Proposal summaries
B4388 - IGF-1 levels and height trajectory in childhood an observational and Mendelian randomization study - 06/10/2023
Insulin-like Growth Factor 1 (IGF-1) is a critical peptide hormone that plays a pivotal role in growth, development, and cellular regulation. It is primarily synthesized in the liver under the stimulation of growth hormone (GH) and acts as a key mediator of GH's growth-promoting effects. IGF-1 plays a fundamental role in various physiological processes, including cellular proliferation, differentiation, and tissue growth. Its actions are particularly prominent during the pre-adolescent and adolescent stages, where it influences longitudinal bone growth and overall somatic development.
The role of IGF-1 in growth regulation has garnered significant attention in the field of developmental biology. Previous research has demonstrated a positive correlation between circulating IGF-1 levels and height in various populations. Higher levels of IGF-1 have been associated with increased linear growth during childhood and adolescence. Randomized controlled trials of GH treatment in individuals with idiopathic short stature (ISS) , aiming to increase IGF-1 levels and final adult height have yielded conflicting results. Consequently, understanding the causal relationship between IGF-1 levels and height SDS across different ages can provide valuable insights into the mechanisms underlying growth and height variation.
In recent years, genetic studies have made significant strides in elucidating the genetic basis of complex traits, including height. Polygenic Risk Scores (PRS) are genetic risk scores that capture the cumulative effect of multiple genetic variants associated with complex traits, such as IGF-1 levels. As such, these PRS provide a comprehensive assessment of an individual's genetic predisposition to higher or lower IGF-1 levels. Also, using genetic variants from large IGF-1 genome-wide association study (Sinnott Armstrong et al, 2021) as instruments for IGF-1, we have generated preliminary results using Mendelian randomization, showing strong evidence of a causal effect of IGF1 on height. We are seeking to replicate these results by undertaking a one-sample Mendelian randomization study in ALSPAC
Body composition has been shown to influence growth patterns and height disparities among populations. Body Mass Index (BMI) has been suggested as a potential confounding factor in the IGF-1-height relationship. Investigating the relationship between a PRS for IGF-1 and height can help us better understand the contribution of IGF-1 to height variation and may reveal mediating effects of weight and potential gene-environment interactions affecting growth patterns.
This study aims to contribute to the growing body of evidence on the associations between IGF-1 levels, IGF-1 PRS, and height SDS, in ALSPAC. Understanding the impact of IGF-1 and of its genetic predictor on height variation at different ages, while accounting for BMI can offer valuable insights into the pathophysiology of growth.
B4361 - Young onset colorectal cancer and childhood exposures to the microbiome YOUTHCLUB - 18/08/2023
Colorectal cancer incidence in individuals younger than 50, referred to as early-onset colorectal cancer (eoCRC), has doubled in many countries. Over the next decade, deaths due to eoCRC are expected to rise globally, with eoCRC accounting for over 20% of all colorectal cancers and becoming the leading cause of cancer-related deaths in 20-49 year olds. However, the factors leading to this increase are uncertain. The gut microbiome, which comprises millions of bacteria, fungi and viruses that are housed naturally within our digestive system, may influence the development of colorectal cancer, whereby some microbiota play a role in inflammation, DNA damage and production of cancer-promoting molecules. Recent studies have shown that there are specific genetic mutations associated with colorectal cancer risk, which occur more often in people of younger ages than in older ages. These mutations are also caused by the toxin called colibactin, which is produced by certain gut microbial bacteria. Our study aims to understand whether these bacteria, if present in early life, cause these mutations within our DNA (via colibactin production) and therefore increase the risk of eoCRC.
B4346 - Genomic methods to investigate the timing of childbirth in humans - 01/08/2023
The duration of gestation is critical for neonatal survival, with early deliveries (<37 gestational weeks) being the leading cause of death in children under five years of age. Despite the global burden, relatively little is known about the processes that determine the timing of childbirth. In part, this limited progress is due to the difficulty in extrapolating findings from animal model systems to humans. However, studies of human genetic variation are starting to shed light on the biology of human labor and the timing of childbirth.
Recent work from our group and others has established robust genetic associations with the timing of childbirth. An easy solution for increasing the number of discovered genes is to increase sample size. However, additional gestational duration associated genes may be discovered from more complex models, in relatively small sample sizes. At the same time, the careful inspection of the known genes may aid in the overall understanding of the biology behind the timing of childbirth.
