocial factors are likely to mediate associations between parent divorce and cardiometabolic health in later life. These will be identified and examined here.

Aims: Using detailed data from the Avon Longitudinal Study of Parents and Children (ALSPAC), the 1993 Pelotas birth cohort from Brazil and the APCAPS cohort from India, we will examine the association of parental divorce with adiposity (BMI, DXA-determined total body fat mass) and cardiovascular risk factors (blood pressure, lipids, glucose and insulin) measured at 15-18 years.

Aims:

To identify individual genetic variants (specifically single nucleotide polymorphisms, SNPs) that are associated with the ability to identify non-happy emotions in the DANVA facial emotion recognition test, controlling for performance on the equivalent test of happy face recognition. Secondarily, to attempt to stratify this analysis by the type of non-happy emotion (angry, fearful, and sad). Thirdly, to test whether variants associated with sensitivity to non-happy emotion in faces are enriched for association with response to cognitive behavioural therapy for anxiety disorders in a separate cohort. Finally, to explore whether the ability to identify non-happy emotion can be predicted by the genetic risk for psychiatric disorders.

Aims

To employ techniques for identifying latent structure in genome-wide DNA methylation data, characterised by high dimensionality, in order to increase statistical power to detect effects due to prenatal alcohol exposure (both maternal and paternal).

Objectives:

1. To identify latent structures in genome-wide cord-blood DNA methylation

2. To correlate these with maternal and paternal alcohol use before and during pregnancy (in search for both maternal-intrauterine and paternal-line effects)

3. To investigate to what extent confounding could explain these associations

4. To investigate the persistence of the latent structures into childhood and adolescence

5. To investigate whether the relationship between exposures and latent structure persist in later childhood and adolescence

Hypothesis

DNA methylation is thought to be one possible mediator of the feto-toxic effects of alcohol use in pregnancy, given the remarkable correspondence between the most alcohol-sensitive gestational periods and the occurrence of major epigenetic events (including erasure of methylation marks around gastrulation). This is further supported by various animal experiments. Further evidence also points at the role of paternal alcohol use around conception on offspring DNA methylation marks, in particular affecting (paternally) imprinted genes.