Proposal summaries
B3092 - epigenetic heritability of child psychiatric phenotypes - 04/04/2018
Growing evidence points to a role of epigenetic alterations in the development of psychiatric disorders. DNA methylation â an epigenetic mechanism sensitive to both genetic and environmental influences â has been linked to a wide range of emotional and behavioral problems in childhood, including anxiety, depression, conduct problems and attention-deficit hyperactivity. However, findings to date have been primarily drawn from candidate gene studies, or EWAS studies investigating single sites across the genome. As a result, how much of the variance in psychiatric phenotypes is collectively explained by the methylome as a whole is currently unknown.
B3111 - Time-dependent associations between body mass/body composition physical activity diet and lung function in childhood - 08/05/2018
The large increase in the prevalence of respiratory diseases over the last decades, in the West more particularly, cannot be explained by genetics only. It has been hypothesized that these increases are a consequence of changing environmental and/or lifestyle factors. Given the multifactorial aspect of these diseases, it is thus important to take into account the interrelations between these factors and respiratory health. The interrelations between body mass/body composition, physical activity, diet and lung function in childhood and adulthood have been incompletely addressed, likely because their time-dependent and bidirectional nature represent a methodologically challenging research question. Marginal structural models (MSMs) allow estimation of causal effects in observational studies by addressing time-dependent confounding (Robins JM et al. Epidemiology 2000). This approach has still limited application in respiratory epidemiology. We aim to investigate the joint and independent causal effects of body mass/body composition, physical activity and diet on lung function during childhood and early adulthood using MSMs in children from the ALSPAC study.
B3127 - Maternal caffeine intake during pregnancy An epigenome-wide association study - 06/06/2018
Rationale: Animal studies have provided some evidence that maternal caffeine consumption can influence offspring DNA methylation (PMIDs: 22970234, 24475304, 25354728, 25868845, 25868845), but what about humans?
B3555 - The EU Child Cohort Networks core variables establishing a set of findable accessible interoperable and reusable FAIR data - 10/06/2020
LifeCycle is a cross-cohort collaboration which brings together data from pregnancy and child cohorts from across Europe and also Australia to facilitate studies on the influence of early-life exposures on cardio-metabolic, respiratory and mental health outcomes. The end product of this collaboration is a sustainable data resource known as the EU Child Cohort Network.
In the proposed paper we provide a detailed description of the EU Child Cohort Networkâs core variables; a set of basic variables, derivable by the majority of participating cohorts and frequently needed as covariates in life-course research. We firstly describe the process adopted to establish a list of core variables and the protocol developed to harmonise these core data, thus making them interoperable. This protocol also defines the harmonisation process adopted generally within LifeCycle. Secondly, we describe the catalogue developed to ensure that all EU Child Cohort Network data are both findable and reusable. Finally, we describe the core data themselves, including the proportion of variables harmonised by each cohort and the number of children with harmonised data.
We would also like to provide some summary statistics (N and % for categorical variables, and N, mean, standard deviation for continuous variables) on some key variables (namely, sex, maternal education at baseline, motherâs ethnic background, motherâs parity, motherâs smoking in pregnancy, size for gestational age, whether the index child was ever breastfed, age of the mother at birth, birth weight and gestational age). These variables have already been harmonised as part of the LifeCycle project. To obtain the requested summary statistics, we have prepared some R code for individual cohorts to run on their harmonised datasets.
The paper is already written and we hope to submit it to the Journal of Epidemiology in the summer.
B3129 - Longitudinal intake of free sugars in ALSPAC children 06-06-2018 - 151010 - 06/06/2018
The current recommendation is that we should limit our intake of free sugars to provide less than 10% of daily energy intake. This study will investigate free sugars intake in ALSPAC children at ages 18 months, 3.5, 5, 7, 10 & 13 years and determine whether those consuming less than 10% energy from free sugars have a more beneficial nutrient and food group intake than those that consuming more free sugars. Then to investigate if there are differences in obesity levels in relation to free sugars intakes.
