Proposal summaries
B2640 - Relationship between non-syndromic forms of Cleft and biological intermediates - 19/04/2016
Non-syndromic cleft is a disease with both genetic and environmental risk factors. Possible environmental risk factors include folic acid, zinc and cholesterol. Genetic scores for environmental factors will be compared between cleft cases and healthy controls to determine if there are differences between cases and controls.
B2637 - Patterns and predictors of response and consent decisions in the PEARL enrolment and data linkage consent campaign - 14/03/2016
Good quality science depends on accurate data and being able to accurately interpret the results of analysis conducted on these data. It is therefore important for studies such as ALSPAC to assess if the way people take part in research has an effect on how researchers should interpret the data.
This study aims to assess the PEARL Consent Campaign - which asked participants to re-enrol into the study upon reaching age 18 and also for consent to link to their routine health and administrative records. We want to understand if the characteristics of participants who responded by returning their consent form, or responded with different consent decisions, differ from other participants - and if these differences may introduce bias into study findings. We will also consider if any lessons can be learnt as to how studies may improve requests for consent in the future. This project will contribute to wellbeing of children by forming part of the documentation used by future researchers to help ensure their findings are accurate.
B2638 - Diet and obesity in childhood comparisons between Isle of Man and Southwest England - 25/02/2016
To compare dietary intakes of children age 7 years between the Isle of Man and the South west of England and investigate whether any dietary differences are associated with differences in obesity levels between the two cohorts of children. Data were collected in exactly the same way in Isle of Man as in ALSPAC so direct comparisons can be made between children growing up at the same time but in different environments.
B2620 - Epidemiology of fetal alcohol spectrum disorders within a UK population based birth cohort - 02/02/2017
Fetal alcohol spectrum disorders (FASD) are a range of lifelong developmental disabilities caused by exposure to alcohol during pregnancy (BMA Board of Science, 2007; FASD Trust, 2013). In addition to developmental disabilities, individuals with FASD have an increased risk of mental health problems, substance misuse and contact with the criminal justice system later in life (Popova et al., 2016; Streissguth et al., 2004). Research from North America, Italy and Croatia suggests that between 3-5% of children in the general population have FASD, making it one of the leading preventable causes of developmental disability worldwide (May et al., 2014; Roozen et al., 2016).
There are no current estimates of the number of children with FASD in the UK. However, there is reason to suspect that FASD may be an issue within this population. The UK has inconsistent guidance on drinking in pregnancy. Some organisations promote an abstinence message and others suggest that low levels of use (one to two units once or twice a week) may be acceptable (Department of Health, 2016; National Institute for Health and Care Excellence (NICE), 2008). In the UK approximately 75% of women drink while pregnant and, although many reduce their intake later in pregnancy, 33% of women report binge drinking within the first trimester (Nykjaer et al., 2014; O'Keeffe et al., 2015). In 2015 the All Party Parliamentary Group for FASD expressed an urgent need for a UK population-based prevalence study in order to guide prevention efforts and policy for alcohol use in pregnancy (All Party Parliamentary Group on FASD, 2015).
B2566 - Inheritance of smoking behavior via maternal gestational smoking and change in DNA methylation
Smoking behavior is influenced by several conditions, including environmental, genetic and epigenetic. One such epigenetic mechanism that contributes to smoking behavior is DNA methylation (DNAM).
However, the pattern of inheritance of DNA methylation is unknown. The erasure of DNAM of all genes (except imprinted ones) contradicts with the belief that it is vertically transmitted. We propose that inheritance of DNA methylation of from grandmother (F0) to grandchildren (F2) is conditional upon in utero exposure in the mother(F1). We use a CpG site cg05575921 of the AHRR gene to demonstrate the inheritance of DNAM.
Additionally, we also propose that maternal smoking mediated differential DNAM of cg05575921 also affects the time of initiation of smoking in the offspring. The primary analysis was done using the study population from the Isle of Wight cohort (UK). We intend to replicate our finding using the data from ALSPAC.
B2636 - The longitudinal relationship between sleep and mood throughout childhood - 14/07/2017
Depression in adolescents is common and can interfere in school, relationships and social activities. Adolescents with depression can struggle to concentrate and spend time with their family and friends. They also commonly experience thoughts about death and suicide, and attempted suicide is a real risk in these young people. Depression during this time can have long lasting negative effects on wellbeing.
