Proposal summaries
B4527 - Inflammation and related metabolic and hormonal biomarkers for depression and other psychiatric conditions - 21/02/2024
What is the project about?
Immunometabolic dysfunction is implicated in depression and other psychiatric disorders, which may moderate the effect of antidepressant treatment. Existing case-control studies show changes in various blood immunometabolic biomarkers in depression, psychosis and other psychiatric disorders compared with controls, but longitudinal studies needed to assess temporality of association is scarce. Existing studies have almost exclusively used circulating blood biomarker levels as exposure which is informative, but does not reflect activity of the biomarker at cellular level accurately. Therefore, there is a need for developing novel measures reflecting biomarker activity/signalling more accurately to better understand the role of inflammation in psychiatric conditions.
My project will address these key issues using: i) longitudinal analysis testing the relationship of blood immunometabolic and related biomarkers with depression and other psychiatric outcomes; ii) develop and implement novel measures of activity/signalling of specific biomarkers (namely, interleukin 6 or IL-6, renin-angiotensin system or RAS) in analyses testing their associations with blood biomarkers and psychiatric outcomes.
Why is the project important?
Depression is a global public health concern, with recent research suggesting that it affects around 1 in 6 people in the UK. About 1 in 3 people with depression do not respond to currently available medications suggesting other mechanisms are involved. Demonstrating prospective associations of blood immunometabolic biomarkers with depression will strengthen causal inference and identify specific biomarkers for future investigation. Demonstrating how the activity of specific depression related biomarkers (e.g., IL-6 signalling) relates to depression risk will highlight specific pathways for intervention.
What do we know already?
While it is known that abnormal functioning of neurotransmitters such as serotonin are associated with depression, there is emerging evidence to suggest that inflammation may play a key role in its development. Studies have shown that individuals with major depressive disorder (MDD) have increased levels of interleukin 6 (IL-6) in the blood than healthy controls. Mendelian randomisation studies suggest a potential causal effect of IL-6 on depression and schizophrenia. However, which particular IL-6 signalling pathway underlies these associations remain unclear.
B4539 - How does physical activity and body composition effect the risk of fracture in adults aged 30-60 - 21/02/2024
Background
Broken bones cause pain, disability, and time out of work in adulthood. Most of what we currently know about the causes of broken bones comes from research on children, adolescents, and the elderly. Little is known about what contributes to the risk of broken bones in people through mid-life.
This project will focus on how different levels of physical activity and body composition, i.e. bone strength and weight, may change the risk of a broken bone in people from early adulthood to mid-life (age 30-60).
Your approach
I will use data collected from large groups of people over many years, including the UK Biobank and the Avon Longitudinal Study of Parents and Children. These data sets have measures of physical activity, obesity, bone fragility and individual genetic data, as well as information on the outcomes of broken bones in adults aged 30-60. I will use classic epidemiology techniques and recent genetically-informed approaches to better understand the complex relationships between physical activity, body composition and broken bones.
Expected impact
Better understanding of the causes of broken bones in middle-aged adults will enable early targeted preventative strategies and hope to reduce the burden of fractures in later life.
B4528 - Associations between mother-child interaction in infancy and depressive symptoms in adolescence - 13/02/2024
Mother-child interaction is an essential element in a child's development that is impacting children’s emotional and psychological well-being. This aspect of early relational dynamics is especially critical in understanding the development of depressive symptoms during adolescence. Despite its significance, current research on how early mother-child interactions influence the development of depressive symptoms in adolescents, particularly using longitudinal data, remains limited. Given the existing literature, a more nuanced exploration into how these early interactions shape mental health outcomes in adolescents is not only necessary but could be instrumental in developing early intervention strategies. Such interventions could potentially mitigate the development of depressive symptoms, thus contributing to healthier adolescent mental health.
B4534 - Measurement Invariance in predictors of dropout from cohort studies - 12/02/2024
Individuals who take part in voluntary studies provide valuable data for health scientists across a range of health-related outcomes. These studies are extremely useful for understanding relationships between health related exposures and health outcomes. Results from studies such as ALSPAC (Children of the 90s) often rely on statistical methods to apply such relationships to the wider population (as the people who take part in these studies are often unusual in some way). One of the most commonly used statistical methods for this is called weighting, where we statistically "up-weight" people who are less likely to take part in a study, and "down-weight" people who are more likely to take part in a study, so that we can apply our findings to populations which are dissimilar to the studied (ALSPAC) population. It is not well understood how these methods perform in cases where the weights are constructed from a complex measure such as mental health - which may be measured differently for people who remain in a study, and those who go on to drop out. This study will provide valuable insights into how we might approach this.
