Proposal summaries
B3806 - Examining the genetic architecture of depression in and around pregnancy in the ALSPAC study - 07/06/2021
Depression is a common and complex disease, influenced by both genetic and environmental factors, with heritability estimated to be from 31% to 42%. However, a recent genome-wide association study meta-analysing data on 807,553 individuals from three largest GWAS studies identified 102 independent variants and 269 genes associated with depression. This result suggests that depression is a polygenetic trait and enables researchers to use these polygenic risk scores to investigate how genetic liability for depression manifests over the life course.
Depression is more common in women during childbearing age, but it has particular importance during pregnancy and after birth due to additional potential consequences for the child. There are many women worldwide suffering from perinatal depression, and according to a meta-analysis, the prevalence of it ranges from 6.5% to 13% at different time points during pregnancy. Perinatal depression has been reported to be associated with many complications, such as hypertension, preeclampsia, and gestational diabetes for mothers and premature birth, low birth weight, fetal growth restriction for foetuses. Furthermore, some pregnant women with depression are reported to have suicidal ideation and thoughts of harming their child. It is clear that perinatal depression is important for both the mother and the child, and thus it is important to examine its aetiology in order to identify potential treatments and interventions. The role of genetics in perinatal presentation of depression is one particular path that could further enhance our understanding of the disease.
There are many studies on heritability of depression, but few about the genetic architecture of perinatal depression. This study will use the polygenetic risk score based on GWAS study on broad depression and examine the association between greater genetic liability to depression and depression across the perinatal period.
B3807 - Sexuality and Family Dynamics - 10/06/2021
Exploring the relationship between family structure (e.g. number of siblings, gender), and sexuality / beliefs towards sexuality.
B3804 - Is there a shared genetic aetiology between autism and asthma - 07/06/2021
Autism and asthma are two common but seemingly unrelated conditions. Autism is a chronic neurodevelopmental condition, characterised by difficulties in social communication as well as repetitive behaviours/restricted interests. On the contrary, asthma is a chronic respiratory condition characterised by periods of wheezing, shortness of breath and chess tightness. Despite the distinct features, there is some evidence suggesting an increased prevalence of asthma in individuals with autism, while maternal history of asthma has been associated with autism in the offspring. The reasons underlying these observational associations are currently unknown. One possible explanation could be that there is a shared genetic aetiology between the two conditions. Testing this hypothesis will be an important first step towards understanding the reasons of their co-occurrence.
B3805 - Lfestyle and genetic predictors of maculopathy in the ALSPAC G0 generation - 10/06/2021
Maculopathy is a term describing a group of diseases of the retina which together are the leading cause of blindness in developed countries. Treatment is at best only able to stabilize progression in some individuals and for many there is no effective therapy and irreversible sight loss cannot be avoided.
The most widespread form of macular disease is associated with ageing and is known as age-related maculopathy (ARM).The incidence of this rises with age (1). In the Beaver Dam study in USA (2), severe blinding macular changes were seen in 1%-2% of the overall population aged 50-80yr, with mild signs in 8-10% of people aged 43-54, rising to 14% in people aged 55-64y and 30% in people aged 75 or more. Subsequent population-based studies report similar findings.
A number of factors that we know are associated with ARM such as diet and smoking, are also associated with other diseases of ageing including cardiovascular disease and inflammatory conditions. These conditions are themselves more frequent in people with maculopathy and so the specific causal pathways that lead to ARM are still unclear and we are unsure how best to prevent the condition. By contrast myopic maculopathy (MM) is related mainly just to age and degree of myopia, although raised blood pressure is a risk factor. As myopia is increasing in prevalence across the world, so is the prevalence of MM and it is becoming a leading cause of blindness (3).
Treatment trials involving lifestyle changes such as dietary supplements have yet to show strong results in reducing ARM and there are no known lifestyles thought to protect against MM. It is likely that we have not yet identified either the correct pathways that lead to these diseases or the groups of people who are genetically more or less likely to be helped by lifestyle modifications.
