Proposal summaries
B3442 - The biological background of attention-deficit/hyperactivity disorder - 14/01/2020
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by persistent patterns of inattention, hyperactivity and/or impulsivity, which interfere with normal functioning or development. ADHD is highly heritable, with heritability estimates from twin studies at around 75%. It is also suggested that epigenetic modifications â alterations in the DNA not changing the sequence itself â play a role in ADHD aetiology. In addition, there is known shared genetic liability between obesity and ADHD. Maternal obesity is a known risk indicator for offspring ADHD, however it is not clear whether this is due to the shared genetic predisposition, or possible intrauterine mechanisms.
B3438 - Novel statistical methods for the analysis of high-dimensional epigenetic data - 10/01/2020
We propose to address the problem of handling large-scale genome-wide DNA methylation data. To this end, we will develop a novel technique for clustering DNA methylation (DNAm) sites which will aid reducing the complexity of the subsequent EWAS. For example, a DNAm site that is hypo-methylated in the smoker cohort but hyper-methylated in non-smoker one merits further analysis for significant association with smoking, while those sites exhibiting no difference in the two cohorts does not.
We will investigate the use of algorithms for large matrix factorisation under constraints to provide a natural clustering of DNAm sites, and study what statistical guarantee is achievable under which conditions. To verify the suitability of the proposed method, we propose to use the DNA methylation data available from ARIES.
B3440 - PLACENTA - 29/01/2020
Few studies have examined a large number of placenta from general population samples. There are therefore many unanswered questions about the links between placental abnormalities and maternal and offspring health in pregnancy and beyond. ALSPAC is unique, with some 10000 stored placentas from the original ALSPAC pregnancies in the early 90s. We will generate pathology data on this collection and study placental findings in relations to short term health in mums and their offspring.
B3439 - A Consolidator Grant to Study the Developmental Trajectories of Physical and Mental Health Multimorbidity in Genetic High-Risk C - 31/01/2020
A subgroup of people in the population have a change in their genetic make-up that greatly increases their risk of physical disorder and psychiatric disorder. The medical consequences of these genetic changes are however still very poorly understood. Particularly, we don't really know how these changes lead to increased risk of combinations of physical and mental health problems over time. As presence of a physical or mental health problem increases risk of other ones developing, it is important to understand how and why this happens in this high-risk group. Because these genetic changes are rare, it is important to bring together large samples to study their role in medical outcomes properly. This is particularly important if we want to understand how these changes influence the combined risk of physical and mental health problems in different groups within the population, for example young people versus adults, different ethnic groups and groups from different socio-economic backgrounds. To study these important questions, we propose to work together across four large UK studies in which these genetic changes have been established and which have collected rich information on physical and mental health as well as relevant risk factors. The data sets we will work with differ in the age and ethnic and socio-economic background of the participants. We will be able to follow over time how risk of physical and mental health problems influence each other and how this may be different in these different age. ethnic and socioeconomic groups. The findings will have important implications for developing better interventions for this group, for understanding complex medical risks in the population more generally and for insights into the biology of complex medical risks.
B3419 - The relationship between cognitive and neural development and a childs environment - 10/01/2020
In the UK 14 million people live in poverty. Four million of these are children. The level of child poverty is rising, and the rate is projected to accelerate in coming years. Growing up in a deprived environment can have a profoundly negative effect on a childâs development. Children from deprived backgrounds are more likely to be placed in special education, fail courses, and complete fewer years of schooling. But the adversities children encounter extend well beyond economic hardship and incorporate multiple familial factors like chaotic home life, poor parental mental and physical health, lack of community support, poor schooling and communication difficulties. These factors have a well-documented impact on multiple child outcomes including educational attainment, mental health, and behaviour. This is a global problem. Up to 50% of children and adolescents growing up worldwide experience at least one episode of childhood adversity in early life: 30% of all mental health problems are attributable to such adversity. The effects are also persistent â early adversity can set a life-long trajectory associated with poor physical and mental well-being and significantly worse occupational and economic outcomes. This results in an inter-generational cycle of disadvantage where deprivation impacts each subsequent generation. Supporting young people who face adversity is one of the major modern challenges for educators, practitioners and policy-makers, as they work to reduce educational under-attainment, poor economic outcomes and address the burgeoning mental health crisis.