B4521 - Investigating the associations between asthma and anxiety/depression - 12/02/2024
Asthma is the most common long-term condition among children and young people in the UK, with over one million children currently receiving treatment for it.
People with asthma often experience anxiety and depression. We do not fully understand the link between all these conditions. We also don’t know if the relationship between them is causal (having one condition causes the other to develop).
Project aims
We want to identify whether there is a link between asthma and mental health disorders. We will do this by using data from the Avon Longitudinal Study of Parents and Children (ALSPAC).
ALSPAC is an ongoing study looking at the health of children born to mothers living in a specific part of England in the 90s. The original study has since expanded to include the next generation of children and their families.
We will use the large volume of data available through ALSPAC to explore the links between being diagnosed with asthma as a child and the likelihood of developing anxiety and depression. We will also look at the reverse, ie. whether having anxiety and depression as a child increases your likelihood of later being diagnosed with asthma.
What we hope to achieve
Findings from this study could support the development of clinical trials targeting patients with asthma and anxiety/depression. In turn, this could improve how people living with asthma manage their condition, reduce the number of exacerbations they experience and decrease the number of times they admitted into hospital.
This research is part of a PhD project and is being led by Dr George Nava. It is a collaboration between the respiratory and mental health themes of the Bristol BRC.
B4529 - Health effects of diet in young children - 06/02/2024
What young children eat can affect their well-being in many ways, and the wide range of food choices and the rising cost of food can make it difficult for parents and carers to choose the best options for their children. The aim of this project is to find out how young children’s diet affects their growth and health as they develop into adults. For example, are children who have more sugary snacks and drinks more likely to be affected by tooth decay or overweight and high blood pressure later in life? Do children who follow a mostly plant-based diet get the right amount of nutrients such as protein for ideal growth? These questions come from a recent UK government review of the gaps in our knowledge on young children’s diets. We will discuss these questions with parents to find out what else they would like us to find out about feeding their children well.
To answer the questions raised we will use information on the diets of pre-school children from two up-to-date national surveys. The National Diet and Nutrition Survey (NDNS) collects information on all foods and drinks consumed over two days as well as the height and weight of children across the UK. Around 1,200 1-5 year-olds are expected to take part between 2019 and 2025. In addition, in 2024 the survey of Diet in Scotland’s children (DISH) will collect information on what around 300 children aged 2-5 years eat and drink and some further questions about their general food habits and household food situation. These surveys will tell us how different types of diets and food choices can provide enough nutrients for health and growth.
To find out how diet in young children affects longer-term growth and health we will use information from the Avon Longitudinal Study of Parents and Children (ALSPAC), a Bristol-based study of 14,000 children born in 1991-2 and their parents who contributed information on the children’s diet and health regularly over the last 30 years. This study will allow us to look at how diet in children under five is related to dental, heart, and lung health when they become young adults. By comparing the diet of young children in ALSPAC with the diet of children in the NDNS and DISH surveys we will be able to assess the changes in children’s diet across the last 30 years.
Studies from around the world have suggested that young children’s diets affect their health throughout their life. This project is designed to provide insights into the importance of these issues in the UK. This will help those who design the programmes and guidance which support all parents and carers to feed their children well.
B4452 - Associations between Early-life Modifiable Exposures with Biological Age of Offspring Multi-omics Analysis of ALSPAC - 13/02/2024
Biological age, of which the calculation primarily involves the use of epigenomic data, such as methylation, could predict the health status and disease risk in humans, and show substantial differences between individuals in early life, sometimes even from birth. Numerous studies have demonstrated that accelerated biological ages were related to increased disease risk and mortality, whereas conversely, deceleration relates to better health and longevity.
The Developmental Origins of Health and Disease (DOHaD) hypothesis suggests that the health and disease risk of offspring could be influenced by exposures during parental pregnancy and early-life experiences. Current research also indicates that parental lifestyle and environmental exposures during early fetal development may have profound and lasting effects on the health of offspring. However, there are still gaps in our understanding of whether and how early-life modifiable exposures during parental pregnancy and early life, such as socioeconomic factors, education, etc., may impact the biological age of offspring, thereby influencing disease risk.