B3113 - NIHR Bristol BRC - Exploring Mental Health and Cognition using Mendelian randomisation - 24/05/2018
Treatment for mental illness often focuses on changing cognitive patterns (for example, cognitive behavioural therapy). There is much evidence to suggest that cognition is different in those with mental illness but whether change in cognition is a causal risk factor has not yet been established. Classic observational studies of cognitive patterns and mental illness do not get around the problems of reverse causation and residual confounding. That is to say that the change in cognition might instead emerge as a result of the mental illness, or both might be the result of other unmeasured factors.
One way to get around this is using Mendelian randomisation. Here we take genetic variants associated with the trait of interest: cognition and use them to naturally randomise individuals to levels of the exposure. Therefore, analogous to a randomised control trial, we can make conclusions about whether or not the relationship is causal. In this study, we will be looking at the cognitive traits of emotion recognition, working memory, cognitive styles and impulsivity. This research could inform the development of cognitive training tasks as interventions for mental illness.
B3559 - Does the Timing of Menarche Affect the Development of Eating Disordered Behaviour - 16/06/2020
Disordered eating behaviour remains a widespread and persistent problem among adolescent girls. The various changes associated with puberty have been implicated in the development of these behaviours (Senia 2018). The link between timing of menarche, as a proxy for pubertal development, and psychological distress more generally has been previously established (Mendle 2007, Joinson 2013). However, many questions remain about the relationship between eating disordered behaviours and pubertal development during adolescence. Previous studies have not adequately assessed the age of menarche due to recall bias. This study examines if early menarche could be relevant in the development of eating disordered behaviour using prospective measures from ALSPAC. Furthermore, this study interrogates if the link between early menarche and disordered eating behaviour holds through late adolescence, when early developersâ peers have caught up. In other words, does the association between early pubertal development and disordered eating result from the discord between a child and their peers or does it have more to do with the actual development itself?
Using questionnaire data collected through ALSPAC, this study assesses various markers relating to puberty as well as identifying timing of menarche and any disordered eating behaviour.
B3082 - Adaptations to Inequality and the Perpetuation of Disadvantages An Evolutionary Developmental Approach - 16/03/2018
Socioeconomic disparities in health across the life-course are well-documented, long-standing, and consequential. Research suggests that a significant proportion of the social gradient in health is due to SES differences in health-risk behaviors. Scholarship investigating the underlying mechanisms whereby lower SES increases health-risk behavior points to the mediating role of risk-increasing (or âriskogenicâ) psychosocial schemas. Specifically, evidence suggests that social context and experiences in development, which are patterned by oneâs social position, calibrate psychosocial orientations, including impulsivity or self-control, sensation seeking, and hostile views of relationships, which influence health-risk behaviors and health outcomes. Although the past decade has seen a spate of published GE-health research, few studies have focused on the role of G-E interplay in shaping psychosocial schemas as mechanisms through which SES adversity shapes health disparities. This project will investigate the effects of SES adversity on changes in psychosocial schemas, conceived as socially-calibrated and genetically-influenced endophenotypes which link SES adversity to increased health risk-behaviors. Additionally, although we know that social experiences âget under the skinâ to have enduring effects on health outcomes, we lack knowledge on the biological pathways through which such effects persist. Thus, second, and more innovatively, we will engage with the nascent field of social epigenetics to examine DNA methylation (DNAm) as a biological mechanism through which SES-adversity calibrates psychosocial schemas. In this project, we will investigate the DNAm patterns underlying psychosocial adaptations to SES adversity that increase health-risk behaviors, building on work that identifies DNAm as an important molecular underpinning of experience-dependent changes in cognitions, decision-making, and behavior.
