Proposal summaries
B3907 - Capturing epigenetic variation in the brain using blood - 25/10/2021
DNA methylation (DNAm) in neurological tissue is often difficult or impossible to use for observational studies, as sample collection must usually occur post-mortem. Studies interested in DNAm changes in brain related to disease outcomes or exposures commonly rely on DNAm measured in less invasive surrogate tissue, like blood, which typically have poorly characterised relationships with the target tissue DNAm levels of interest.
Early analysis has shown that some correlation exists between blood DNAm levels and DNAm at four different brain regions,1 but so far such work has been limited to comparisons at individual CpG sites. More recently, analyses developing multi-CpG prediction models have been able to serve as proxies for other types of molecular phenotypes, such as circulating protein levels in a variety of contexts. Thus, robustly trained, multi-CpG site blood DNAm models may be able to improve the variance explained of brain DNAm levels, especially in comparison to single CpGs. However, availability of appropriate paired blood-brain DNAm datasets required for model training has been limited to date.
We propose to develop models of brain DNAm using blood DNAm using an existing non-ALSPAC dataset and then apply the best performing models in ALSPAC DNAm to determine if they are associated with phenotypes and exposures relavant to the brain.
B3910 - Genetic determinants of distinct body mass index trajectories to young-adulthood obesity - 25/10/2021
Different body mass index (BMI) trajectories that result in obesity may have diverse aetiologies and health consequences, yet this heterogeneity is poorly understood. Previous research in the ALSPAC cohort has identified patterns of BMI development between ages 7 and 24 (Norris et al). Analyses using these patterns showed that people who have high and stable BMI across childhood may have lower cardiometabolic disease risk than individuals who do not become overweight or obese until late adolescence. How genetic factors relate to these patterns of BMI development is not known.
B3901 - The relationship between pubertal timing and depression in males - 25/10/2021
It is now well-established that an early timing of puberty is associated with a greater risk of depression in girls during adolescence, and there is evidence that this relationship is causal. Far fewer studies have examined whether pubertal timing is related to depression in boys and findings are inconsistent. Some studies have found that boys with an early puberty have a greater risk of depression in adolescence, whilst others have found that a later puberty confers a greater risk. Such inconsistency is often attributed to measurement difficulties in capturing pubertal development in boys. It is also unclear whether any effects of pubertal timing on depression in boys persist beyond adolescence.
B3911 - Describing the ALSPAC religiosity data and identifying potential confounders - 23/10/2021
This project aims to describe the ALSPAC data on religious and spiritual beliefs, as well as identify any potential sources of bias, particularly regarding confounders of religiosity. There are studies that have described the religious/spiritual beliefs and behaviours (RSBB) data collected by ALSPAC, however, to date no study has described this data in detail by exploring various associations between RSBB and other relevant factors (such as socioeconomic background or psychological traits). We will explore and describe associations with RSBB to inform future analyses, especially regarding the choice of potential confounders.
B3906 - Do Religious Behaviours and Beliefs Impact Study Participation - 23/10/2021
This project aims to describe the ALSPAC data on religious and spiritual beliefs, as well as identify any potential sources of bias. One of these associations that is of particular interest is whether RSBB has an affect on participation in the study. This is because studies like ALSPAC rely entirely on continued participation for the study to work, meaning if there are unknown factors behind participant's likelihood of continuing with the study this may result in bias when using these variables in analyses.
B3914 - Predicting lack of adherence to guidelines and intention to vaccinate The role of locus of control and spiritual beliefs - 23/10/2021
Julian Rotter (1966) introduced the concept of locus of control of reinforcement (LOC) as a generalised expectancy within his social learning theory. It refers to an individual’s generalised expectancy regarding the consequences of their own behaviour. The more an individual believes their behaviour affects what happens to them the more Internal (ILOC) they are. Contrastingly, the more a person perceives God, luck, fate, chance, or powerful others as the instrument by which they have no control over what happens to them, the more External (ELOC) they are. Previous research has demonstrated ELOC individuals are more likely to believe that their adverse health results from God’s will, fate, or something outside their control such as the Covid-19 pandemic. A literature review has shown that both LOC and strong religious beliefs have influenced whether an individual will follow official guidelines to mitigate the spread of Covid and/or their decision to take up the offer of a vaccine. We will analyse ALSPAC data collected in 2020 before the Lockdown on LOC and religious beliefs/behaviours plus that collected in the ALSPAC Covid questionnaires. How can we use this information to develop programmes to help externally controlled, highly religious individuals be more open to accepting of following official mitigation guidelines and offers of a vaccination.