This project aims to investigate the causal relationship between early-life modifiable exposures with the biological age and the disease risk of offspring using data from the ALSPAC cohort. We will employ a multi-omics approach and longitudinal data analysis to explore the underlying biological mechanisms, providing new opportunities and valuable guidance for early detection and health interventions.
B4526 - THE PLACENTA IN MATERNAL AND FETAL CARDIOVASCULAR HEALTH AND DISEASE - 12/02/2024
The placenta is the crucial interface between mother and developing fetus during pregnancy, enabling exchange of nutrients, oxygen, and waste products. The placenta is essential for a healthy pregnancy; placental pathologies underlie some of the most common pregnancy complications, referred to as placental syndromes (PS). PS include hypertensive disorders of pregnancy (preeclampsia and gestational hypertension), fetal growth restriction, and preterm delivery, which are leading causes of maternal and neonatal mortality and morbidity. PS are associated with adverse cardiovascular health beyond delivery and throughout life, both in the mother and offspring. Yet the placenta remain understudied and the mechanisms linking PS, congenital heart disease in offspring and cardiovascular health in both mothers and offspring are not well understood. In this project we aim to understand the the basis for primary placental disorders as the cause of secondary heart and vascular disease, both in the offspring and in the mother.
B4500 - The additional effect of paternal mental health on early childhood neurodevelopment - 31/01/2024
Accumulating data from epidemiological and molecular studies indicate that adverse early childhood neurodevelopment is a risk factor of neuropsychiatric illness in later life. Among several factors that can affect early childhood neurodevelopment, maternal health, including both her physical and mental health, have been convincingly identified as predictors of children’s neurodevelopment. However, the evidence concerning the additional effect of paternal mental health on the child`s neurodevelopment is sparse warranting further research in this area. This research fits in the Paternal Origins of Health and Disease concept (POHAD).
B4513 - International Multicohort Pediatric Biomarker Collaboration Biomarkers4Pediatrics - 12/02/2024
Health monitoring and clinical decision making in paediatric care largely depend on the availability of reference values for clinical parameters. Hence, the diagnosis of highly prevalent conditions in children and adolescents such as metabolic dysfunction has been hampered by the lack of a worldwide consensus on diagnostic criteria, as definitions and cut-offs being used in the paediatric population are frequently derived from the adult population. Providing globally applicable reference curves for the metabolic syndrome and its components, in early life - from birth to adolescence - represents a big step towards the ultimate goal: developing cut-offs for clinically relevant biomarkers for paediatric practice. By making use of the increasing availability of research data worldwide, we aim to establish a global pooling initiative building on a previously published special issue of the International Journal of Obesity "Filling the gap: international reference values for health care in children" (edited by Ahrens W, Moreno LA, Pigeot I), and further taking advantage of increased statistical power and variations across age groups, geographical regions and socio-cultural backgrounds. Thus, biomarker data for the metabolic syndrome are being collected, subsequently calibrated, harmonized, combined and analysed to provide age-, sex- and ethnic-specific reference curves for metabolic biomarkers to facilitate the diagnosis of metabolic syndrome in early life globally.
B4514 - Urban exposome and body mass index trajectories from birth to adolescence - 06/02/2024
This project will investigate whether the environment in which children live affects their likelihood of becoming overweight or obese as they grow up.
There is evidence that some factors of the urban environment, such as air pollution and whether the street design encourages walking, are linked to body mass index in children. There is a need to build on this evidence though, by considering how different factors might interact with each other, for example if a person lives near a busy road they will be exposed to noise and air pollution from it, so it is important to determine whether these factors are both related to body mass index, or whether it is one or the other. We will also investigate whether characteristics of individual people, like age and socio-economic status, affect the relationships found in previous studies.
This project will use height and weight measurements collected from children in the ALSPAC study and combine them with information on the environment in which they live, for example air pollutant levels, the amount of green and blue space, and the amount of public transport. We will use this information to determine whether the environment in which a child grows up affects their likelihood of becoming overweight or obese in later life, and also whether there are interactions between these factors. Understanding how these factors might affect overweight and obesity in childhood, and how it progresses into adolescence, is important for identifying communities that may be at increased risk, and to provide information that local communities may wish to use to address any relevant risk factors.
