Proposal summaries
B3599 - G1 Substance Use questions for the next sweep - 25/08/2020
We would like to find some additional data collection for the G1 cohort
These data would facilitate the continued longitudinal modelling of G1 substance use into adulthood
and be particularly useful in the event we are successful in the MRC grant we submitted in May 2020.
B3595 - Assessing the contribution of poylgenic risk to pediatric lipid levels and longitudinal trends - 14/08/2020
Genetic studies have found connections between a person's genes and their cholesterol. These studies have been conducted in adults. Cholesterol is much less variable during childhood. We aim to see if the associations seen in adults also extend to children.
B3596 - Pubertal development and psychobiological health - 14/08/2020
During adolescence there are changes in how adolescents experience and regulate their emotions, and this is related, in part by changes in the body related to puberty and development of the neuroendocrine system. These changes can begin at different ages for people, and can also be influenced by the general physical health of the person, as well as their life experience of stress, social relationships and learning opportunities. Physical health influences psychosocial development in several ways, and there is an accumulation of evidence that biomarkers of physical health, including markers of inflammation, cortisol levels, and other indicators of stress, influences when, and how, adolescents develop skills in emotional regulation and stress management. There is a related body of evidence that puberty, inflammation and stress interact to influence emotional experience in childhood and adolescence, and may influence mood, and the risk of mod disorders, for example anxiety and depression. Much of the research on the psychobiological predictors, correlates and consequences of mood and behaviour have been done with adults, and so there is still much to know about if and how adolescent development may be influenced by inflammation, biomarkers of stress and experiences, and further, how these interactions may be influenced by pubertal development.
B3594 - Large-Scale Genomic Analysis of Aging-Related Cognitive Change Prior to Dementia Onset - 14/08/2020
This project will provide the most comprehensive interrogation of the genetics of aging-related cognitive changes during prodromal, so-called âsilent,â periods of ADRD progression. Identifying the genetic risk factors and mediating biological mechanisms underlying progression to Alzheimerâs disease and related dementias of aging is crucial to developing interventions to prevent, delay, or otherwise mitigate ADRD disease progression.
B3589 - The moderating role of genetic propensity in the relationship between depression/anxiety and substance use during Covid-19 era - 11/08/2020
Previous studies have reported that addictive behaviors decrease when infectious disease first occurs but increase as the disease continues. It shows that especially among health workers, the addiction problems can get even more serious compared to the period when the infectious disease did not occur. This study wants to examine predictive factors that are associated with addictive behaviors before and after Covid-19.
B3593 - Genetic impact on youth vaping extending known genetic risk factors in smoking to vaping - 11/08/2020
Adolescents who smoke cigarettes are more likely to start vaping, and the reverse is also true: vaping can lead to smoking. In former smokers, vaping can also increase the risk for relapse back to smoking. While some young people report vaping to help them quit smoking, most continue to smoke resulting in dual use. The high rate of dual use suggests that vaping could prolong smoking and increase harms in young people who would have otherwise quit. Biomarker data show that dual users are exposed to higher levels of harmful chemicals known to cause tobacco-related illnesses compared to those who only smoke.
Genetic variation influences cigarette smoking. People with gene variants that increase the rate at which nicotine is inactivated smoke more cigarettes, have a higher risk for tobacco-related illnesses, and are less likely to quit, compared to people with slow nicotine metabolism. In ALSPAC, we propose to study whether youth smokers with genetically faster nicotine metabolism have a higher risk for becoming a dual user and continuing smoking once they start vaping. In former smokers, we will test whether faster nicotine metabolism increases relapse back to smoking among vapers. As a secondary goal, we will also test whether other genes, for example those that alter the response to nicotine in the brain, also influence the risk for vaping.
The reasons underlying the popularity of vaping and dual use among youth are not well understood, and our work will show whether genetic factors play a role.
