Proposal summaries
B3940 - The DASH-style dietary pattern in childhood in relation to Cardiometabolic Risk in early adulthood in the ALSPAC cohort - 10/12/2021
The Dietary Approaches to Stop Hypertension (DASH) diet is considered a healthy dietary pattern that is associated with lower blood pressure, reduced risk of cardiovascular diseases, type 2 diabetes and related cardiometabolic risk factors in adults. However, research into the cardiometabolic benefits of this dietary pattern during childhood and adolescence is scarce, especially from large studies following-up children into adulthood.
We plan to use dietary data collected in ALSPAC when the children were 7 years, 10 years and 13 years old to assess how closely their diets aligned to a DASH-style dietary pattern. Apart from being low in salt, this dietary patter is high in fruits and vegetables, nuts and pulses, wholegrains, and low-fat dairy products and low in red and processed meat, sweetened drinks and saturated fat. We will explore whether the children with more DASH-style dietary patterns during childhood have better overall cardiometabolic health when they are 17 years and 24 years old, and if so which aspects of cardiometabolic health are benefited most. Overall cardiometabolic health will be measured using a Cardiometabolic Risk (CMR) score that takes into account each participants’ glucose, insulin, triglyceride and cholesterol levels, blood pressure and body composition.
B3905 - Developmental origins of thyroid function regulation in the Avon Longitudinal Study of Parents and Children ALSPAC birth cohor - 10/12/2021
Thyroid dysfunction due to hypo- or hyperthyroidism affects 200 million people worldwide and is a major health burden. Thyroid hormones are vital for healthy metabolism, tissue differentiation, neurodevelopment, growth, immune function, reproduction, and ageing, yet the relative contribution of environmental exposures (e.g. nutrition, psycho-socio-economic adversity, etc.) in shaping thyroid function regulation remains unknown. The thyroid axis is especially important for the health of (pregnant) women and their children , but currently there is a lack of intergenerational data that can help understand the complex interplay between environment and genetics in thyroid function regulation. We aim to fill that gap by analysing thyroid function related variables in the ALSPAC data. Specifically, we will (1) investigate critical periods in which environmental and life-history influence thyroid function regulation, (2) analyse the impact of thyroid function on reproductive health outcomes, and (3) explore the epigenetic pathways by which thyroid function affects health outcomes in mothers and children. Within these analyses we will look at both natural variation in thyroid function parameters as well as pathological variation due to thyroid dysfunction. Identifying critical periods of thyroid function plasticity may have significant implications for the optimal timing of comprehensive public health interventions that can decrease the burden of thyroid dysfunction and its health consequences over the life course.
B3948 - Investigating DNA methylation changes during pregnancy as a mechanism for altering disease risk in women replication study - 17/02/2022
Abstract of the R21 titled “Investigating DNA methylation changes during pregnancy as a mechanism for altering disease risk in women”
Pregnancy is an important transition period that parous women (those who have given birth) undergo and it is linked to changes in risk of various diseases as compared to nulliparous women (those who have never given birth). The number of completed pregnancies changes the risk of autoimmune disease, Alzheimer’s disease, cancers of the ovary, breast and liver, as well as asthma death later in life. However, it is unknown how these disease risks are altered by the child-bearing experience. DNA methylation (DNA-m) - the addition of a methyl group to cytosine in cytosine-phosphate-guanine (CpG) dinucleotides sequences in DNA - has been shown to be associated with multiple health outcomes later in life, such as atopy, eczema, hypertension, diabetes mellitus, and cancer. Our preliminary studies have shown that more CpGs (5.6% vs 0.7%) change levels of methylation during pregnancy (measured between age 18 years and again during pregnancy in women not yet pregnant at age 18) compared to pre-pregnancy (between ages 10 and 18 years), which may represent a plausible mechanism for altering post-pregnancy disease risks in parous women if these changes remain after pregnancy. To better understand the links between methylation changes during pregnancy and parous-related diseases later in life, we propose to identify pregnancy-related CpGs with significant pre- and post-pregnancy methylation changes through an epigenome-wide study. In Specific Aim 1, we will identify CpGs with significant methylation changes in parous women between ages 18 and 26-27 years compared to nulliparous women over the same time period. Then in Specific Aim 2, we will focus on the CpGs identified in Specific Aim 1 and test what proportion of them change from age 18 years to pregnancy and remain stable after parturition up to age 26-27 years. This proposed research has the potential to significantly contribute to 1) the discovery of biomarkers affected by a healthy pregnancy, 2) a better assessment of the long-term effects of parity on women in later life, and 3) the future development of epigenetic tools to detect these modified disease risks. Our collaborative research team is well-positioned to do this work with complementary expertise in genetics and epigenetics, reproductive epidemiology and (bio)statistics, and clinical medicine. We have a long track record of successful collaboration investigating DNA methylation changes during critical transition periods,
such as puberty and pregnancy.