We propose to make use of a unique opportunity - to “piggyback” onto a soon-to-start data collection sweep within the most detailed cohort study in the world- the Avon Longitudinal Study of Parents and Children, (ALSPAC, http://www.bristol.ac.uk/alspac). This sweep will involve 7000 very well-documented adults aged approximately 50-70 years4 who are the parents (the “G0 generation”) of a cohort of children (“G1 generation”) recruited in utero during the early 1990s. Detailed lifestyle and health data relating to these G0 parents are available stretching back 30 years, as well as detailed genetic data. We will collect high quality images of the retina and measurements of the eyes for these participants, to identify those with ARM or MM and we will use all the existing data to investigate the ways in which genetic, lifestyle and medical risk factors may have led to these diseases, over the last 30 years. A session for vision testing is already funded by a grant held by Prof Golding and Dr Northstone and we propose to take the retinal images in this session.
The costs of contacting the participants, bringing them to clinic and examining them, plus the collection of all the previous lifestyle and genetic data are already met and we have requested the costs of the retinal imaging, grading and analysis. There may be the chance to use old equipment to take some basic images showing existing ARM and MM assuming the clinic sweep starts before the grant we have submitted is decided upon. Thus, we will obtain results that will improve our understanding of the antecedents of ARM and MM and therefore potentially how to prevent them, by enhancing the vision data collection that is already planned.
References:
(1) Owen CG, et al; BJO 2012;96:752-756; (2)Emily Chew; Ophthalmology 2020. 127 S120-121 (3) .Baird PN al. Myopia. Nature Reviews Disease Primers. 2020; 6:99 (4) A Fraser et al; Int J Epidemiol 2012: 42 pp97-110:
B3683 - Common maternal variants and the occurrence of Cleft in their children - 03/06/2021
The Cleft Collective Cohort Studies investigates the biological and environmental causes of cleft, the best treatments for cleft and the psychological impact of cleft on those affected and their families. With the help of every cleft team in the UK, up to 3,500 children and their families will be recruited into the study.
After an extensive recruitment period we are now ready to start the investigation into the genetic contributions to Cleft. With the results of our analysis of both children with Cleft and their mothers we hope to increase our knowledge of the causes of cleft and inform the best treatments. We hope that by focusing on the mother's genetics we will be able to highlight areas that have not previously been investigated in depth.
B3795 - Evaluating the effect of school closures during the COVID-19 pandemic A natural experiment in South Korea - 01/06/2021
This study aims evaluate the impact of school closure during the COVID-19 pandemic in South Korea. Using another cohort consisting of South Korean adolescents in the 7th to 12th grade, we found that physical activity was significantly reduced due to school closures. This provides a chance to evaluate the effect of physical activity reduction in adolescents on other health-related outcomes. On the other hand, Mendelian randomisation is an alternative study design that can measure the effect of physical activity on other health-related outcomes. Our goal is to compare the two study designs on the same subject so that we can critically evaluate the validity of these study designs.
B3791 - The effect of inflammation on cognitive processing - 01/06/2021
Mental health problems are common, affecting one in four people (Mcmanus et al., 2009). Despite the increase in availability of treatment, many people do not seek or respond to currently available treatments (Fava, 2003). The heterogeneity of these disorders has highlighted the need for new targeted treatments.
One promising therapeutic target is inflammation (Khandaker et al., 2018). There is growing evidence that inflammation may play a causal role in the development of mental health problems, at least for some individuals. Patients with depression and schizophrenia have higher levels of circulating inflammatory markers (interleukin 6, IL-6; C-reactive protein, CRP) compared to healthy controls (Howren et al., 2009; Miller et al., 2011; Wang & Miller, 2018). Longitudinal studies also report that higher IL-6 at age 9 is associated with an increased risk of depression and psychosis at age 18, in a dose dependent fashion (Khandaker et al., 2014). Moreover, Mendelian Randomization (MR) studies provide stronger evidence of causality: genetic variants which regulate the level/activity of IL-6 and CRP are associated with risk of depression and psychosis (Hartwig et al., 2017; Khandaker et al., 2020). Nevertheless, there are divergent findings in MR studies regarding different inflammatory markers, with evidence of a risk-increasing effect of IL-6, but a risk-decreasing effect of CRP, on depression (Ye et al., 2021).