B4383 - Variance in adult height explained by blood-based DNA methylation - 01/08/2023
Height is a complex trait that is underscored by a combination of genetic and environmental factors. A large number of studies have defined the genetic basis of human height. Recent statistical genetics efforts have shown that ~40% of the variance in height can be explained by the combined additive effects of >10,000 individual variants. In this study, we will examine the utility of blood DNA methylation (DNAm) in capturing additional trait variance and in understanding the molecular architecture of height.
B4381 - The Effects of Pre- and Postnatal Exposure to Paternal Anxiety on their Offspring - 31/07/2023
Anxiety disorders (AD) are the most prevalent psychiatric condition in the general population worldwide, and it is estimated that between 6.57 and 13.54% of new fathers suffer from an AD (Leiferman et al., 2021), a considerably higher proportion than the prevalence for anxiety in men generally estimated by the World Health Organization (World Health Organization, 2017; range between 2.2 − 3.8%). The mental health of children is robustly associated with the mental health of their parents (Jami et al., 2021). In particular, children whose parents suffer from ADs, compared to children whose parents do not, have a higher risk of struggling with their mental health (e.g., Connell & Goodman, 2002; Micco et al., 2009; Lawrence et al., 2019). However, the specific role played by fathers in children's mental health difficulties has been under-investigated, and the particular risk posed by paternal anxiety for offspring mental health difficulties is not well understood.
B4382 - Blood-based epigenome-wide analyses of chronic low-grade inflammation - 01/08/2023
Chronic inflammation is a hallmark of ageing and age-related disease states. The effectiveness of inflammatory proteins such as C-reactive protein (CRP) in assessing long-term inflammation is hindered by it's high within person variability. DNA methylation (DNAm) signatures of CRP may act as more reliable markers of chronic inflammation. This project will develop a series of DNAm predictors of CRP in the Generation Scotland Cohort and evaluate their performance in ALSPAC parents and children as well as several other UK based study populations.
B4384 - Innovating the collection of self-reported data with voice input - 04/08/2023
Cohorts like ALSPAC typically collect data on their participants over several years, but since data collection is usually both expensive and burdensome these data collection events tend to take place every few years, measuring or recording information at a particular instance in time e.g. via questionnaires or clinic visits. Hence, these data contain a limited amount of information on phenotypic variability across the life-course, and restricts the research questions that can be asked using these data. There is much more scope to exploit existing and emerging technologies to collect data ‘continuously’ over the longer term in cost-effective and less burdensome ways.
Digital health devices have been successfully used to collect data on specific traits over a number of days (e.g. physical activity measured with accelerometers), but these devices tend to each focus on particular traits such that collecting data in this way is expensive (having to buy specific devices to collect specific phenotypes), and many types of phenotypes do not lend themselves to this type of data collection, in particular, those that can only (currently) be collected via self-report. Recent advances in artificial intelligence and voice recognition technologies means it is now feasible to use voice-based systems to collect self-reported data continuously over several days or weeks in a less burdensome way. However, to date, voice-based data collection has not been exploited for collecting health data.
B4380 - Exploring bidirectionality and genetic confounding of the associations between excessive screen time and mental health in adoles - 31/07/2023
Digital technology has become an indispensable aspect of children's lives, providing unparalleled prospects for learning, entertainment, and social interaction. Nonetheless, the excessive and problematic utilization of digital devices has emerged as a prominent global concern. Based on the statement of the American Academy of Paediatrics (AAP), children aged two years or older were recommended to limit the amount of total entertainment screen time to no more than two hours. Excessive screen time may lead to harmful health outcomes among children and adolescents, including mental health problems.
However, whether the link between screen time and mental health is causal is questionable. There may be bidirectional associations, with poor mental health affecting screen time and vice versa. And associations may be affected by gene-environment correlations/genetic confounding.
B4372 - Ideal cardiovascular health and the development of subclinical heart and brain disease in the young - 18/07/2023
In 2010, the American Heart Association (AHA) created ‘Life’s Simple 7 (LS7)’ – a risk score aimed at quantifying ideal cardiovascular health behaviours within large populations. This risk score consisted of seven modifiable factors known to influence cardiovascular disease; namely body weight, physical activity, diet, smoking, total cholesterol, glucose, and blood pressure. Over the last 12 years, LS7 has been shown to be effective in predicting a wide-range of future cardiovascular events in older cohorts, as well as the subclinical development of early cardiovascular risk in the young. In 2022, the AHA revised and updated this risk score to become ‘Life’s Essential 8 (LE8)’, adding sleep quality as a new modifiable risk factor for disease and altering definitions of what constitutes ‘ideal behaviours’ in many of the other risk factors. The comparability of this new score to LS7, however, and feasibility of using it in large population datasets to predict outcomes such as early changes in heart and brain health remains unknown.