B3947 - A deep clinical phenotyping study of a group of participants on a low lung function trajectory - 16/12/2021
Chronic lung diseases such as Chronic Obstructive Pulmonary Disease (COPD) are incurable but potentially preventable. Studies in cohorts such as ALSPAC have identified that everyone’s lung capacity increases in childhood, peaks in their early 20s and declines from the age of 30. Some groups never reach a normal peak, and some decline more quickly than others. Those on low lung function trajectories are at higher risk of developing lung diseases, diseases of other organs and dying younger. The reasons that these different trajectories exist are not fully understood. Without addressing this question, we cannot improve outcomes for patients with poor lung health and reduce the burden of chronic lung disease. This project aims to improve this understanding and identify potential targets for future interventions.
We will undertake a series of detailed assessments on a small group of ALSPAC Generation 1 participants to look for evidence of early lung disease. We will compare those on a low lung function trajectory with those on a normal one. The assessment will include an interview with a respiratory doctor, breathing tests and a state-of-the-art scan of the lungs at the University of Sheffield, which is a safe new technique of looking in detail at the structure and function of the lungs. This will complement the lung function tests that are aiming to collect data for >4000 participants in the Clinic at 30.
This study will have a range of applications and create future research opportunities to improve our understanding of normal and abnormal lung function development and finding ways of improving everyone’s lung health.
B3941 - The temporal dynamics of prosocial behaviour-executive functions relations during child development - 17/12/2021
The current project is a student project linked to the already approved project: B3840 Developmental pathways to mental health
problems.
Prosocial behaviour and inhibitory control are essential components of social competence and self-regulation, respectively, and both are considered important in child development, and in preventing behavioural problems in children and adolescence. Current knowledge about the developmental relationships between prosocial behaviour and inhibitory control is however limited. In light of the existing literature, a deeper understanding of the developmental relations between prosocial behaviour and inhibitory control may have implications for interventions aimed at preventing problem behaviour in children.
B3938 - Windows of vulnerability Sensitive periods for social adversity in adolescence - 02/12/2021
A large body of research has shown adverse childhood experiences (such as parental neglect, mental and physical abuse) can impact children’s developmental trajectories and have lasting effects on their cognitive function and mental health. In comparison, there is little consensus as to what types of adversity affect adolescents and the timing at which young people are most vulnerable to different types of adversity. This impedes the development of effective policies for prevention and intervention. Initial evidence suggests that for adolescents, other types of adversity, such as social exclusion by peers, may be particularly detrimental. With respect to timing of adversity, protracted sensitive periods of brain development in areas underlying complex skills, e.g., flexible thinking and building relationships, could present a window of vulnerability where young people are particularly sensitive to adversity exposure. The aims of this research project are twofold. First, to investigate what types of adversity impact cognitive and mental health outcomes in adolescents, and secondly, to determine when different adversities have the greatest impact. This will provide an opportunity for informing policies on how we can prevent and alleviate adversity in youth.
B3942 - Chronic adolescent loneliness Methods to capture and understand its developmentmanifestation and experience among young people - 10/12/2021
Loneliness is a deeply troubling experience of feeling unwanted by, excluded from and/or unworthy of the social companionship a person desires. Our concern relating to loneliness is part of a global concern for the strong mental health of adolescents which addresses to how young people experience life as they shift from childhood to adulthood, a turbulent time in their development. Our proposed research aims to use an innovative interdisciplinary mixed-methods approach to help grow the evidence base on how loneliness drives poor mental health in order to design new solutions that most effectively nurture the relationships that sustain people.
B3934 - InterPLAY Building a data-informed framework to understand how play influences childrens psycho-social and mental health outco - 30/11/2021
This project is designed to determine the associations between play, and social emotional and mental health outcomes in children to inform future empirical work around how play can be used to support children’s psycho-social development. The project will use four international cohort data sets to investigate how play is best theorised and measured in longitudinal cohort studies, develop data-driven models of the associations between play and social emotional and mental health outcomes in children, and evaluate whether those models require adapting for children with a mental health diagnosis.