B3591 - Exploring the progression of mental illness Identifying predictors of recovery - 11/08/2020
Depression is the leading cause of global disability with over 300 million people suffering world-wide. Estimates suggest that up to two thirds of patients do not recover following their first antidepressant treatment and up to one third do not recover after multiple treatments. Therefore, it is critically important to identify factors that predict recovery and reduce risk of relapse. Current methods in genetic epidemiology focus on predictors of mental illness onset. While this is crucial to prevent new diagnoses, it does little to help individuals already suffering. Therefore, the Recover project aims to extend current genetic epidemiology methods to better understand recovery from depression. The methods developed here will begin with a focus on depression but can also be extended to other mental illnesses. First, we will develop trajectories of depression using continuous longitudinal measures in two critical time points, 1) adolescence and early adulthood and 2) during and post pregnancy. Second, using these trajectories as outcomes we will explore many modifiable predictors of recovery. Third, we will use cutting-edge causal inference techniques to test whether or not these predictors are causal. And finally, we will develop novel technologies to capture fine-grained fluctuations in mood. Taken together, this work will lead to better interventions and inform adjuncts to treatment having real impact for the growing number of individuals suffering from depression.
B3590 - Early signs and predictors of ADHD A population cohort study - 11/08/2020
Attention deficit Hyperactivity disorder (ADHD) is a disabling neurodevelopmental disorder that affects 5% of the population. There is emerging evidence that early detection and intervention improves neurodevelopmental disorders outcomes. This knowledge, coupled with clear evidence that the first signs and symptoms of developmental disorders may be evident for many children by 30 months of age, has led to increased early detection efforts. However, it is still uncertain how best to identify the very first signs of these disorders. For example, early speech, motor delay or global developmental delay, birth and neonatal complications may index future neurodevelopmental disorders. Investigations using prospective designs may be especially fruitful because they are less affected by retrospective recall biases.
In this project I propose to utilise data from a large, prospective population-based cohort, ALSPAC. The aim is to test the hypothesis that early developmental difficulties in the first year of life precede ADHD and other neurodevelopmental disorders emergence by ages 7 to 9 years.
This work will represent a step towards earlier detection of ADHD and other neurodevelopmental disorders prior to the onset of behavioural symptoms.
B3587 - Optimizing Adult Mental Health Outcomes in Children with Neurodevelopmental Problems Interplay of Social and Genetic Factors - 05/08/2020
Previous research has indicated that individuals with ADHD have an increased likelihood of developing mental health problems such as depression, anxiety and antisocial behavior. Despite mental health problems being increased in individuals with ADHD, not all children go on to develop poor mental health outcomes. Research has indicated that resilience is a dynamic process that arises from normal adaptive mechanisms and can be influenced by many factors. However, why some individuals with ADHD show higher levels of resilience and better outcomes compared to others is not yet well understood. One way of defining resilience is better-than-expected long-term mental health outcome than predicted by initial severity of childhood ADHD. Therefore, the current research project will focus on first identifying risk mechanisms which increase the likelihood of individuals with childhood ADHD developing adult mental health problems, and then will aim to identify potentially modifiable protective factors that could be the focus of prevention and intervention programs.
B3583 - The course of autistic traits in the population from childhood to adolescence and educational attainment - 05/08/2020
Children and young people with autism may do less well in school compared to others. This has a negative impact on their future. Even children with mild symptoms may have problems with school or finding a job when they are older. We want to find out how the development of autistic symptoms over time impacts future success in education.
B3582 - Understanding how patterns of glucose levels and variability relate to health exposures and outcomes - 05/08/2020
Epidemiological and clinical studies interested in circulating glucose as a risk factor or outcome typically measure levels in the blood at a single or widely spaced time points (e.g. every few years). While these are important health indicators, there has been an increasing appreciation that glucose levels and variability in free-living conditions during both the day and night, may also provide important health measures in clinical (e.g. diabetic or obese) and âhealthyâ populations.