B4375 - Heart rate variability and arterial stiffness in young adults with and without type 1 diabetes - 18/07/2023
Individuals with childhood-onset type 1 diabetes (T1D) have a life expectancy 17 years lower than that of their healthy peers, with over 2/3 of this increased risk of premature mortality due to the development of cardiovascular disease. A significant proportion of young people with T1D have evidence of cardiovascular risk factors which are already detectable by adolescence / young adulthood; including well-established markers of future heart attacks and other events such as nervous system problems (autonomic dysfuntion), high blood pressure (hypertension), and stiffening of the major arteries (early vascular ageing).
B4376 - Ideal cardiovascular health and the development of vascular disease in the young - 18/07/2023
In 2010, the American Heart Association (AHA) created ‘Life’s Simple 7 (LS7)’ – a risk score aimed at quantifying ideal cardiovascular health behaviours within large populations. This risk score consisted of seven modifiable factors known to influence cardiovascular disease; namely body weight, physical activity, diet, smoking, total cholesterol, glucose, and blood pressure. Over the last 12 years, LS7 has been shown to be effective in predicting a wide-range of future cardiovascular events in older cohorts, as well as the subclinical development of early cardiovascular risk in the young. In 2022, the AHA revised and updated this risk score to become ‘Life’s Essential 8 (LE8)’, adding sleep quality as a new modifiable risk factor for disease and altering definitions of what constitutes ‘ideal behaviours’ in many of the other risk factors. The comparability of this new score to LS7, however, and feasibility of using it in large population datasets to predict outcomes such as early changes in heart and brain health remains unknown.
B4379 - Heatwaves wellbeing questionnaires to inform adaptation - 22/08/2023
This is part of a work package is Eunice Lo's fellowship proposal to the Royal Society. It will investigate the wellbeing effect of heat on humans, because wellbeing is difficult to model due to a lack of long-term data.
B4378 - Developing and piloting heat wave questionnaires in ALSPAC - 08/08/2023
Extreme heat (> 40°C heat) is becoming more and more commonplace in the UK meanging overheating in homes and buildings is a key risk. It is important to understand how this affects people’s physical and mental health, wellbeing and behaviour during heatwaves so that strategies can be developed to help people adapt.
Most research in the UK related to heat and health is focused on outdoor temperatures and population-scale health outcomes (e.g., mortality in South-West England) rather than people’s experiences and perceptions of heat, which varies between individuals and the buildings they live in.
We will fill these gaps by working with ALSPAC to develop and test a questionnaire that will ask participants about their experience and behaviour during a heatwave. The data collected from this plot will not be linked back to any ofther data but will help us to understand how heat might affect the health and wellbeing ofdifferent people, help to inform the development of early warnings and contribute to a fellowship application leading to more detailed research in ALSPAC.
B4370 - Heart rate variability and early vascular risk in young adults with and without type 1 diabetes - 18/07/2023
Individuals with childhood-onset type 1 diabetes (T1D) have a life expectancy 17 years lower than that of their healthy peers, with over 2/3 of this increased risk of premature mortality due to the development of cardiovascular disease. A significant proportion of young people with T1D have evidence of cardiovascular risk factors which are already detectable by adolescence / young adulthood; including well-established markers of future heart attacks and other events such as nervous system problems (autonomic dysfuntion), high blood pressure (hypertension), and stiffening of the major arteries (early vascular ageing).
B4345 - Maternal serum cardiometabolic biomarkers in pregnancy with offspring cardiovascular health - 18/07/2023
The association between maternal cardiometabolic markers and offspring cardiometabolic health has remained elusive. Barker et al. have postulated that the intrauterine environment and early-life development serve as potentially important determinants of cardiovascular disease (CVD) later in life. However, previous studies were constrained by limitations such as small sample sizes, short durations of follow-up, or inadequate control for confounding variables. Consequently, a systematic investigation of maternal gestational cardiometabolic biomarkers and their relationship with offspring cardiometabolic health in a large-scale cohort is warranted.