Cognitive function is also a core feature associated with psychiatric risk. For example, people with depression display impairments across a range of cognitive tasks including executive functioning, memory, attention and emotion recognition (Dalili et al., 2015; Nikolin et al., 2021; Rock et al., 2014). Cognitive dysfunction in prodromal psychosis is also associated with an increased risk of transitioning to schizophrenia and poorer prognosis (Bolt et al., 2019; Fusar-Poli et al., 2012; Seidman et al., 2016). However, an outstanding question is whether inflammation contributes to cognitive functioning in the general population.
We will address this question using cross-sectional associations, MR, and trajectory-based modelling. Triangulating across multiple methods to assess the role of inflammation on cognitive functioning will enable more robust conclusions to be drawn about the relationship.
B3797 - Interrelations between sleep and ASD/ADHD symptoms and diagnoses in children - 01/06/2021
Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD) are among the most prevalent neurodevelopmental disorders. ASD is characterized by persistent deficits in social communication and social interaction with restricted, repetitive patterns of behavior, interests, or activities; ADHD characterized by deficits in attention, organization, activity levels and impulse control.
Both disorders are commonly associated with sleep problems, especially short sleep duration, in adults and school-aged children. Less is known in preschoolers. In addition, it is not clear whether sleep troubles are risk factors, consequences or comorbidities of the neurodevelopmental disorder.
B3798 - Does socioeconomic status moderate the relationship between adolescent drug use and mental health - 01/06/2021
Substance use represents a primary global burden of disease for young people (1) as it has been associated with a wide range of adverse outcomes. These include physical health outcomes, such as infectious diseases and chronic bronchitis, social outcomes, including lower educational attainment and criminal activity, as well as increased substance dependence, risk of overdose, and mental health issues (1). Mental health symptoms and disorders have previously been associated with increased cannabis use in adolescence, including depression, suicidality, anxiety (2), and psychosis (3) . However, substance use and mental health are both complex, multifaceted issues that are likely to be affected by a number of risk factors (3).
One possible risk factor that may influence the relationship between substance use and mental health issues is socioeconomic status (SES), resulting in a greater burden of substance use on individuals of low SES. Research has identified that cannabis use is greater amongst individuals from low SES groups and may potentially be increasing over time (4). Whilst increased use amongst low SES individuals may result in worse mental health outcomes, it is also possible that, either alternatively or additionally, the social environment associated with reduced SES may exacerbate the harms associated with substance use, thus resulting in worse mental health outcomes. Increased harm related to other substances, such as tobacco, amongst low SES individuals has been observed previously (5), and therefore it may be plausible that a similar pattern is true for cannabis. This indicates that SES may be an important moderator of the relationship between adolescent cannabis use and mental health issues, including depression, anxiety, and psychotic experiences.
However, much of the current literature focuses on either substances other than cannabis or the impact of adult substance use and therefore further investigation is needed to understand the impacts of adolescent cannabis use . In addition, many studies have limited ability to draw causal inferences as a result of the high plausibility of reverse causation owing to the utilisation of cross-sectional data. This project aims to investigate the moderating role of SES in the relationship between adolescent cannabis use and mental health using longitudinal data from the ALSPAC cohort.
B3796 - Identifying psychiatric risk factors for body dysmorphic disorder - 02/06/2021
Body dysmorphic disorder (BDD) is characterised by excessive preoccupation with perceived flaws in physical appearance (most commonly facial features), which appear minimal or completely unobservable to others. Sufferers typically engage in a range of compulsive and repetitive behaviours, such as extreme grooming rituals, often in an attempt to conceal or correct their perceived appearance flaws. The disorder usually starts during adolescence, with an average onset at age 16. BDD affects about 2% of the general population at any one point in time, although up to 15% experience subthreshold symptoms that are impairing in their own right. The disorder has a devasting impact on quality of life, and is linked with high risk of suicidality. Is it estimated that one in four people with BDD attempt suicide, making it one of the most high-risk of all psychiatry disorders. Despite the prevalence and morbidity of BDD, it remains strikingly under-researched.