B4517 - Early metabolic and proteomic features of endometrial cancer - 22/01/2024
Cancers develop for many years before they are diagnosed. Using data from first-generation ALSPAC offspring, we aim in this study to estimate the effects of being more genetically susceptible to endometrial cancer on metabolic and proteomic traits measured in blood across early life; this should help to reveal what early stages of endometrial cancer development look like and when they occur. More specifically, we will examine associations of genetic risk scores for endometrial cancer that has been shown to be influenced by obesity with traits from targeted metabolomics measured in childhood (age 8y), adolescence (age 15y), and young adulthood (age 18y and 24y) and proteomics measured in childhood (age 8 y) and young adulthood (age 24). This allows us to view subtle changes in the circulating metabolome and proteome over time which precede the onset of clinically detectable endometrial cancer by several decades. Recognizing the early signs of endometrial cancer development is vital for informing early detection, preventing its onset in older age, and improving survival.
B4520 - Genetics of anorexia nervosa and associations with physical and psychological dimensions of childhood development - 22/01/2024
Anorexia nervosa (AN) has the highest mortality out of all psychiatric conditions, early onset (between 12-15 years), and long-term health issues. Although the exact cause of AN is not yet fully understood, it is known that a complex combination of environmental and genetic factors plays a role in its development. Genetics alone are estimated to explain 50 to 60% of risk for AN. Recently, a large-scale genome-wide association study (GWAS) identified eight genomic regions associated with AN, as well as evidence that the genetic architecture of AN overlaps that of metabolic and anthropometric traits, such as body-mass index (BMI) and risk for type-2 diabetes. In this study, we will analyze AN GWAS results to compute polygenic risk scores (PRS) for ALSPAC participants, allowing us to estimate the genetic risk for AN for each participant. We will test how genetic risk for AN is associated with behavioural and emotional problems during childhood and whether these associations are development-specific by modeling psychopathology measures longitudinally. We will also test associations between AN and physical growth during early life. Given the patterns of genetic associations between AN and BMI, we will test whether genetic risk for AN that has been adjusted for genetic correlations with BMI affects previously identified associations.
B4519 - UKLLC Investigating the association of long-term air pollution exposure with risk and severity of SARS-CoV-2 infection - 22/01/2024
Information can be obtained from ALSPAC (B number folder) or the UK LLC on request
B4518 - Social psychological cognitive and biological mechanisms underlying the impact of early life adversity on anxiety-related dis - 31/01/2024
Adverse childhood experiences (ACEs, e.g. family violence, parental mental health problems, bullying) carry a higher risk of anxiety-related disorders, yet the underlying mechanisms remain unclear. We will use cohort studies in the UK and Brazil to assess the mechanisms linking ACEs to anxiety-related disorders.
The depth and breadth of measurements in the cohorts enables us to examine: 1) multiple levels of explanation: social, cognitive, psychological, biological, plus within- and between-level interactions, 2) the developmental trajectory of onset and persistence of anxiety, and how this can be prevented or interrupted, 3) the role of commonly co-occurring conditions (e.g. depression, neurodivergence), and 4) consistency/specificity of mechanisms across ACEs and anxiety-related disorders.
Comparisons across generations and the UK and Brazil, where social contexts and levels of ACEs vary, will enable assessment of the degree to which interventions need to be culturally/generationally specific.
Multiple analysis approaches will support causal inference: difference-in-difference, sensitivity analyses to assess environmental and genetic confounding, and causal mediation analysis. Where possible, we will triangulate cohort analyses with Mendelian randomization studies using large biobanks.
The research has been co-designed, and will be co-produced by, UK-based people with lived experience of anxiety. We will develop and evaluate lived experience involvement in Brazil.
B4516 - CC16 in childhood and resilience to airflow limitation in young to mid-adult life - 21/02/2024
Club cell secretory protein (CC16, also known as CC10, CCSP, and uteroglobin) is a homodimeric pneumoprotein encoded by the SCGB1A1 gene that is mainly produced by club cells and other airway epithelial cells but can be readily measured in circulation. A growing body of evidence indicates that this molecule plays a critical role in enhancing resilience to respiratory infections and reducing airway inflammation. In this context, our hypothesis is that low levels of circulating CC16 in childhood may serve as an early indicator of individuals who will develop airflow limitation, a precursor of early chronic obstructive pulmonary disease (COPD), in their young adult life. Because of the expected low prevalence of airflow limitation in young adult life, testing this hypothesis will require a large epidemiological consortium of birth cohorts that have serum/plasma samples available from childhood and have characterized the lung function of a large number of participants from birth into adult life.