B4368 - Using large cohort studies to identify scar-associated genetic variants for mechanistic testing in mouse and zebrafish models of - 03/07/2023
Repair of adult tissues involves a complex interplay of several key cell lineages and inevitably leads to formation of a fibrotic collagenous scar, whereas embryonic tissues heal perfectly without any resulting scar deposition. This dramatic difference in repair efficiency between embryonic versus neonatal/adult tissues has been instrumental is guiding us towards potential causes of scarring. Indeed, we now believe that one major driver of scarring is the wound inflammatory response which doesn't initiate until a transition period in fetal development which, in turn, coincides with the developmental onset of tissue scarring. This insight has led us towards further mechanistic cell and molecular studies in model organisms, such as mouse and zebrafish, which help us better understand the scarring process and how one might modulate the wound inflammatory response in order to improve or prevent scarring.
Whilst these approaches, motivated by comparing embryonic versus adult healing, have been fruitful, it is clear that scarring is a complex, multifactorial response likely driven by a number of interacting mechanisms. We would like to use a conceptually similar comparative approach to gain further insights into the fundamental cell and molecular mechanisms of scarring by analyzing differences in degree of scarring, not between embryo and adult, but rather across human adult populations since we know there is a range of “scarring phenotypes” from “minimal scarrer” to keloid scarring individuals. This use of human phenotypic variation in a population based, genetic association approach (genomewide association studies – GWAS), has the potential not only to yield gene variant correlates of scarring, but also to point towards specific biological contributions to wound healing. The use of natural human experiments (e.g. Bacillus Calmette–Guérin (BCG) vaccination wound healing, Caesarean section (C-section) wound scarring and examples of human disease related fibroses) has never before been used for identification of scarring genes, even though the approach has proven to be powerful for discovering genes associated elsewhere with a wide variety of complex health outcomes (www.ebi.ac.uk/gwas/). Furthermore, alongside a growing number of catalogues charting the results of human genetic association studies for health outcomes and intermediates there are tools able to consider (in frameworks of causal analysis) the existence of potentially causal and modifiable relationships between exposures of interest (e.g. inflammation, differential wound repair or scar) and health outcomes (e.g. wound healing, recovery, and disease).
Using human genetic data to help explore the potential of biological pathways contributing to health and disease in applied epidemiological designs is an approach that we have refined and developed and is an integrated approach to health research that has yielded important clinically relevant insights, but has also indicated opportunities (e.g. associated signaling pathways for targeting) to unify basic science approaches with human population based health data (see below).
B4364 - The genetics of learning difficulties and related outcomes - 14/07/2023
Dyslexia is a common and highly heritable conditions. New sequencing technologies allow us to identify potential mutations that might increase the risk of developing dyslexia. This project aims to identify such mutations and access whether they might contribute to dyslexia specifically or other related cognitive traits, e.g. language or mathematical abilities. We will conduct our analysis in clinical cohorts enriched for dyslexia cases and will follow the top results in the ALSPAC cohort to validate and better interpret our results.
B4363 - Longitudinal mental health outcomes for people with childhood eye disease - 28/06/2023
Children with squint may be more likely to have depression in their teenage years. We do not know why this happens but think it could be:-
-because children with squint are treated differently by others, or
-because children with squint are different to others in some way (for example, they may be more likely to have autism).
A sample of 7,825 children taking part in the ALSPAC study had their eyes tested for squint when they were 7 years old. In addition, the participants have completed a variety of tests for depression throughout their adolescent, and young-adult lives.
Our study is going to use these data to:
a) Find out if childhood squint is associated with adolescent mental health conditions.
b) Explore other associations with squint and identify possible causes of the association.
We will do this by looking at all the children who had their eyes tested at age 7 years and compare the adolescent depression scores of those that had squint to those that did not.
B4360 - Co-occurrence of homelessness and autism in a population based cohort - 28/06/2023
There is emerging evidence of high levels of (often undiagnosed) autism within homeless populations, with current estimates of around 12-18% of people receiving support for homelessness meeting criteria for an autism diagnosis. However there is a lack of population-wide studies exploring the co-occurrence of homelessness or insecure housing and autism diagnosis or traits.
B4341 - Lifelong understanding of cerebrovascular health - 26/07/2023
Currently, vascular ill-health appears to be the most preventable component of cognitive decline in older age. There is however very limited understanding about the time at which signs of damage are already present in diseases that take decades to result in symptoms. In this project we will work to identify through imaging the markers that can help us quantify the health status of vessels and associated tissues in the brain. We will also work to better understand their relationship to known risk factors for cardiovascular disease.