B3930 - Green space and child cardiometabolic health A structured life course approach - 29/11/2021
This project aims to understand how access to green space in pregnancy, infancy and early childhood impacts subsequent child cardiometabolic health (BMI/obesity and blood pressure). Although research is mixed, there is some evidence that access to green space may be associated with lower childhood BMI/obesity and blood pressure (Luo et al., 2020; Markevych et al., 2014). As childhood BMI and blood pressure predict these traits in adulthood, and that these are key risk factors for cardiovascular disease, child cardiometabolic health is a serious public health concern; if access to green space can lower BMI and blood pressure, this may constitute a potentially modifiable public health intervention.
We will use a structured life course approach to answer this question, which is able to distinguish between different life course trajectories, such as critical periods, sensitive periods, accumulation of risk, and others (Smith et al., 2016; Ben-Shlomo & Kuh, 2002). We will use repeated data on access to green space to explore if and how this is related to child cardiometabolic health in ALSPAC children. In addition, this project will explore whether there is an interaction between socioeconomic position and access to green space in shaping these outcomes. These analyses will also be replicated in an independent UK cohort (Born in Bradford; BiB)
References:
Ben-Shlomo, Y. & Kuh, D. (2002). What is a Life Course Approach to Chronic Disease Epidemiology? Conceptual Models in Life Course Epidemiology. Int. J. Epidemiol., 31, 285–293.
Luo, Y.N., Huang, W.Z., Liu, X.X., Markevych, I., Bloom, M.S., Zhao, T., et al. (2020). Greenspace with overweight and obesity: A systematic review and meta-analysis of epidemiological studies up to 2020. Obes. Rev., 21, 1–28.
Markevych, I., Thiering, E., Fuertes, E., Sugiri, D., Berdel, D., Koletzko, S., et al. (2014). A cross-sectional analysis of the effects of residential greenness on blood pressure in 10-year old children: Results from the GINIplus and LISAplus studies. BMC Public Health, 14, 1–11.
Smith, A.D.A.C., Hardy, R., Heron, J., Joinson, C.J., Lawlor, D.A., Macdonald-Wallis, C., et al. (2016). A structured approach to hypotheses involving continuous exposures over the life course. Int. J. Epidemiol., 45, 1271–1279.
B3931 - Causal inference in the study of adverse childhood experiences and adolescent mental health advancing concepts methods and evi - 29/11/2021
Adverse childhood experiences (ACEs) are “experiences which require significant adaptation by the developing child in terms of psychological, social and neurodevelopmental systems, and which are outside of the normal expected environment” (McLaughlin, 2016). Abuse and neglect; parental substance misuse, intimate partner violence, psychiatric disorders, and separation; and peer victimisation are often considered ACEs. Children who experience ACEs are more likely to develop neurodevelopmental or mental health problems (hereafter referred to collectively as mental health).
The vast majority of the literature documenting associations between ACEs and mental health simply describes associations, with limited attempt to investigate confounding. Study designs specifically intending to interrogate causality are seldom applied to ACEs research. Describing associations between ACEs and mental health can provide valuable information about support needs. However, the optimal design and prioritisation of policies and interventions necessitates higher-quality evidence to establish which aspects of an adolescent’s experiences are causally influencing mental health, and through which causal pathways.
This project will advance research into ACEs and adolescent mental health by looking at whether experiencing ACEs derails people from their mental health trajectory.
B3922 - Understanding the role of inflammation in cognitive function and depression - 29/11/2021
Cognitive dysfunction is proposed to be a feature and risk factor for depression. Evidence from observational and experimental studies suggest a role of low-grade systemic inflammation in depression, which could also be relevant for cognitive dysfunction. Existing cross-sectional studies suggest that inflammation is associated with cognitive dysfunction, particularly poor memory, processing speed, executive function and emotional bias. Limited longitudinal evidence, often based on the elderly population, also suggest a potential link between inflammation and impaired learning, memory, attention, and general cognitive functioning and decline. While these studies point to a potential role of inflammation in cognition, there are key unanswered questions.
First, much of the existing evidence around inflammation and cognition is based on the elderly population, so it is unclear whether inflammation is associated with cognition earlier in the life course. Second, it is unclear whether inflammation plays a causal role in cognitive dysfunction, as cytokine elevation could alternatively be a consequence of cognitive impairment (i.e., reverse causality) or due to confounding. I propose to address these issues using epidemiological approaches.