B3080 - Micronutrients in Mood Disorders - 24/05/2018
Depression and anxiety disorders are becoming increasingly common. There is some research suggesting that our diet, (what we eat) might make us more likely to become depressed and anxious. This type of research is called 'Nutritional Psychiatry' research. Many research studies have shown that people with depression and anxiety disorders do not have enough of certain 'micronutrients' either in their food, or in their blood. One example is magnesium, which is contained within green leafy vegetables, and is lacking in processed foods. It is possible that our society is not consuming enough magnesium, which could be increasing the number of people with depression and anxiety. However, it is difficult to say whether a low magnesium in depressed people was the cause of their depression. It may be because people with depression eat less healthily, or because people with other problems (alcohol use or long term illnesses) are more likely to get depressed.
This research will aim to get around these difficulties by using our DNA or genetic code to look at whether genetic changes that cause us to have lower magnesium, are also linked to us having depression.
B3132 - Genetic and epigenetic variation in the newborn brain in relation to neurodevelopmental outcomes in childhood - 14/06/2018
This study aims at exploring the possible influence of genetic and epigenetic variants in the newborn brain on neurologic and mental traits and outcomes. This project aims to combine research from the Bristol Neonatal Gene Study and from ALSPAC. This will represent an interesting opportunity to study in detail the effect of specific genetic and epigenetic variants both in newborns and in childhood. We specifically aim to study the main candidate pathways involved in perinatal brain injuries (glutamate signalling and inflammation) and long-term motor, cognitive and behavioural outcomes. We have produced interesting preliminary findings within the Bristol Neonatal Gene Study, which support the involvement of candidate genetic variants in the glutamate signalling and inflammation pathways. The ALSPAC cohort provides a unique opportunity to validate and add to these findings in a large sample with genetic, epigenetic and phenotypic data collected longitudinally from birth to childhood. With the availability of maternal data, it also offers the opportunity to expand the analysis to maternal-neonatal gene-gene and gene-environment interactions. We have the appropriate expertise in genetic and epigenetic research required for this project. In addition, we are coupling this approach with in vivo work on animal models of newborn brain injuries, exploring the (dys)regulation of key genes involved in glutamate transport and inflammation during perinatal insults.
B3560 - Relationship between serum sclerostin and cardiovascular disease - 19/06/2020
Anti-sclerostin antibody treatment has recently been licensed as a monthly injection for treating osteoporosis (Evenity), a condition in which bones become fragile and more susceptible to fracture. Though effective at treating osteoporosis, concerns have been raised that Evenity increases the risk of developing cardiovascular disease (CVD) and stroke, either via a direct effect on arteries, or by modifying associated risk factors. This project aims to examine this question, by studying whether circulating levels of sclerostin are related to CVD end-points, related phenotypes and risk factors. This will be achieved by examining these relationships in a range of independent cohorts, including ALSPAC. Furthermore, we aim to triangulate our findings by Mendelian Randomisation, using a genetic instrument for circulating sclerostin which we recently published and are currently refining.
B606 - Microvascular Architecture Growth Patterns and Adult Chronic Disease
27 SEPT 08 Update from Robyn - The data collection for this project is complete. A number of manuscripts are under various stages of completion.
B3083 - Exploring the relationship between bone turnover and serum levels of citrate - 16/03/2018
Osteoporosis is a metabolic disorder of bone, characterized by increased bone resorption. Serum collagen type 1 cross-linked C-telopeptide (CTX) is increased during bone resorption. In our preliminary metabolomic analysis, which aimed to identify the metabolic consequences of reduced bone turnover in a cohort of adults with high bone mineral density, we identified a positive relationship between serum CTX and NMR-assessed serum citrate levels (unpublished data). Citrate is a component of bone mineral with a potential structural function (Costello et al 2013). We aim to repeat our cross-sectional analysis of the association between serum CTX and serum citrate in both the ALSPAC mothers and adolescents population to determine if this association replicates, firstly in a general population cohort of a similar age, and secondly in a younger population, which would suggest that serum citrate is a novel marker of bone resorption.