Continuous glucose monitoring (CGM) systems measure interstitial glucose levels âcontinuouslyâ by implanting a sensor subcutaneously. This produces a sequence of measurements for each participant (e.g. the average glucose level every 5 minutes over several days), that can be used to assess how a personâs glucose levels vary over both the day and night. We have recently published a novel software package called GLU, for deriving a consistent set of summary variables from CGM data. The derived summary variables can be used in analyses to assess how different characteristics of glucose levels and variability relate to health exposures and outcomes.
B3586 - Super Cohort for COVID Research - 07/08/2020
We propose that a âSuper Cohortâ - comprising of multiple existing UK Longitudinal Population Studies (LPS), including ALSPAC/Children of the 90s â is formed. The data from ALSPAC participants will be linked to whole population NHS and subsequently administrative records and rapidly used for COVID-19 (COVID) research. This work is part of UK government strategy for COVID pandemic research developed by the NHS, government officials and academic health and social science research community. The Super Cohort envisages centralised (by UK nation) sets of key NHS records which are minimised to the purpose, joined together and regularly refreshed during the COVID pandemic. All records will be stored, processed and used for research in a 'Trusted Research Environment'. This is a high security research server which is de-identified and allows researchers to access individuals (including ALSPAC participants) records without revealing individual identities. No data is allowed to exit the server, only anonymous statistical research findings can be exported. These findings will contribute to government policy development and the international understanding of COVID as a disease and the impacts of social distancing and other protective measures.
B3584 - Understanding the health implications of using different definitions of attention deficit hyperactivity disorder - 06/08/2020
Individuals with Attention Deficit Hyperactivity Disorder (ADHD) have difficulties with sustaining attention, being overactive and being impulsive. It is one of the most common childhood disorders and causes difficulties in school, and with family relationships and friendships, whilst those with ADHD are also at higher risk of other difficulties such as anxiety and depression both in childhood and later life. Not all individuals with ADHD have the same problems though, so it is important to understand who is at greatest risk of them. Difficulties with attention or hyperactivity are present across many people whilst only some have sufficient problems to be diagnosed with ADHD. International guidelines indicate where the dividing line between having a diagnosis or not is set, but we know that individuals who do not meet this diagnostic threshold can still have difficulties due to their ADHD symptoms whilst even in those with a diagnosis, the specific constellation of problem behaviours differs between individuals. This project aims to examine how differences in the symptom presentation and impairments in children are linked to other difficulties they have in childhood and as they grow into adulthood. It will also look at how genetic risks for ADHD and other disorders are related to these different presentations. This will be examined in both the general population (the ALSPAC cohort) and a clinical sample of children with ADHD, with additional replication in other international cohorts.
B3579 - Associations of COVID-19 Risk Perceptions with Mental Health Wellbeing and Risk Behaviours - 24/07/2020
Risk perceptions are subjective judgements that people make about the characteristics and severity of a risk (Darker, 2013), and they can influence emotions and behaviours (Ferrer & Klein, 2015; Paek & Hove, 2017). Accuracy is critical; underestimating or overestimating the level of threat and danger can have negative consequences. For example, underestimation of risk in a pandemic can reduce adoption of protective and preventative health behaviours (Dryhurst et al., 2020; Khosravi, 2020; Leppin & Aro, 2009). While overestimation of risk can increase hoarding behaviour, potentially leading to shortages of medications and personal protective equipment (Abrams & Greenhawt, 2020). Overestimation of risk may also lead to reluctance to return to normal activities as national lockdowns ease.
As well as influencing behaviour, risk perceptions can negatively impact mental health and wellbeing. Among young adults in the Avon Longitudinal Study of Parents and Children (ALSPAC), wellbeing has reduced, and anxiety levels have almost doubled during the COVID-19 pandemic, compared to pre-pandemic levels (Kwong et al., 2020). This is an important public health issue, given that anxiety is associated with maladaptive coping strategies such as increased alcohol use (Dyer, Heron, Hickman, & Munafò, 2019). High risk perceptions may be one factor associated with this increase in anxiety and reduction in wellbeing. In this project, we will examine the bi-directional associations of COVID-19 risk perceptions with mental health, wellbeing, and risk behaviours, using genetic and self-report data. It is also important to examine the mental health and behavioural precursors of COVID-19 risk perceptions, given their influence on health behaviours.