There is currently a lack of clarity about how BDD relates to other mental health disorders. BDD was previously classed as a “somatoform disorder”, but was recently reclassified under “obsessive-compulsive and related disorders” in the major diagnostic systems (DSM-5 and ICD-11). This classification remains a focus of debate. For example, data from recent cross-sectional studies have indicated BDD has stronger links with eating disorders and depression than obsessive-compulsive disorder. However, the longitudinal associations of other psychiatric disorders with BDD remain unclear. This study therefore aims to determine the extent to which different psychiatric symptoms during adolescence predict body dysmorphic symptoms in adulthood.
B3792 - Socioeconomic position SEP influence on the early-life individual exposome - 03/06/2021
This project will study how the child SEP at birth drives the personal exposome during infancy (0-2 years), accounting for geographical variability among cities and countries. The SEP will be measured using the EHII (Equivalized Household Income Indicator) developed within task 3.1.1 and maternal education. The exposures considered for this analysis include the urban environment exposures created within task 3.1.3, the diet exposures created within task 3.1.4, breastfeeding, passive smoking and exposure to pets.
We will study the SEP-exposome relationship using two main different approaches: i) we will fit standard regression models to evaluate the effect of SEP on each exposure accounting for multiple comparisons (Exposome Wide Association Study - ExWAS approach, but with the exposures as the dependent variables); ii) we will perform city-specific principal component analysis to reduce the exposome dimension and derive summary exposure indicators (the first principal components) and then fit standard regression models to evaluate the association between SEP and these summary indicators. We will conduct cohort/cities-specific analysis to take into account the fact that the role of SEP likely varies among cities and countries and considering maternal age, parity and ethnicity as potential confounders.
B3790 - Atopic disease impact on later educational attainment - 03/06/2021
The global burden of atopic diseases, in particular atopic dermatitis (AD), is on the rise. While most research is focused on the medical outcomes, a more encompassing approach is needed to highlight the effect of AD on social outcomes which has implications on future interventions and social support.
1 in 5 children in the UK suffers from AD, and to date, data are rather conflicting regarding its effect on educational attainment. A previous study on Swedish men who underwent military conscription at ages 17-20 years showed an association with attending university but no significant association between AD and secondary educational attainment after adjusting for family-related factors. Another cohort study on Dutch children found no association between AD and school performance at age 11.
Since educational attainment predicts future health and wellbeing, it is important to investigate any potential association with AD. AD may impact educational performance due to a multitude of factors: itching, poor sleep efficiency, and the use of sedative antihistamines could lead to absenteeism or poor concentration. AD stigma and comorbidities could increase depression, psychological distress, and the risk of attention deficit hyperactivity disorder, which may also adversely impact educational outcomes in affected children.
Additionally, neither have previous studies explored the effect of AD on exam results nor addressed the effect of the three main atopic diseases (AD, Hay fever, and Asthma) simultaneously. These diseases often co-occur, and it is important to determine the interplay and broader effect of atopic diseases on educational outcomes.
B3771 - Testosterone and polygenic score and sex dimorphisms - 24/05/2021
Testosterone has an influence on social behavior and cognition, such as brain response to faces. Testosterone exposure during puberty can modulate the effects of adult testosterone on brain response to faces. Genetic variants contribute to inter-individual variations in testosterone levels, and a polygenic score can be used as a summary index of such genetic variants. We will use the ALSPAC dataset to investigate (1) the relationship between average testosterone exposure during puberty and polygenic score for testosterone; (2) interplay between the polygenic score for testosterone and adult testosterone in brain response to faces. In addition, we will also explore the relationships between the polygenic score for testosterone and brain structure.
Prenatal testosterone is one of the critical factors influencing sexual dimorphic phenotypes. Stress can alter levels and function of testosterone, and in turn, lead to a reduction in biological effects of testosterone on body and brain function and structure. Thus, we expect that prenatal stress can modulate the levels of prenatal testosterone and, therefore, influence the degree of sexual dimorphism in the brain and body in later life.