B3937 - Scrambling ALSPAC genotype data for use in genetic course practicals - 29/11/2021
We teach on many genetic epidemiology courses, and we need realistic genetic data that is relatively large and also non-sensitive for many of these projects. We have used a modified version of ALSPAC G1 individuals in the past in which genomes have been scrambled. In doing so, a representative set of samples with realistic correlation patterns is developed but contains no individuals that correspond to any real participants
B3939 - Mapping disparities in childhood lead exposure in England - 09/12/2021
Our project aims to estimate the prevalence and distribution, in terms of geography and socioeconomic status, of lead exposure in England and its costs in terms of children’s wellbeing and development. While scholars and practitioners believe lead exposure to be widespread in England, a dearth of data on this issue has so far hindered policymaking. This proposal seeks funding for the initial project stage - a secondary data analysis, building on international evidence to project exposure burden in England, based on the existing data and the piloting of surveys to collect primary data to map exposure sources and prevalence.
B3863 - How the interaction of genetic and environmental factors influences human traits - 23/11/2021
Subtle differences in a person's genes can affect their susceptibility to disease and cause them to respond differently an environmental exposure compared to other people. Interestingly, some people may develop a disease after being exposed to specific genetic and enviromental factors while others may not.
This project will combine genetic and environmental information from thousands of people aiming to understand how these factors influence risk to disease and characteristics like immune system response and vision.
As we learn more about the connection between genes and the environment, we can pursue new approaches for preventing and treating disease.
B3936 - ALSPAC - Enhancement of Transcriptomic Resources - 25/11/2021
ALSPAC collected samples at the 24 year clinic to preserve RNA. This can be used to look at which genes are being expressed in blood. We are hoping to obtain money to analyse some of these samples by a process called RNA sequencing. This will allow us to see which genes are switched on in different people. The data generated will create a resource for molecular research.
B3928 - Mechanisms linking early life exposures to comorbidity in young adulthood - 19/11/2021
Exposure to childhood adversity, including interpersonal violence, financial stressors, and household dysfunction, has been consistently linked to a variety of adverse physical and mental health outcomes in adolescence and adulthood. However, our understanding of the biological, behavioral, and social mechanisms that link different patterns of childhood adversity to specific outcomes is currently limited. In particular, the risk of co-occurring mental health, substance use, and physical health problems in young adulthood may stem from different pathways during the course of childhood and adolescence. In this study, we will examine the biological, behavioral, and social mechanisms through which trajectories of childhood adversity influence comorbid behavioral and physical health conditions in young adulthood. This project expands on our previous work using ALSPAC data to identify relations between childhood adversity trajectories and distinct outcomes in young adulthood, including depressive symptoms and violent behaviors. We will examine epigenetic and biologic mechanisms including differential DNA methylation, inflammation, heart rate, and stress-related biomarkers, as well as potential behavioral mediators like temperament, impulsivity, locus of control, mental health, parental supervision, and self-esteem. Social mechanisms will include the intergenerational transmission of behaviors from parents to children and peer influences. We will also consider characteristics at different stages of the life course, including in utero exposure to environmental toxicants, a positive home environment during childhood, and the presence of other supportive relationships in adolescence, as potential moderators of the relation between childhood adversity trajectories and subsequent outcomes. Finally, we will incorporate relations of interest into a computational agent-based model that can be used to simulate hypothetical interventions to prevent the development of adverse health outcomes.
B3927 - Social Skills in a Changing Labour Market - 02/12/2021
Across the developed world, employment has declined in middle-wage "routine" jobs and increased strongly in jobs requiring a degree. Recent evidence from the U.S. and Sweden indicates this change is associated with an increase in the demand for jobs requiring social skills. Over the last 30 years the UK labour market has witnessed a well-documented increase in the supply of graduates while the occupational structure has shifted towards managerial jobs. However, there is no strong evidence as yet that these changes have benefitted workers with higher social abilities.
In this project we will investigate the labour market returns to social skills in the context of the UK. Thanks to the availability of long-running cohort studies, the UK offers an opportunity to examine unique data on individual’s characteristics, such as cognitive, socio-emotional, and physical abilities. ALSPAC is particularly suitable to our purposes as it collects detailed information on these abilities.
The changing labour market is at the centre of some of the most important social policy debates worldwide, especially those focused on the effect of artificial intelligence on the demand for different types of skills. We will contribute to these debates by providing novel evidence of the relationship between different types of skills and labour market outcomes.