Yet not all children who face adversity go on to experience poor outcomes: certain factors appear to insulate children from hardship, such that they demonstrate resilience (broadly defined as succeeding in a particular domain, such as education, despite experiencing adversity). Resilience within mental health is an increasingly recognised phenomenon, but our knowledge about which factors foster resilience across a broader range of outcomes, different populations and in response to diverse sources of adversity is currently limited. Understanding the cross-domain factors that promote resilience is vital to drive the development of interventions that improve the outcomes of child and adolescent victims of adversity. This is the purpose of our project. We want to explore how different environmental factors interact with cognitive and brain development, whether particular features of a child's environment are most strongly linked with these outcomes, and whether some factors foster resilience.
B3437 - Examining the association between alcohol use cognitive functioning and self-harm - 10/01/2020
Alcohol use during adolescence is a major public health concern, in particular because the brain is still developing and undergoing considerable structural and functional changes. Identifying risk factors that influence adolescent alcohol use is important to appropriately target prevention programs. One area of research that has received considerable attention is the role cognitive functioning (e.g., working memory and inhibition) play as risk for involvement in adolescent alcohol use. There is also a large literature showing a relationship between substance use and self-harm. It is possible that alcohol may increase the risk of self-harm by lowering inhibitions and impairing working memory, which is central to decision making. There is also evidence to suggest that there may be a bi-directional relationship, as several longitudinal studies have reported an association between adolescent self-harm and alcohol problems in adulthood. Although previous prospective studies have examined this association, they are often limited by the use of small sample size, different alcohol use phenotype (i.e. bingeing vs frequency), different follow-up periods, or lack of control for relevant confounders.
B3436 - Mapping the shared genetic architecture of human blood multi-omics phenotypes at cardiovascular disease risk loci - 08/01/2020
The majority of the disease risk variants identified by genome wide association studies (GWAS) fall inside of non-coding regions, leading to the conclusion that their effects are likely to be mediated by regulation of gene expression or other molecular phenotypes. This highlights the value of utilizing multiple molecular phenotype QTLs (collectively, xQTLs) to establish the link between the regulatory genetic variant (risk allele) and various traits and diseases. In this study we will employ DNA methylation QTL, expression QTL, histone QTL, protein QTL and metabolite QTL data from peripheral blood to map shared genetic influences on multiple intermediate molecular traits in GWAS and EWAS associated loci and investigate the molecular pathways in which they play a role.
B3435 - Sex differences in the association of socioeconomic position with cardiovascular health across the life course - 08/01/2020
Socioeconomic differences in cardiovascular health are evident in adulthood. When these inequalities emerge and how they change through the life course is not well understood. Understanding when inequalities in cardiovascular health emerge may inform early life prevention opportunities.
B3434 - Methylation of the glucocorticoid receptor gene in the development of child psychopathology - 10/02/2020
B3431 - Association of Maternal education with DNA-methylation - 16/12/2019
Maternal education, a predictor of social-economic status, has been associated with several offspring health outcomes during the life course (e.g. obesity, type 2 diabetes, cognitive function...). The biological mechanisms regulating this association are yet to be understood. Possible mediation in the maternal education-offspring health outcome relationship might be played by DNA-methylation epigenetics markers. We therefore aim to investigate how epigenetics changes are associated to maternal educational attainment.
B3427 - The effect of historic digit sucking on facial shape at 15 years of age - 16/12/2019
A previous study in 350 6-year-old children has suggested that digit sucking has no effect on craniofacial parameters but may affect occlusal development. It is reasonable to expect that if digit sucking has an effect on the dentition this also should also influence facial shape. We have a large sample and we should be able to determine whether the frequency of digit sucking and hand used have and long-lasting changes in face shape.