Disturbed sleep is one of the most common symptoms of depression, experienced by over 75% of depressed adolescents. Research has found evidence that sleep problems are often associated with more severe depression and increase suicidal thoughts. However, surprisingly little is known about the relationship between sleep and depression in teenagers. Does depression lead to sleep problems or do sleep problems increase the risk of developing depression? Sleep disturbances are commonly known to be a symptom of depression, but they could actively contribute to the onset or course of the disorder, making them a treatment target.
This project will use data from a large sample of children born in the early 1990s and their families. Measures of children’s mood and sleep were taken regularly throughout childhood and are available up to teenage years when depression is at peak onset. This information will help to identify when sleep problems develop and if they predict depressed mood at a later age. If this project finds that early sleep problems do predict later depression this would open up the possibility that early sleep interventions might reduce the risk, or severity, of depression.
B2635 - Lifecourse influences on long-term health and development - 19/02/2016
We will analyse data from birth cohorts in the USA, Belarus and Singapore, to identify a number of potentially modifiable early-life factors which are associated with common child health conditions of obesity, intelligence problems, asthma, and allergies. We will perform similar analyses using ALSPAC birth cohort data, and compare findings across countries that have differing social, economic and cultural characteristics, and determine if the findings are the same in different settings.
B2634 - The definition measurement and lifecourse determinants of healthy ageing - 19/02/2016
The remarkable advances in life expectancy since the 19th century have resulted in unprecedented population growth and increasing proportions of older people in many countries worldwide. Consequently, the costs of care and pensions spending are expected to increase and this may impact negatively on economies and younger generations. This has prompted many nations to develop policies concerning ways to prolong quality of life and increase the prevalence of healthy, active older people, but reliable evidence is needed to inform this.
Chronological age changes at a constant rate yet within a group of people of the same age, there is considerable variation in bodily status, concerning risk of disease and death or level of functioning. The term ‘healthy ageing’ (HA) refers to the promotion and maintenance of health and functioning with age. The lifecourse approach to HA focuses on the early identification and determinants of accelerated ageing trajectories, with an aim to understand and inform steps to moderate the onset or rate of ageing.
The aim of this project is to define, develop and test a measure of HA, as currently, no common definition or standard measure of HA exists, and use it to investigate the lifecourse determinants (e.g. birthweight or height) and genetic influences on HA. The HA measure will also be compared the ‘epigenetic clock’ method proposed for determining biological age.
B2633 - Frequency of KLK3 deletions in ALSPAC - 19/02/2016
One of the kallikrein genes (KLK3) encodes Prostate Specific Antigen, a key biomarker for prostate cancer. A number of factors, both genetic and non-genetic, determine variation of serum Prostate Specific Antigen levels in the population. We have found KLK3 deletions in individuals with very low Prostate Specific Antigen levels, suggesting a link between abnormally reduced kallikrein gene 3 expression and deletions of kallikrein gene 3 (Rodriguez et al., 2013, Clin Chem. 59(1):234-44). We have also identified common deletions in the KLK3 gene in the 1958BC, and have also found in silico evidence for KLK3 deletions in the NBS cohort (Al-Ghamdi et al., 2013 [PhD thesis]), Rodriguez et al., (submitted).
B2632 - The overlap between eating disorders and Obsessive compulsive disorder 09/02/2016 - 2349 - 28/10/2016
Eating disorders, in particular anorexia nervosa (AN) and obsessive-compulsive disorder (OCD) are often debilitating brain-based disorders that place significant burdens on patients, families and the larger economy. Although we know that both disorders run in families due to genetic factors, we do not have a good way to measure an individual’s genetic risk for these illnesses. This study will provide new measures of shared and unique AN and OCD genetic risk and will examine how these genetic risk scores predict problems with emotional, behavioral and cognitive functioning and eating disorders symptoms in order to better prevent, detect, and treat these disorders.