B3090 - Epigenetics in peer victimization and behavioural and emotional development - 05/04/2018
Peer victimization is a widespread phenomenon with many harmful and persistent consequences, such as anxiety, depression, and even suicidal ideation. However, consequences of can vary widely in presentation and severity, which hinders development of appropriate interventions targeted at alleviating the effects of peer victimization. This may in part stem from the fact that little is known about the biological mechanism through which bullying affects children's psychological development and wellbeing. Therefore, we aim to study how peer victimization is related to epigenetic development and explore to what extent epigenetics mediate the association between peer victimization and negative outcomes in children. We will do this by combining data of two large comparable cohorts, ALSPAC in England and Generation R in Holland.
B3118 - Genome-wide association study of anxiety and depression - 24/05/2018
Genome-wide association studies (GWAS) have been instrumental in highlighting associations between genetic variants and 1000s of traits. A recent GWAS of major depressive disorder (MDD) by the psychiatric genetics consortium (PGC) has recently identified 44 genetic variants associated with the disorder (Wray et al., 2018). We plan to include ALSPAC data from the mothers and the children in the next round of analysis for both forthcoming MDD and anxiety PGC GWAS. We will prepare summary statistics from the GWAS to be shared with the PGC and perform subsequent in cohort analysis. This will be a big step towards incorporating ALSPAC data into psychiatric genetics. The summary statistics will contain no identifiable information.
B3133 - Exploring the longitudinal effect of early maturation on physical and mental wellbeing - 14/06/2018
Research suggests that children who reach puberty early are at risk of poorer health and wellbeing. Such âearly maturingâ children also tend to take part in riskier health behaviours, such as smoking, drinking alcohol and risky sexual activity. However, most studies look at these links at a single point in time, which limits how confident we can be that early maturing causes poorer wellbeing. Few studies have looked at what factors may increase or decrease some of these risks. Our study aims to use the ALSPAC data explore three questions relating to the longer-term health risks of adolescents who mature early. The first builds on work we have done with parents, showing many believe we should judge whether or not a child is overweight differently if they are an early maturer, to avoid labeling them as overweight when they are not. This is a particularly important time to consider how we respond to children's weights, as it is the point at which over 95% of children in England are weighed and measured as part of the National Child Measurement Programme. Some parents have been strong critics of this process, so public health teams and parents alike are interested in exploring how we could interpret and use this information better. To explore whether it is appropriate to use the same means of classifying early and on-time maturers as overweight, we will apply an adjustment for maturity to our calculations of weight status for children at age 11, and explore whether this is a better way of predicting which children will have higher/lower future health risks at age 17 (including obesity, blood pressure and other risk factors). Second, we will compare which factor at at age 10/11 is the stronger predictor of wellbeing in later adolescence; being overweight, or maturing early. Finally, to explore what factors might help children to avoid some of the potential consequences of maturing early, we will look at whether childrenâs views of the strength and importance of their relationships with parents and peers influence the effect of being an early maturer on their wellbeing by the age of 17 (including depression, positive wellbeing, and risk behaviours such as smoking and drinking).
B3067 - DNA methylation and brain structure - 01/03/2018
Studies highlighted the role of genetic variation in brain anatomy (Hibar et al., 2015), but environmental factors might also be involved. The aim of the current study is to investigate to what degree epigenetic variation (DNA methylation) at birth is associated with brain structure across different ages. Secondary analyses aim to follow-up on promising methylation markers at later time points.
This project is part of a collaborative effort within the PACE consortium.
B3561 - Exploring how much complex trait variation is captured by DNA methylation in epigenome-wide association studies - 23/06/2020
There are small chemicals that can be added to or removed from genes. These chemical changes may be related to changes in various human traits. For example smoking may cause a decrease in the number of these chemicals present at one or many genes. Currently it is not fully understood how these chemical changes are related to changes in human traits and this project aims to assess how chemical changes across many genes may relate to changes in human traits.