1. Campos MPMS, Valença PAM, Silva GMD, Lima MC, Jamelli SR, Góes
PSA. Influence of head and linear growth on the development of malocclusion at six years of age: a cohort study. Braz Oral Res. 2018 Oct 11;32:e98.
B3429 - Obesity and Inflammation - 16/12/2019
Between 2015 and 2016, obesity affected approximately 13.7 million children and adolescents in the United States. Children with obesity are more likely to have high blood pressure, abnormal lipids and insulin resistance even though overt cardiovascular disease may not develop for decades.Additionally, children with obesity are at increased risk for musculoskeletal and mental health disorders, as well as certain cancers. This project aims to to better understand the development and progression of the metabolic derangement seen with obesity in children as well as the associations with development of comorbidities. Inflammation is considered to be the common link between obesity and its progression to various comorbidities. If we are able to identify an early signal in children with obesity who are more likely to develop diseases such as asthma, cardiovascular disease and cancers we will be able to address the problem in a timely fashion and offer focused intervention and treatment to these high risk children
B3432 - Hypothesis-free and pQTL analysis of deep vein thrombosis aetiology a Mendelian randomization study - 16/12/2019
Deep vein thrombosis (DVT) usually presents as a blood clot which forms in the deep veins of the legs. It can be a life-threatening disease if not identified in time, leading to pulmonary embolism or heart failure. While research have found some risk factors using observational epidemiological studies, little is known about the exact causes of DVT.
B3428 - Epigenetic trajectories of mental health - 19/12/2019
Mental illness accounts globally for one third of years lived with disability, leading to tremendous loss of human, societal and economic potential. Most symptoms (e.g., depression, anxiety, conduct problems) emerge before adulthood, highlighting the first two decades of life as an important period of heightened vulnerability. Epigenetics has emerged as a biological system that captures the underlying genetic and environmental risk factors, but we do not yet understand the developmental dynamics in this system over time. Such knowledge, however, is critical if we are to understand how mental health disorders develop, and thus how they may be prevented.
B3430 - Liver measures in F30 clinic - 10/01/2020
Liver disease remains the only disease where mortality is rising in the UK. Alcohol-related liver disease (ARLD) and non-alcoholic fatty liver disease (NAFLD) are the two commonest indications for liver transplantation in this country.
ALSPAC analysed the prevalence of these diseases in the F@24 clinic using a modality called transient elastography, also known as Fibroscan. This gives measurement on how fatty the liver is (steatosis) and how scarred it is (fibrosis). This demonstrated over 1 in 5 participants had NAFLD, with 1 in 40 having evidence of fibrosis. Individuals with harmful drinking patterns AND obesity were at greatest risk of fibrosis. This is all the more alarming as ARLD and NAFLD tend to be diseases that manifest in the 4th and 5th decade.
ALSPAC has an opportunity to be, to the best of our knowledge, the only birth cohort to sequentially assess its participants for liver disease. We are proposing to re-assess the participants that remain in the G1 cohort for liver disease to see if there has been a progression in the number of cases seen. This would be one of the first attempt to map the development of liver disease in the general population setting.
B3426 - The longitudinal association between childhood sleep disturbances and psychotic experiences in adulthood - 03/12/2019
Sleep disturbances during childhood are common and often resolve spontaneously without intervention (Touchette et al., 2005; Galland et al., 2012). However, those that are persistent and frequent have been shown to be associated with the development of later psychopathology including psychotic like experiences (Jeppesen et al., 2014). Previous research exploring data from the Avon Longitudinal Study of Parents and Children has shown that children, aged 2.5 and 9 years old, experiencing frequent nightmares were more likely to report psychotic experiences at age 12 (Fisher et al., 2014). Similarly, nightmares at 12 years old was also found to be associated with an increased risk of psychotic experiences at aged 18 (Thompson et al., 2015). Such findings suggest that nightmares during childhood may represent an important and clinically significant indicator for risk of psychotic experiences in adolescence.
