Proposal summaries
B3950 - Identifying the genetic markers associated with within-individual variability in blood pressure - 21/12/2021
Evidence suggests that erratic (highly-variable) blood pressure, as well as high mean average blood pressure, could be associated with cardiovascular disease (CVD). As such, a better understanding of the associations of genes with blood pressure variability could provide further insight into the development of CVD. However, whilst there has been considerable research identifying the genetic factors associated with mean average blood pressure, little is known about the associations of genetic factors with blood pressure variability. The project aims to address this by analysing data from ALSPAC to investigate associations between blood pressure variability and genes.
B3960 - Replication of trans-ancestry adiposity genetic scores - 20/12/2021
There is a growing interest in the use of "genetic scores" to investigate the contribution of traits such as obesity and blood pressure to disease and disease risk. However, scores developed using individuals of one ancestry (e.g. Europeans) typically are less useful when applied to populations from another (e.g. East Asians). We are investigating the performance of scores generated using data from multiple ancestries, compared with those from a single ancestry, and have found that there can be substantial improvements. As part of this, to make sure that our results are reproducible, we need to do analyses in sets of individuals who were not used in generating the scores. This project tests how our "improved" scores perform in ALSPAC mothers and fathers.
B3952 - Orienting causal relationships between sleep and adiposity traits using genetic risk scores and mendelian randomisation - 20/12/2021
Poor sleep and obesity are problem that permeates though much of the UK population. Up to 67% of UK adults report disturbed sleep, 26 – 36% experience insomnia and 23% sleep for < 5 hrs per night1. Furthermore, a 2019 health survey for England found that 28.0% of adults in England are obese and a further 36.2% are overweight2. Similarly, obesity is a growing problem in the UK, amongst both children and young people. In 2019, a study by the National Child Measurement Programme (NCMP) found that by the age of five, 13.1% of children were overweight and 9.9% were obese. Between 2007 and 2019, the same study found that prevalence of obesity in year six children had increased from 17.5% to 21.0% 2.
Sleep traits such as chronotype (morning- or evening-preference), insomnia (difficulty initiating or maintaining sleep) and sleep duration (length of time spent sleeping) have previously been studied in relation to adiposity. In previous studies, increased odds of obesity has been associated with evening-preference chronotype4, occurrence of insomnia symptoms 5, and both short (<6h) and long (>9h) sleep duration5. Many studies have also found that individuals involved in night shift work are more likely to become overweight or obese6,7. In addition, associations have been found between increased obesity and both sleep apnoea8 and restless leg syndrome9, both of which may result in poor quality sleep10,11. However, it is often difficult to determine causal relationships and direction of effects in many of these studies, given the observational and often cross-sectional nature of the data.
We have recently performed preliminary Mendelian randomization to establish direction of effects between adiposity- and sleep-traits using summary data from genome-wide associations studies. We wish to follow up these findings using data from the Avon Longitudinal Study of Parents and Children (ALSPAC).
References:
1. Aviva. Aviva health check UK report. (2016).
2. Baker, C. Inside: 1. Obesity in adults, England 2. Obesity in children. 3336, (2021).
3. Cole, T. J., Freeman, J. V. & Preece, M. A. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Stat. Med. 17, 407–429 (1998).
4. Sun, X., Gustat, J., Bertisch, S. M., Redline, S. & Bazzano, L. The association between sleep chronotype and obesity among black and white participants of the Bogalusa Heart Study. Chronobiol. Int. 37, 123–134 (2020).
5. Cai, G.-H. et al. Insomnia symptoms and sleep duration and their combined effects in relation to associations with obesity and central obesity. Sleep Med. 46, 81–87 (2018).
6. Liu, Q. et al. Is shift work associated with a higher risk of overweight or obesity? A systematic review of observational studies with meta-analysis. Int. J. Epidemiol. 47, 1956–1971 (2018).
7. Brum, M. C. B. et al. Night shift work, short sleep and obesity. Diabetol. Metab. Syndr. 12, 13 (2020).
8. Romero-Corral, A., Caples, S. M., Lopez-Jimenez, F. & Somers, V. K. Interactions between obesity and obstructive sleep apnea: implications for treatment. Chest 137, 711–719 (2010).
9. Gao, X., Schwarzschild, M. A., Wang, H. & Ascherio, A. Obesity and restless legs syndrome in men and women. Neurology 72, 1255–1261 (2009).
10. Bogan, R. K. Effects of restless legs syndrome (RLS) on sleep. Neuropsychiatr. Dis. Treat. 2, 513–519 (2006).
11. Miyahara, L. K. et al. Evaluation of sleep quality and risk of obstructive sleep apnea in patients referred for aesthetic rhinoplasty. Sleep Sci. (Sao Paulo, Brazil) 12, 126–131 (2019).