B3929 - Quality of relationship confounder or mediator of religious beliefs and health outcomes - 19/11/2021
Another existing project using ALSPAC data (B3397) is examining if religious and spiritual beliefs are related to healthy behaviours, disease end-points and biological biomarkers such as epigenetics. One possible way such associations may exist is that these beliefs may enhance the quality of intimate relationships either through shared beliefs and practices e.g. going together to a religious place of worship or helping to sustain them through difficult periods. This would imply that the quality of relationship may partially mediate the benefits. However, it is more complex than this as it is also possible that it is the relationship which also drives religious beliefs and hence this may confound any association. Furthermore both religious beliefs and relationships can change over time getting either stronger or weaker. We will use the repeat measures available in ALSPAC to examine these important questions.
B3923 - Examining the relationship between leptin levels in childhood and lifetime anorexia nervosa using observational and genetic epid - 16/11/2021
In this project we plan to use longitudinal observational data and human genetics to examine the relationship between leptin and anorexia nervosa
Leptin is a hormone with pleiotropic functions that affect several tissues in animal and human subjects (Hebebrand, 2006) and is shown to be involved in eating behaviour (Farooqi, 2007). Several symptoms in individuals with anorexia nervosa have been reported to be related to low leptin levels (Hebebrand, 2006) and a recent MR investigation found that a low endogenous leptin synthesis represented a risk factor for developing anorexia nervosa (Peters, 2021). Whether this association is dependent on leptin levels at particular time periods in the lifecourse is yet to be determined. In this project we plan to use longitudinal observational data and human genetics to examine the relationship between leptin in childhood and anorexia nervosa later in the lifecourse.
B3849 - Testing for interaction between early life adversity and adolescent alcohol use in the development of alcohol use disorders in a - 16/11/2021
Alcohol use disorders (AUDs) affect over 100 million people worldwide with alcohol use accounting for 4.2% of global disability adjusted life years (DALYs) (Degenhardt et al. 2018).
Adolescence and young adulthood is recognised as a critical window for the development of AUDs due to the vulnerability of the corticolimbic system to alcohol-induced damage during this period (Nixon and McClain, 2010). AUDs commonly develop during late adolescence and early adulthood, with a median age of onset for alcohol abuse of 21 and alcohol dependence of 23 (Kessler et al, 2005). Adolescent alcohol use has both immediate and longer-term effects on the development of AUDs. In adolescents that used alcohol for the first time between the ages of 11 and 14 the rate of alcohol dependence measured ten years post exposure was 15.9% in contrast to those who used alcohol for the first time after the age of 19, where rates of alcohol dependence ten years post exposure were only 1% (DeWit et al, 2000). A prospective cohort study in the UK demonstrated that following adjustment for other predictors, frequent teenage alcohol use and antisocial behaviour held persisting and independent associations with later alcohol dependence (Bonomo et al 2004).
Early life stress and traumatic experiences are widely recognised to contribute to AUDs in humans (Viner and Taylor, 2007). In the UK the association between trauma and substance use disorders has been recognised by the Department of Health with services required to use a trauma-informed model of addiction care (Clinical Guidelines on Drug Misuse and Dependence Update 2017). In epidemiological studies the presence of Adverse Childhood Events (ACEs) is associated with an earlier onset of alcohol use and increased levels of alcohol consumption (Rothman et al. 2008). ACEs specifically linked to alcohol use include physical abuse, sexual abuse, having a mentally ill household member, substance abuse in the home, and parental discord or divorce (Rothman et al. 2008). All forms of childhood trauma act as risk factors for adolescent binge drinking; with earlier adverse alcohol consumption potentially lying on the causal pathway between trauma and alcohol use disorders (Shin et al. 2009). One pathway that may explain how early life adversity and adolescent alcohol use lead to AUD in adulthood is through long term changes in gene expression as a result of epigenetic modification. Exposure to early life adversity and adolescent alcohol use independently lead to long-term epigenetic changes (Houtepen et al. 2016, Kyzar et al. 2016). Markers of early life adversity have been demonstrated to show conserved epigenetic changes between human and rat hippocampal tissue providing scope for translation between preclinical and epidemiological studies (Suderman et al. 2012).
This study aims to explore the interaction between early life adversity and adolescent alcohol use in the development of alcohol use disorders in adulthood using the ALSPAC cohort. This study will quantify ACEs in the ALSPAC cohort using previously developed approaches (Houtepen et al. 2018) and develop an approach to quantify adolescent alcohol use. These measures will be used as predictors of a diagnosis of AUD using DSM V criteria at age 25. Epigenetic associations with early life adversity and adolescent alcohol use will be explored with the intention of using these findings to bridge between this study and a parallel programme of preclinical experiments taking place Department of Physiology, Pharmacology and Neuroscience at the University of Bristol.