B3783 - An exploration into the links between educational attainment intelligence and wellbeing - 24/05/2021
In a recent Mendelian Randomisation (MR) study we found a casual link to suggest an independent positive impact of staying in school on wellbeing, but a negative impact of intelligence on wellbeing. In the current project, we aim to explore further the extent to which either of these effects are moderated by the other. To do this, we will use available data from genome-wide association studies (GWAS) on educational attainment and intelligence to construct polygenic scores. These scores will be used in an interactive model to predict wellbeing in ALSPAC participants. This will allow us to investigate whether the positive effects of educational attainment are driven by those with higher intelligence, and whether negative effects of intelligence are moderated by spending more time in school. We also aim to understand more about the factors driving the main effects of educational attainment and intelligence on wellbeing. We will therefore investigate the potential role of socioeconomic status (SES), personality, and peer relations. Previous findings have shown that children more likely to complete more years of schooling tend to grow up in families with more socioeconomic resources (Krapohl & Plomin, 2016), have certain personality traits (Heckman, Stixrud & Urzua, 2006), and more extensive social networks (Chen, 2012). Thus, we aim to explore the extent to which these factors mediate or moderate associations between educational attainment and wellbeing, and between intelligence and wellbeing.
B3788 - Parental depression and young peoples higher education - 24/05/2021
Higher education attendance has important implications for individual’s future outcomes with those who attend higher education having higher earnings on average, as well as better health outcomes.
Attendance at higher education is already known to be affected by socioeconomic status, with those from lower socioeconomic backgrounds attending lower quality institutions and courses, relative to their attainment. However less is known about the role maternal depression may play in young person’s attendance at higher education and how it may influence their course and institution. Maternal depression has previously been shown to affect development and wellbeing with maternal distress being associated with worse socioemotional development, as well as being associated with worse educational attainment. This research will build on this existing knowledge by exploring the influence maternal depression has on higher education attendance.
B3789 - Exploring the associations between ADHD symptoms mental health and higher education - 24/05/2021
This dissertation will explore any associations between ADHD symptoms (exposure), educational attainment (mediator) and mental health (outcome). Previous studies have suggested that severe ADHD symptoms lead to difficulties in university life and have a negative effect on mental health. A literature review found that young people with ADHD are less likely to pursue higher education and those who do are less likely to graduate a the same time as their peers. The majority of studies conducted on this topic are based in North America and use a small sample size from a single university. A study found that the majority of individuals with ADHD have comorbid disorders such as anxiey or mood disorders. This dissertation will attempt to understand what role higher education plays in this equation: does it have a protective or harmful effect on the association between ADHD and mental health. Unlike other studies, this study uses a large UK-based sample size and isn’t focused on a single institution. It aims to assess how partaking in higher education for individuals with ADHD affects their mental health later in life.
B3777 - Air pollution exposure during pregnancy and associations with child gene expression at birth - 24/05/2021
Exposure to air pollution increases the risk of cardiometabolic diseases. Inhaling air pollution, initiates inflammation, oxidative stress, and receptor activation, which in turn increases the risk of cardiovascular disease (CVD). Although the underlying mechanisms are largely unknown, altered gene expression may be involved in mediating the effects of air pollution on CVD risk. Already before birth, mothers’ exposure to air pollution is associated with foetal growth restriction and low birth weight, which may be caused by epigenetic changes and altered gene expression. In fact, air pollution may have a larger effect on gene expression in children than in adults. In this project, we will investigate the association between air pollution exposure during pregnancy and gene expression in cord blood in ALSPAC. Moreover, we aim to do pathway analyses to get insight into pathways that are associated with air pollution prenatally, and to investigate if the pathways involved have any associations with birth weight and cardiometabolic risk factors such as blood lipids. This work will be a part of the LongITools project, and we aim to do similar analyses in other cohorts, including Generation R (9-year old children) and in the Rotterdam study (adults, 40-100 years). By comparing findings between the different cohorts, we can get insight into biological pathways associated with air pollution throughout the life course.