B3900 - Testing the role of physical activity in promoting resilience against stress-related psychopathology - 18/10/2021
Stress-related psychopathology (e.g. depression and anxiety) affects one in eight children in the UK. It is therefore crucial to identify modifiable protective factors that can promote mental health in young people. Physical activity is a promising target for the prevention of depression and anxiety. However, the extent to which it can reduce the burden of mental disorders in young people is not known. This is due to the breadth of environmental, social, and genetic factors that could explain the relationship between physical activity and psychopathology. Furthermore, it is unclear whether physical activity can promote resilience to psychopathology in children who are at higher risk by virtue of genetic liability or adversity. This project will apply cutting-edge causal inference methods, including G-methods, fixed-effects regression, mendelian randomisation, and twin designs, to test whether physical activity can promote resilience against the development of stress-related psychopathology, using data from large population-based cohorts of children from the UK, Netherlands, Norway, and Finland. By comparing results across different studies and analytical approaches, the project will strengthen causal inferences from observational data and minimise potential biases associated with each method. In turn, the results will allow us to draw more confident conclusions regarding whether interventions targeting physical activity could help to reduce the burden of mental health problems in young people.
B3889 - Proteomic study of reproductive ageing in ALSPAC women - 21/10/2021
We are studying how the reproductive system ages in women, with the aim of improving fertility treatment and giving women better information about their likely reproductive lifespan. Fertility in women declines with age as the number of eggs in their ovaries decreases over time. When there are almost no eggs left a woman will go through menopause and periods stop. The timing of menopause varies between women, some going through it in their 20s, while others continue having periods into their 60s. We are investigating the factors that govern this variation in menopause age and aim to be able to predict it better, which will allow women to make informed choices about their reproduction. We know that genetic factors are important and so far we have identified around 300 genes that are involved in the variation in the timing of menopause. In this study we want to test proteins present in the blood to see if any of these are different in women who go through menopause early. ALSPAC is ideal for this study because there are samples available from young women, the mums and children and information has been collected or will be collected over the course of our study, about menopause.
B3890 - Daily mental health symptoms in high risk depression groups a feasibility EMA study - 19/10/2021
Mental health disorders like depression and anxiety are common and have consequences on all aspects of health. Mental health disorders like depression have a complex aetiology comprised of genetic and environmental risk factors, but importantly these risk factors predict different longitudinal profiles of depression (i.e., those with persistent depressive symptoms across adolescence compared to those who experience early adult onset depressive symptoms compared to those who experience low symptoms; Kwong et al., 2019 - JAMA Network Open). We have also shown that these depression profiles are associated with poorer downstream consequences like lower educational attainment and NEET status (Lopez-Lopez et al., 2019).
However, these studies are subject to measurement error and potential biases in recall which can weaken evidence. In order to identify the mechanisms underpinning poorer mental health and design appropriate interventions and preventions, it is important to understand the processes of mental health in granular detail. Ecological momentary assessment (EMA) provides one alternative design to address these biases and provides in depth information on mental health in real time via multiple assessments per day or per week over a given period of time. Crucially, EMA of mental health can be paired with other forms of data collection such as sleep, exercise and diet to examine relationships between mental health and wellbeing.
The purpose of this project is to conduct a small scale feasibility study to examine how EMA studies could be collected in ALSPAC and in particular, if they can be collected in individuals from different depression profiles. The results from this study would provide initial results that would inform how to run a large scale study in subsequent work.
B3897 - The relationship between maternal psychopathology and offspring incontinence at school age a prospective cohort study - 11/10/2021
Exposure to maternal anxiety and depression in the antenatal and/or postnatal periods has been linked to an increased risk of adverse child health and developmental outcomes. Attainment of continence is a key developmental milestone in early childhood, and there is evidence that exposure to maternal anxiety and depression increases the risk that offspring will fail to attain continence by primary school age. It is unclear, however, if (i) anxiety and depression have independent effects on offspring incontinence, and (ii) whether the relationship with offspring incontinence is due to exposure to maternal anxiety/depression during the antenatal or postnatal period.