The relationship between childhood sleep disturbances and the presence of psychotic experiences beyond the age of 18 is still yet to be understood. Research has shown that the incidence of psychotic experiences often peaks during adolescence to early adulthood (McGrath et al., 2016) and sleep disturbances frequently co-occur with psychotic like experiences during this time (Taylor et al., 2015). Consequently, understanding which early sleep problems present as a risk factor for the development of later psychotic experiences is key. This project will explore the longitudinal associations between childhood and adolescent sleep problems between the ages of 2.5 - 17 years old and self-reported psychotic experiences at 24 years old.
Fisher, H.L., Lereya, S.T., Thompson, A., Lewis, G., Zammit, S. and Wolke, D., 2014. Childhood parasomnias and psychotic experiences at age 12 years in a United Kingdom birth cohort. Sleep, 37(3), pp.475-482.
Galland, B.C., Taylor, B.J., Elder, D.E. and Herbison, P., 2012. Normal sleep patterns in infants and children: a systematic review of observational studies. Sleep medicine reviews, 16(3), pp.213-222.
Jeppesen, P., Clemmensen, L., Munkholm, A., Rimvall, M.K., Rask, C.U., Jørgensen, T., Larsen, J.T., Petersen, L., van Os, J. and Skovgaard, A.M., 2015. Psychotic experiences coâoccur with sleep problems, negative affect and mental disorders in preadolescence. Journal of Child Psychology and Psychiatry, 56(5), pp.558-565.
McGrath, J.J., Saha, S., Al-Hamzawi, A.O., Alonso, J., Andrade, L., Borges, G., Bromet, E.J., Oakley Browne, M., Bruffaerts, R., Caldas de Almeida, J.M. and Fayyad, J., 2016. Age of onset and lifetime projected risk of psychotic experiences: cross-national data from the World Mental Health Survey. Schizophrenia bulletin, 42(4), pp.933-941.
Taylor, M.J., Gregory, A.M., Freeman, D. and Ronald, A., 2015. Do sleep disturbances and psychotic-like experiences in adolescence share genetic and environmental influences?. Journal of Abnormal Psychology, 124(3), p.674.
Thompson, A., Lereya, S.T., Lewis, G., Zammit, S., Fisher, H.L. and Wolke, D., 2015. Childhood sleep disturbance and risk of psychotic experiences at 18: UK birth cohort. The British Journal of Psychiatry, 207(1), pp.23-29.
Touchette, Ã., Petit, D., Paquet, J., Boivin, M., Japel, C., Tremblay, R.E. and Montplaisir, J.Y., 2005. Factors associated with fragmented sleep at night across early childhood. Archives of pediatrics & adolescent medicine, 159(3), pp.242-249.
B3425 - Does socioeconomic position modify associations between grandparental body composition and that of the grandchildren - 04/12/2019
The worldwide prevalence of obesity has tripled since 1975, and nearly a third of the world's population is now classified as overweight or obese. This rising prevalence of obesity is not only due to single genetic or environmental factors, but largely attributed to complex gene-environment interactions. Genetically predisposed individuals may be more prone to obesity in an obesogenic environment. Previous studies have focused on the identification of specific environmental factors that interact with genetic predisposition to obesity. The results indicate that physical activity, diet, age, gender and ethnicity could modulate the risk for obesity. Socioeconomic position (SEP) is relevant to all realms of behaviors and lifestyles, is a key factor that determines health across the lifespan, and may carry over to subsequent generations. The fact that BMI inequalities have persisted across different generations means that SEP is a significant factor to consider when understanding the role of environment. Parental SEP could influence the offspringâs risk of obesity through shared lifestyles such as dietary profile, home environment, social networks, and physical activity patterns early in life, which may be exacerbated by predisposition to obesity. Emerging studies have started to focus on SEP mobility across the life course, or intergenerational SEP mobility across two generations. The findings show evidence that higher parental education may be favorable in lowering obesity risk in offspring, especially for women. Longitudinal research should minimize reverse causation and allow us to investigate the dynamic interplay between oneâs social strata of origin and own achieved social strata on obesity. However, it is still unclear how early the ancestorsâ influence emerge and to what extent susceptibility to obesity is attenuated by SEP mobility.