B3782 - Genome-wide association study of menstruation-related traits - 17/05/2021
Female reproductive health and research into menstruation disorders/traits is an incredibly underfunded area of medical research. It is commonplace for data to be collected as part of questionnaires, yet much of the data collected by UK Biobank and the ALSPAC cohort has had little attention to date. Conducting a Genome-wide association study (GWAS) would be a promising approach to improve the knowledge and understanding of the genetic contribution and variants associated with these phenotypes. Heavy menstrual bleeding and painful periods are considered common conditions, yet the prevalence is unclear, with studies reporting between 16-91% for painful periods and 20-54% for heavy menstrual bleeding in different populations(1, 2). It is clear further research is needed within this field to better understand the genetic architecture of menstrual disorders. In this student project, the student will conduct GWAS of menstrual conditions in UK Biobank and seek replication in ALSPAC.
B3765 - Metabolomics of Asthma Chronic Obstructive Pulmonary Disease Lung Function and Allergy Phenotypes with COMETS - 17/05/2021
Metabolomics, the systematic profiling of the small molecules in a biological system, represents a powerful tool to increase the understanding of the mechanisms of respiratory health. Several studies have used metabolomics to explore diseases including asthma and chronic obstructive pulmonary disease (COPD), suggesting there are alterations in the metabolome that reflect changes in the respiratory system. However, few studies have validated their findings in independent populations and few studies have investigated the metabolome of forced expiratory volume in one second (FEV1) or the ratio of FEV1 to forced vital capacity (FEV1/FVC), two key indicators of pulmonary function in both children and adults. Furthermore, large scale studies of allergic phenotypes that are relevant to respiratory disorders such as asthma are lacking. Consequently, metabolomic profiling of lung function and related allergic phenotypes warrants further investigation.
In this work we will evaluate relationships between metabolite concentrations with lung and allergic phenotypes, including asthma, Chronic Obstructive Pulmonary Disease (COPD) and lung function measurements (FEV1, FVC, FEV1/FVC, etc.) in ALSPAC. Our findings will be combined with those from other cohorts by analysts of the COMETS Lung Working Group within the Consortium of Metabolomics Studies.
B3785 - Modelling longitudinal BMI and height over childhood for GWAS - 17/05/2021
GWAS have been enormously successful in uncovering novel genetic variants associated with a range of complex human diseases, but the majority have used cross-sectional data and relatively simplistic statistical tests. Longitudinal studies are advantageous for investigating genetic associations as they: 1) facilitate the detection of genetic variants that influence change in a trait over time; and 2) allow the detection of genes that are associated with the age of onset of a trait. Improving analytic techniques for conducting longitudinal GWAS offers the opportunity to advance our understanding of the aetiology of health and disease.
To test statistical methods for modelling trajectories, we have selected two growth traits: height and body mass index (BMI). These traits were selected as most cohorts within EGG (The Early Growth Genetic consortium) have data available for analysis, therefore maximizing our sample size. Height was chosen as its trajectory has a relatively simple (linear) shape, whereas BMI is more complex but is of interest to a large number of groups within the consortium. Ideally, the methods we define will be transferable to other traits of interest across the consortium.
Childhood obesity is associated with poor mental and physical health and is one of the strongest predictors of adult obesity. BMI, the most commonly used quantitative measure of adiposity, follows a well-characterised trajectory throughout childhood: a rapid increase soon after birth until approximately 9 months, the adiposity peak, followed by a gradual decline until around 4–6 years of age, the adiposity rebound, followed by an increase again until the end of puberty. Although the community has identified a large number of genetic variants associated with adult BMI, relatively little is known about the genetic determinants of BMI throughout infancy and childhood, or the rate of growth across early life.
Distinct height growth patterns, particularly during puberty, have also been linked with adverse health outcomes such as poor cardio-metabolic health. Analysis in the EGG consortium using SITAR growth curve analysis has shown that velocity of height growth throughout puberty is genetically correlated with adult health, including glycemic traits, metabolites, bone density measures, lung function and lung cancer. By investigating height growth across childhood, rather than just puberty, we will be able to investigate whether these genetic correlations are more generally related to early life growth.