B3894 - Maternal stress and the biological and epigenetic pathway to childrens development - 08/10/2021
This project aims to investigate the effect of parental stress on children’s development of non-cognitive skills and both emotional and behavioural disorders. In particular, we plan to investigate parental stress in the forms of: (a) maternal exposure to stressors during pregnancy; and (b) COVID-19 related health and financial stress during the height of the pandemic. This project will employ rich longitudinal datasets and use questionnaire data to examine parenting styles as well as epigenetic, genetic, and clinical biomarkers to examine the potential pathways of parental stress on children’s developmental outcomes.
B3895 - Pubertal disparity in the development of attention symptoms - 08/10/2021
Attention problems occur in many mental health disorders, but they are the key symptom in ADHD. Many mental health disorders find their origin in adolescence. Internalising problems such as depression and anxiety have been related to pubertal development. This project is aimed at investigating trajectories of attention problems in relation to pubertal development to examine whether they show a parallel trajectory. and whether this parallel trajectory is sex specific.
B3896 - Defining association of early life infection with differences in cellular composition of blood samples - 08/10/2021
Exploration of ethnic differences in DNA methylation patterns show that differences in methylation are largely driven by differences in cell composition of the blood samples methylation is measured from. This raises important questions about when and how differences in cell composition arise. One possibility is that they occur in response to early life infection and persist through life. This project investigates the potential link between early life infection (using H. pylori infection as a marker) and variation in cellular composition of blood samples collected at the same study timepoints.
B3893 - Associations between religion and diet - 06/10/2021
This project aims to explore the associations between religion and diet in ALSPAC. Several studies have suggested that Religious/Spiritual Beliefs and Behaviours (RSBB) such as belief in God and church attendance are associated with health (VanderWeele, 2017; Koenig et al 2012). The mediators of this association are not fully known, but likely include social support and health-promoting behaviours (e.g., reductions in smoking/alcohol/drug use; VanderVeele, 2017), as well as potential direct effects of religion on health (Hill & Pargament, 2003). One possible mediator on the causal pathway between RSBB and health is through diet. Many religions have rules and norms surrounding diet, and promoting health lifestyles more generally, so we may expect associations between religion and diet, and potentially downstream health effects. This project aims to explore these associations in ALSPAC.
References:
Hill, P. C., & Pargament, K. I. (2003). Advances in the conceptualization and measurement of religion and spirituality: Implications for physical and mental health research. American psychologist, 58(1), 64.
Koenig, H., Koenig, H. G., King, D., & Carson, V. B. (2012). Handbook of religion and health. Oup Usa.
VanderWeele, T. J. (2017). Religious communities and human flourishing. Current Directions in Psychological Science, 26(5), 476-481.
B3892 - A latent variable approach to examining the role of maternal RSBB in offspring mental health - 04/10/2021
We are investigating whether a mother's religious beliefs are related to their child's mental health.
B3891 - Methylome sequencing using nanopore - a pilot analysis - 20/10/2021
A powerful avenue into researching the functional consequences of changes in DNAm levels is to correlate DNA sequence variants such as single nucleotide polymorphism (SNPs) to DNAm levels to find both local and distal (for example on other chromosomes) effects. Having completed the largest genetic study of DNAm worldwide to date (through the Genetics of DNA Methylation Consortium) by scanning 10 million SNPs genome-wide, we have identified 270k SNP-DNAm associations. This was achieved by analysing about 400,000 DNAm sites in blood, which is only 2% of 28 million DNAm sites across the genome. There is a huge potential for improved understanding of DNAm variation between individuals and its influence on health and disease by studying other regulatory regions of the genome. We therefore will use novel sequencing technologies based on long reads with the ability to measure all 28 million sites and to determine both the DNAm level and the genotype at single molecule level.
B3887 - Sex differences in the association between alcohol use during adolescence and cardiometabolic risk in early adulthood - 30/09/2021
Evidence suggests that alcohol use has different impacts on cardiovascular risk in females and males but results are somewhat conflicting. Few studies to date have examined sex differences in the association of alcohol use with risk factors earlier in the life course (for instance during early adulthood) and to our knowledge no studies to date have examined sex differences in associations of alcohol use with key molecular cardiometabolic traits that are known causes of cardiovascular disease.