We hypothesize that higher grandparental SEP, and upward SEP mobility across generations would diminish the grandchildrenâs risk of obesity, compared to those who are always in social disadvantaged strata. The approach to consider ancestorsâ SEP as a modifier in the heritability of BMI will add in tailoring appropriate interventions in future work.
B3424 - Is normal variation in brain activity during sleep related to liability for schizophrenia - 10/12/2019
Different parts of our brains communicate with one another as we learn new information during the day, then continue to communicate âofflineâ as we sleep. This overnight brain activity helps file memories for long-term storage, but the process is complex and delicate: lots of genes influence brain activity in ways we do not yet understand. We also need to establish why and how this process is disrupted in disorders like schizophrenia, which are associated with impaired sleep-dependent brain activity and memory. This study will investigate links between a set of schizophrenia-associated genes and brain function during sleep.
Participants will be asked to wear a âfitbitâ-like device for 2 weeks of normal activity, so we can track when and how much they sleep. We will then use a comfortable sleep cap that contains an array of recording devices to monitor EEG brainwaves while participants sleep at home for 2 nights. By analysing the EEG data using machine learning methods (similar to those used for speech recognition), we will identify patterns of activity that make up their personal âsleep fingerprintâ. This will allow us to test whether these fingerprints vary according to genetics in a healthy population, without interference from things like medication that complicate patient studies.
The main outcomes will be (1) development of novel analysis methods allowing us to capture brain activity, (2) a deeper understanding of the mechanisms that determine variation in patterns of brain activity during sleep and (3) a route towards understanding mechanisms of schizophrenia liability.
B3421 - Brain signatures of adolescent depression and depression risk - 29/11/2019
Population-based genetic and imaging studies of depression in adults have greatly advanced our understanding of this leading cause of global disability, particularly regarding associated neurobiological features. However, the causes and timings of such brain changes remain unknown, highlighting the need for a targeted study of the origins of these differences in younger individuals.
The largest risk factor for depression is a positive family history, and the major risk period for its development is during adolescence. The current project will therefore investigate whether the origin of these imaging features in adults (from work in UK Biobank, Enigma and Generation Scotland) is seen earlier in life in relation to increased risk for the disorder (including family history, polygenic risk, and associated traits such as depressive cognition, locus of control and self-esteem) using genetic and imaging data from children and parents in ALSPAC. Only now are there adult samples of sufficient size to inform such a focused study of adolescent depression, and this will form the first step towards determining potential causative associations between risk factors, associated neurobiology and depressive symptoms.
Summary data from these investigations in future could be combined in meta-analyses with other cohorts (e.g. MoBa) and consortia for discovery and replication. This would be under strict governance structures, where data would remain in Edinburgh and no individual data would be shared and this would be the focus of a separate application.
B3423 - Characterising the ALSPAC mothers who are also UKBiobank participants - 29/11/2019
Many of the ALSPAC mums and fathers/partners may have also volunteered to take part in the UK Biobank cohort study. It is important that the study Data Managers and the researchers understand who is in both studies. This is because studies such as ALSPAC and UKBiobank are often used together in order to study rare events or small associations (where you need large numbers of participants for the statistical tests to work) or they are used to check and confirm whether findings in one study are also seen in another study. Finding the same patterns means there can be more confidence the findings are genuine, rather than occurring by chance or due to error. In both cases, the statistical tests assume the people in one study are different to the people in the other study. However we now know there is substantial overlap between participants in ALSPAC and UK Biobank (and possibly other studies).
ALSPAC and UKBiobank are ensuring that any duplication is flagged so researchers can take account of this (without knowing the identities of the participants). To inform thinking on how to best deal with this issue, it is necessary to produce descriptive statistics describing the characteristics of the ALSPAC participants who are in UKBiobank and how these differ from ALSPAC participants who are not in UKBiobank.