B2626 - Gene Expression and Cardiovascular Development 10/19/2015 - 1346 - 07/12/2016
We know that events in early life such as being born small or premature can increase the risk of developing diabetes, high blood pressure, heart disease and stroke in later life. The mechanisms through which these adverse early life events increase the risk of these diseases is not clear. To address this in a previous study we have used a technique to look at the activity of all the genes at once (this is known as gene expression profiling). We compared two groups of children:
1. Those born small but with good growth in early childhood (high risk cardiovascular disease) and
2. Children born small with poor growth in childhood (low risk cardiovascular disease). We were able to identify changes in pathways related to insulin (involved in diabetes) and the renin-angiotensin system (involved in blood pressure). This study involved only 33 children. We will examine how levels of activity these pathways vary in healthy children and in those exposed to adverse early life factors (obesity, prematurity, being born small) and how the levels of pathways activity relate to blood pressure, blood fats and blood sugar levels.
The proposed study seeks to extend these preliminary data. By using the ALSPAC gene expression profiles we will be able to examine the activity of the genes in the pathways we previously identified in a much larger group of children (approximately 1000).
We will be able to examine the effects of several different early life events on these pathways - prematurity, being born small (with or without good postnatal growth) and obesity. We will also examine how, in a group of normal healthy children, changes in activity levels of these pathways affect measures of health such as blood pressure, cholesterol and blood sugar levels.
B2624 - Causal Relationship between variation in DNA methylation and Type 2 Diabetes linking epigenetic and gene expression evidence - 11/05/2017
Type 2 diabetes (T2D) is an important complex disease caused by environmental and genetic factors. Its current growing rates translate into economical loses, with a reduction of the workforce and higher costs to the healthcare system. High cholesterol, obesity and a sedentary life are all lifestyle factors strongly associated with T2D, although they are not perfect indicators of disease risk. Family history of T2D is also an important factor to predict disease risk. Study of common genetic variants in the population has led to the discovery of more than 80 loci (genetic regions) associated with the disease, but they only explain 5% of the genetic risk. The aim of the present project is to strengthen the evidence of the genetic contribution to T2D by testing the association between levels of methylation in the DNA with prevalent and incident cases of T2D, the latter coming from the offspring of affected mums during the gestational period. Associations identified will be verified by the use of causative analyses. The advantage of using DNA methylation over common genetic variants is that they provide information about the cellular response to potentially stressful conditions, and also DNA methylation can archive priming signals of disease risk that could have been established early-on in development. Therefore, DNA methylation can provide more reliable data about a changing molecular environment associated with the development of T2 diabetes.
B2625 - Investigation of aetiological mechanisms of atopic dermatitis from association to causation through data integration - 24/05/2016
Atopic dermatitis (eczema), is a common chronic skin disease affecting up to 20% of the
population. I recently led an international study of 377,000 individuals which identified several
genetic variants associated with the disease. The challenge now is to understand how these
genetic variants work to cause eczema.
Along the pathway from genetic mutation to disease, there are many steps that are not well
understood. For example, though we have identified a mutation that seems to be important, in
many cases the actual gene (and protein) affected by the mutation is not known, the molecular
changes that occur within cells have not been determined, and even the cell type or tissue affected
is not well established. In this fellowship I will use a wide range of biological data from thousands of
individuals (including ALSPAC) to investigate these questions and to better understand genetic risk of eczema. In addition to studying eczema, I will also investigate the relationship between eczema and other
related conditions, such as asthma, allergy and other immune diseases.
This work will help us understand the mechanisms of eczema, which in turn will enable better
management of symptoms, and ultimately the design of more effective treatments.
B2628 - Deployment of SPHERE technology in a segment of the ASLPAC cohort - 08/02/2016
The EPSRC IRC SPHERE is a flagship project that aims to build critical mass in disruptive sensing systems in order to have a transformative impact on prediction, diagnosis and monitoring in healthcare. This proposal is part of a larger deployment which aims to recruit 100 homes in Bristol, the deployed platform will record behaviours at home, data currently non-existent and with great predictive healthcare value. SPHERE requests to recruit a subset of ALSPAC participants to be involved in this health monitoring project as explained in the project outline. Data obtained will not only be of incredible value to the SPHERE project but will also enrich the ALSPAC dataset. At the same time, epidemiological data available for this subset of participants will inform the research carried out with the data obtained by the SPHERE platform.
B2619 - Testing the feasibility and user acceptability of integrating wearable air pollution monitors into population based studies - 04/02/2016
Air pollution constitutes a threat to human health at any stage of life, and from short as well as long-term exposure. Air pollution contributes a wide range of health problems, including asthma, heart disease, and diabetes. Children may be especially susceptible to the effects of air pollution. Both outdoor and indoor air pollution likely contribute to poor developmental outcomes in children, including cognitive deficits and behavioral problems.