B3866 - The role of sensory function for academic achievement in gene-environment correlations - 14/10/2021
What is it that makes us successful when it comes to education? The fact that human intelligence and educational attainment are partly genetically influenced has been incorrectly interpreted in favour of a genetic determinism. However, genetic and environmental factors are not completely independent from each other. For example, children with a genetic disposition towards higher educational attainment are more likely to enroll in advanced classes and therefore further increase their educational attainment. In this context, it is fundamental to pinpoint the specific genetically-influenced traits that affect likelihood for children to select cognitively stimulating environments. Sensory functions (hearing and vision) in childhood are less explored than personality and motivational traits, but are particularly interesting as they can be modified through appropriate aids. In this project, we aim to investigate the role of hearing and vision in childhood for educational attainment in the course of gene-environment correlations. If parts of the genetic factors associated with intelligence and educational success actually exert their influence via hearing and vision abilities in childhood, these findings contradict the idea of a genetic determinism. Analysing these associations on a longitudinal scale will help to determine time points for early interventions (such as correction of minor hearing and vision impairments). Since children with a lower socioeconomic status show reduced hearing as compared to those with a higher socioeconomic status, disadvantaged children could particularly benefit from interventions, which would result in a reduction of social inequalities.
B3881 - Associations between mitochondrial and nuclear DNA variants in human populations - 28/09/2021
Present in nearly all types of human cells, mitochondria generate the majority of our cellular energy and are thus often referred to as the ‘powerhouse of the cell’. In addition, mitochondria play important roles in signalling between cells and cell death (known as apoptosis). Although most of our DNA is within the nucleus (the ‘nuclear genome’ or nDNA), mitochondria contain their own DNA (the ‘mitochondrial genome’ or mtDNA), and human health is dependent upon the coordination of the products of these two genomes.
Genetic variants within mtDNA can cause disease (1) and are also linked to a growing number of age-related complex diseases (2), particularly neurodegenerative diseases including Parkinson’s disease, Alzheimer’s disease, schizophrenia and multiple sclerosis (3). In addition, there are examples where the progression or severity of mtDNA disease is modulated by nDNA variants (e.g. LHON (4, 5)). Conversely, there is evidence in complex diseases where nuclear susceptibility factors are implicated, that common, inherited, mtDNA variation can influence traits such the age of onset (e.g. Alzheimer’s disease (6) and cardiomyopathy (7)).
More recently, the development of mitochondrial replacement therapy, a technique designed to avoid transmission of defective mitochondria from parents to offspring, sparked discussions on mitochondrial nuclear incompatibilities that would require matching donor and recipient mitochondrial and nuclear backgrounds, and more generally on whether the genetic makeup of healthy individuals reflects such incompatibilities (8).
This raises the question whether specific variant combinations of nuclear and mitochondrial alleles are depleted or enriched in the general population. This can be assessed by comparing their frequencies with the frequencies expected from the frequencies of the corresponding nuclear and the mitochondrial alleles assuming independent segregation. Such associations between variants can reflect mixing of different populations or selection against or in favour of particular variant combinations. Associations between nuclear and mitochondrial variants have been repeatedly reported (9, 10). However, it is unclear to what extent the observations reflect population stratification. This is of particular interest because mitochondrial genetic variants have been extensively used to track migration of populations and ancestry.
The aim of this study is to use the ALSPAC cohort genotyping data to: 1) identify combinations of mitochondrial and nuclear variants that are over or underrepresented in a well-characterised population, 2) ascertain whether under or over representation can be explained by heterogeneity within the population and 3) assess the effects of factors such as age or sex. The results will also provide a reference for studying the role of such combinations in human disease.
B3883 - Data Note-ALSPAC participants and the Bristol Self-Harm Register - 28/09/2021
To describe and cross reference the incidence of self-harm episodes of ALSPAC participants in (i) the Bristol Self-Harm Register collected by the local NHS Trusts, (ii) nationally collected Hospital Episode data from NHS-Digital, (iii) nationally collected Mental Health data from NHS-Digital, and (iv) self-reported in ALSPAC survey responses. This is intended to provide a future resource for researchers.