B3959 - Rethinking mental health difficulties - 20/12/2021
The symptoms experienced by young people with mental health difficulties rarely fit neatly into one diagnosis. For more than half of young people with difficulties, the symptoms experienced can be divided into two, or even more, diagnoses, while for others, there is no diagnostic category into which they fit. These problems with our diagnostic categories make it difficult for researchers and doctors who want to know how and why, some people develop mental health difficulties, and how best to support them.
To solve these problems, we need to look at mental health difficulties in a different way. In the last five years, researchers have started using ‘person-centred’ statistical techniques, which produce an alternative to the diagnostic categories we use at the moment, to look at mental health difficulties in teenage groups. Person-centred techniques look for patterns in data that show how symptoms might group in certain ways for some individuals, and in different ways for others. For example, having poor concentration might be grouped together with feeling anxious and being withdrawn in some young people. In others, poor concentration might, instead, be grouped together with feeling restless and breaking rules. With traditional diagnoses, both sets of young people might be diagnosed with ADHD, but using a person-centred perspective we can find these different groupings that reflect the variety of difficulties being experienced. This should give researchers a better chance of understanding what might make it more (or less) likely that somebody has the problems they do, and what type of support might help them most.
The challenge we face is that person-centred techniques are still quite new and we don’t yet know whether the new groupings they produce are consistent, or any more representative or useful than the current ways we diagnose. This is what this project aims to assess. At the same time, we want to get input from young people with experience of mental health difficulties as we do this. Phase 1 will start by understanding more from young people about their experiences of mental health difficulties and the diagnostic journey. We want to know what has been important to them, what they think might have influenced the symptoms they live with, and what sorts of things help make life easier. Researchers will use the understanding we gain from these sessions to plan how they will do the statistical analysis in phase two to make sure that it captures what is important to young people. Phase 2 will be the statistical analysis, shaped by Phase 1. We will use ALSPAC data, which has followed up thousands of people from childhood and through the teenage years, and use person-centred techniques to find new groupings with shared patterns of symptoms. We will then test the statistical strength and consistency of the new groupings, and use understanding gained from Phase 1 to see whether the new groupings can help us to learn more about the factors that impact mental health. In Phase 3, we want to come back to young people to see how far they feel the new perspectives on mental health difficulties that were generated in Phase 2 fit with their experiences. They can help us to see what will and won’t be an improvement over existing diagnoses, and can consider with us how the findings can be used to improve the diagnostic journey. During this phase, we also want to discuss the findings with groups who make decisions about how CAMHS runs, to identify positive ways to use the knowledge that has been generated.
B3951 - Recognising ADHD in ID - 20/12/2021
Individuals with Intellectual Disability (ID) often have other neurodevelopmental conditions, such as Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD), that lead to further impairments and reduced quality of life. This triad of conditions contributes to difficulties in teasing apart symptoms, adding diagnostic complexity. No ADHD screening tools have been developed specifically for ID populations and they do not take ASD into account. This project will use ALSPAC data to explore the manifestations of ADHD in children and young people with and without ID. The ultimate aim is to enhancing methods for detection of co-occurring ADHD in ID.
B3933 - Understanding Genetic Risk for Externalizing across Development and in Conjunction with the Environment - 17/12/2021
Externalizing refers to a constellation of behaviors characterized by under-controlled or impulsive action and antagonism and which manifests in multiple psychiatric disorders (e.g., ADHD, substance use disorders) as well as personality, temperament, and behavioral traits. Twin and molecular genetic studies indicate that externalizing phenotypes are highly heritable and that multiple externalizing phenotypes are influenced by the same genetic factors. This project aims to characterize genetic risk for externalizing in longitudinal samples to better understand the spectrum of phenotypes associated with identified genetic variants, across development, across sex, and in conjunction with the environment.
B3945 - Coming of Age in a Pandemic Transitions to Adulthood and Long-Term Mental Health - 17/12/2021
The COVID-19 pandemic has disrupted the lives of many people in many ways. For young people who were becoming adults, it may have disrupted or delayed moves out of education and into employment, or from living with parents to forming families. This may have long-term implications for their lives and mental health. We will combine information from three surveys that followed people from their youth into adulthood before the pandemic, with information from a survey of young people who were just becoming adults as the COVID-19 pandemic happened. In doing so, we aim to find out what impact the COVID-19 pandemic has had on the economic and family situations of this generation of young adults, and what the longer- term impacts of this on their mental health could be.
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.