B3581 - Dissecting PCOS Physiology by Defining Phenotypes Associated with PCOS Genetic Risk Factors in Children - 24/07/2020
Polycystic ovarian syndrome (PCOS) is a major health concern that affects up to 10% of reproductive-aged women. This complex, heterogeneous condition is often characterized by a triad of ovulatory dysfunction, hyperandrogenism, and cardiometabolic dysfunction. Despite extensive physiologic and genetic studies, the treatment of PCOS remains limited by an incomplete understanding of the pathophysiology of the disorder. Identification of the genetic variants and pathways associated with PCOS susceptibility may provide insights into the pathogenesis of the condition and potential targeted treatments.
We propose to study phenotypes in children that may be associated with PCOS, including obesity, dyslipidemia, and premature adrenarche. Premature adrenarche is a pediatric condition characterized by early production of adrenal androgens such as DHEAS and androstenedione and has been proposed to be a precursor to PCOS in girls. We will calculate a polygenic risk score for PCOS in prepubertal children and test for associations with premature adrenarche and associated cardiometabolic and hyperandrogenic outcomes and biochemical and anthropometric traits. In addition, we will examine these outcomes during the pre-pubertal period in girls who later develop a diagnosis of PCOS in adolescence and young adulthood.
The extension of PCOS genetics to prepubertal children provides the unique opportunity to 1) classify the PCOS pathways into ovarian-dependent factors and nonovarian-dependent factors and 2) characterize the pediatric phenotypes associated with PCOS genetic risk factors, and 3) understand the pre-pubertal manifestations of a future PCOS diagnosis. Overall, investigations in prepubertal children have the potential to provide valuable insights into the mechanisms of pathogenesis and targets for treatment for PCOS.
B3580 - Investigating the Activity of Transposon-Derived Regulatory Sequences in the Human Placenta - 04/08/2020
The placenta is crucial for the initiation and maintenance of pregnancy. Common complications of human pregnancy, such as preeclampsia, often have unknown etiology but feature contributions from genetic and non-genetic causes. DNA exists in the cell bound by proteins and other molecules, forming a structure known as chromatin. The structural conformation of chromatin is just as important as the DNA code itself, since chromatin structure dictates which components of DNA are active, and therefore able to regulate the cell. Formalin-fixed placentas maintain the structural conformation of their chromatin, making them a uniquely valuable resource to identify the location and activity of regulatory DNA. My proposal seeks to investigate the causes of preeclampsia by comparing the chromatin structure in formalin-fixed placentas from control pregnancies and those complicated with preeclampsia. I will focus on regions of non-coding DNA that regulate gene activity, so-called gene promoters and enhancers, including a special subset of these regions known as transposons. Placental chromatin exhibits a unique structure compared to other tissues, featuring an open conformation around transposons, indicative of their activity in placenta. The activity of gene-regulatory DNA provides the basis of tissue and organ-specific developmental programs. As such, the development and function of the placenta is dictated by the activity of regulatory DNA, and structural variation at these regions can cause disease. I will test the hypothesis that chromatin structure variation of DNA regulatory sequences contributes to the causes of preeclampsia.