Most epidemiological studies carried out to date have derived air pollution measures from fixed site monitors extrapolated to individual home addresses. These models only approximate the air pollution exposure experienced by an individual and have limitations—they do not account for considerable amounts of time spent indoors or at locations other than the home. The emergence of small, wearable, and affordable air pollution monitoring devices provides unprecedented opportunity for the inclusion of personal air monitoring into large population studies. These devices are of particular interest for use with children, who 1) are highly vulnerable to the effects of air pollution exposure and 2) spend considerable amount of time in locations other than the home (daycare, etc), as well as outdoors in play and transit. However, before such devices can be rolled out on a large scale, the logistics of incorporating monitors into study protocols, as well as user acceptability, need to be tested to inform the methodology of larger studies to reduce the likelihood of poor participation or data quality.
B2618 - Development of a multilevel and mixture-model framework for modelling epigenetic changes over time - 19/04/2017
The epigenome sits on top of genes (DNA sequences) and controls whether genes are act or do not. It explains for
example why 'identical' twins differ in their behaviours and health outcomes like their blood pressure. Scientists are increasingly interested in epigenetics, the study of the epigenome, to better understand the links between behaviours (such as smoking), genes and disease. Epigenetic patterns are known to change over time, which may partly be due to the
influence of environmental factors (e.g. pollution), characteristics (such as our blood pressure) and behaviours (like smoking). In addition epigenetic patterns seem to change as we get older. Being able to understand which part of the epigenome changes over time, and how and when it changes could be important for understanding how risk factors interact with genes to cause disease and the general decline in health as we get older.
At the moment we do not have good statistical methods for doing this research because of how complex epigenetic dataare. The first issue is that there is a large number of methylation (epigenetic) sites for each person - 450,000 with one of
the common technologies used to measure these. This means that identifying a small number of these sites that are related to a given environmental factor, characteristic or health outcome is difficult. Secondly, identifying how epigenetic sites changes over time is not straightforward because the way in which these are measured which makes it difficult to know whether change over time is because of large change between a small number of sites or small changes between a large number of sites. Thirdly, epigenetic sites are clustered (group together) within regions of our genome, and thus two
sites from the same region may be more similar than two sites from different regions.
In this project, we aim to develop sophisticated statistical methods for identifying sites which show change in methylation
over time, and relating those changes to risk factors and later health outcomes. This will ensure the best possible use of
this emerging technology in investigating how the environment and lifestyle interact with genes to cause disease. We will
make sure our new methods can work in commonly used statistical packages and make them freely available to all
scientists.
B2616 - PheWAS of heart wall thickness collaboration with Ewan Birney - 08/02/2016
This project seeks to identify traits that may be related to heart development. We will use genetic variants previously associated with heart wall thickness, and test the association of these with all traits in the ALSPAC dataset to identify those that may be related.
B2623 - ALSPAC analysis for YGen consortium - 08/02/2016
Analysis of quantitative traits in ALSPAC with Y DNA SNPs
B2617 - Publication Metadata Augmentation - 02/02/2016
Development of a tool to organise and augment the metadata of publications listed by cohort studies.
B2529 - A molecular genetic study of Theory of Mind
Our capacity to negotiate the complex social world represents the remarkable evolutionary development of a wide range of mechanisms for the processing of social information. Some of our most advanced skills, such as language and empathy, mediate our interaction with our social environment. Our social skills are crucial in navigating our social milieu, in terms of independent living, vocational success and wider interpersonal relationships. Using a variety of experimental paradigms research is now beginning to unravel the brain’s mechanisms for social skills. Moreover, twin and family studies have demonstrated that a number of these mechanisms are heritable, pointing to an underlying genetic contribution; however, the specific genes involved are not known. We therefore plan to undertake a study to map the genes involved in one aspect of interpersonal interaction termed ‘theory of mind’ (or ToM). We will use a method called genomewide association. This method looks for relationships between many genetic markers and variation in ToM skills as measured using an established experimental paradigm called the ‘triangles task’. Any markers that demonstrate a significant relationship with ToM indicate that a gene important in this skill is located nearby. We will leverage additional power to map these genes using available low-coverage whole genome sequence data. We anticipate that this will be the first step in furthering our understanding of the genetic basis of social skills.