Here we propose to measure CC16 levels in plasma samples collected at ages 7, 9, and 15 years from ALSPAC participants to determine whether deficits in circulating CC16 in childhood predict the development of airflow limitation and small airway disease, as precursors of early COPD, in young adult life. We will integrate multiple longitudinal measurements of CC16 in childhood and link them to lung function measurements (both spirometry and IOS) completed in adult life.
B4515 - What determines the risk of type 1 diabetes in antibody positive adults - 29/01/2024
Type 1 diabetes occurs when a persons immune system attacks their pancreas stopping them producing insulin. The only current treatment is insulin replacement. Recently a new treatment has been found, which delays the onset of type 1 diabetes giving people more years without insulin. This exciting new treatment can only be given to people before they have diabetes symptoms. To date all research into how to find these early cases has been in children. You can detect early cases by testing children for markers of the immune attack called antibodies. Based on the number and type of these antibodies we can predict a child’s future type 1 diabetes risk and if they will benefit from the new treatment. Half of type 1 diabetes develops in adults but we do not know an adults future type 1 diabetes risk if we find antibodies and thus who needs treating. This study aims to answer this question by looking for antibodies in adult blood samples taken over 5 years ago. We will recontact all adults with antibodies in these old samples and some people without (controls) asking for a finger prick sample (taken at home or in hospital) to measure their antibodies and blood glucose level now. We will also ask if they have developed diabetes and their treatment and diabetes type if they have. This study will allow us to screen for antibodies in adults and predict those most likely to develop type 1 diabetes and therefore benefit from new treatments.
B4492 - DNA methylation profiling by capture sequencing - 23/01/2024
DNA methylation is the addition of a methyl group to DNA. Patterns of DNA methylation have a variety of roles cells, the most well-known is determining the activity of genes. These patterns are known to change in response to lifestyle factors such as cigarette smoking and diet and to be useful in diagnosing disease and predicting future disease risk. Measuring patterns of DNA methylation is challenging as there are about 28 million locations in the human genome that can be methylated. Fortunately, we can obtain useful information about health from a small subset of these locations. A new method for cheaply measuring a small, selected subset uses a system that captures DNA fragments containing specific nucleotide subsequences and then measures the methylation patterns on those fragments by DNA sequencing. A couple of ALSPAC DNA samples have had DNA methylation measured using more expensive methods (beadchip and nanopore sequencing). We would like to evaluate the performance of our new method by applying it to these samples and then comparing the results to these other methods.
B4509 - Investigating the association between romantic relationships and experiences of psychosis over time - 15/01/2024
Psychosis refers to the experience of hallucinations and/or delusions. Psychotic experiences range from short-lived symptoms that are not fully believed through to persistent severe symptoms that characterise psychotic illnesses such as schizophrenia. Compared to the general population, the prevalence of romantic relationships in people who experience psychosis is low. This is problematic. Firstly, because people with psychosis, like members of the general population, see romantic relationships as being a fundamental aspect of life and often report being dissatisfied with their intimate relationships. Secondly, because there is some evidence to suggest that having a partner is associated with reduced symptoms for people who experience psychosis, especially for those under 35 years old.
Unfortunately, much of the available literature is limited and as a result, the direction of influence between romantic relationships and psychosis remains unclear. This project aims to use data collected at various timepoints to better understand whether being without a partner increases vulnerability to developing psychosis / contributes to the maintenance of symptoms, or if those who experience fewer symptoms are simply more able to form romantic relationships.
B4511 - Hypertensive disorders in pregnancy and risk of ADHD in offspring - 15/01/2024
Attention Deficit Hyperactivity Disorder (ADHD) is a chronic neurodevelopmental condition, characterized by difficulties in behavioural and neurocognitive functioning. Many studies have suggested that some maternal factors during pregnancy are associated with ADHD in the offspring. However, the mechanisms and whether the associations are causal is still unclear. This project will be conducted to understand the impacts of maternal hypertensive disorders during pregnancy on attention deficit hyperactivity disorder (ADHD) in offspring as little is known about this. As ADHD is becoming more prevalent, more research is needed to thoroughly understand factors that may increase risk of this disease. We will investigate the role of hypertension during pregnancy in ADHD using genetic, clinic and questionnaire data from the ALSPAC cohort.