B3577 - Understanding the relationship between adverse childhood experiences and later mental health outcomes - 23/07/2020
Adverse childhood experiences (ACEs) such as abuse, bullying or family disruption are increasingly recognised as one of the most potent determinants of later mental health problems. Estimates suggest that mental health problems, including depression and self-harm are at least double among those who have been exposed to ACEs. Despite the recognised importance of ACEs to later mental health outcomes, relatively little is known about the characteristics of ACEâs that have the greatest impact. Firstly, many studies have relied on cumulative scores, whereby ACEâs are simply dichotomised and summed. This approach assumes that each ACE contributes equitably to the outcome of interest and that they operate via the same mechanisms. Other research has focused on the relationship between individual ACEsâ and mental health. Although such studies have provided useful insights, it is known that ACEâs often co-occur and most have failed to take account of this clustering. Person centred approaches such as Latent Class Analysis (LCA) could be used to identify variability in ACE profiles between individuals and investigate potential differential associations with mental health, demographic factors, and mechanisms. Secondly, little attention has been paid to the role of timing, chronicity, or recency of exposure in relation to mental health, and findings from existing studies have been inconclusive. Disentangling these effects is challenging as it may be that those who have been exposed earlier in childhood have also been exposed for longer. This PhD will address these limitations and generate valuable new insights into the relationship between ACEs and two mental health outcomes â depression and self-harm.
B3578 - Genetic and non-genetic influences on the development of psychiatric outcomes in children born with cleft lip and/or palate - 23/07/2020
Cleft of the lip and/or palate is a common birth defect worldwide and occurs at a rate of one in 650 live births in the UK. Being born with cleft places a significant burden on children, their families and the health system as they require surgery (multiple times depending on cleft type), and other interventions to improve appearance, speech, hearing, dentition and other adverse outcomes. They are also at increased risk of psychological, psychiatric and cognitive problems [1]. There are several possible mechanisms underlying these associations that may be operating alone or together. First, they may reflect the psychological, developmental and social impacts of clefting and its treatment. Second, they may reflect genetic factors either as pleiotropic outcomes of genetic susceptibility to clefting or as independently inherited genetic risk.
The aetiology of both cleft and of psychiatric disorders is complex, with common risk alleles [3] [4] of individually small effects as well as rare genetic mutations of large effect and environmental factors playing roles. One group of rare mutations of large effect are Copy Number Variants (CNVs), referring to deletion or duplication of a part of the genome leading to differences between individuals in the number of copies of genes within the affected region. CNVs are known to increase risk of neurodevelopmental disorders (ND-CNVs), such as ADHD and autism, as well as mental health disorders but the presence and the impact of CNVs have not been studied in cleft [5].
The PhD project will provide the first detailed description of neurodevelopmental and mental health outcomes in children with cleft and examine the contributions of genetic and environmental factors. For this we will use two unique genetically informative clinical cohorts of children; the Bristol University Cleft Collective and the Cardiff University longitudinal ExperiencCes of people witH cOpy number variants (ECHO) study. Control samples will consist of the Avon Longitudinal Study of Parents and Children (ALPSAC) and the Millennium cohort which are deeply-phenotyped cohorts of typically developing children.
B3574 - Causes of Chronic Pain in ALSPAC - 28/08/2020
Pain which lasts for more than 3 months is termed "Chronic Pain". It often occurs in the absence of obvious injury. It can be very difficult to treat.
We believe that the body may produce antibodies (part of the natural defence against infections) that can activate "pain" nerves. This may contribute to Chronic Pain.
Antibodies, produced by the body are known to sometimes interfere with the nerves in diseases such as Myaesthenia Gravis.
If we can demonstrate that these antibodies can cause chronic pain, we will be able to treat patient with chronic pain much more effectively.
B3575 - Socioeconomic disparity placental pathology and child development - 07/10/2020
Socioeconomic disadvantage and stress are associated with adverse pregnancy and child health outcomes. There is some evidence to suggest that these associations may be mediated by changes in placental development and function. However, studies of the placenta are often small or limited to pathologic samples, which may not be representative. ALSPAC routinely collected placentas of participants, including term deliveries, and ALSPAC has rich parental sociodemographic information and longitudinal follow-up on child health and development. This presents a unique opportunity to estimate associations between socioeconomic disadvantage and child development and to examine the mediating role of placental pathology in a well-characterized, representative sample.