Proposal summaries
B3093 - Traits phenotypes and prognosis of childhood asthma - 29/03/2018
The proposal is to continue the collaborative work we have been doing with this Swiss group over the past few years. Ben Spycher was a Marie Curie Fellow who worked with ALSPAC data previously. Prof Kuehni leads eth Leicester Asthma Cohorts and has established the Swiss Paediatric Airway Cohort (SPAC). OUr joint objective is to discover influences that determine the onset and progression of asthma in children, how asthma varies between individuals in type and severity and whether we can predict the outcome of asthma using individuals' information. The data in eth Leicester adn Swiss cohorts is complementary to data held in ALSPAC and we have had joint publications where ALSPAC is able to replicate findings in the other cohorts run by the Swiss group.
B3104 - Impact of Breastfeeding on Cardiovascular and Metabolic Outcomes in Women with a History of Hypertensive Disorders of Pregnancy - 26/04/2018
Women who experience a hypertensive disorder of pregnancy are at greater risk for diseases of the heart and blood vessels. Breastfeeding may reduce this risk in women in general and particularly in those who have had a hypertensive disorder of pregnancy. This proposed study will examine if the duration/amount of breastfeeding has a beneficial effect on markers of heart health in later life in women who did and did not develop a hypertensive disorder of pregnancy.
b1234 - TEST PROJECT PLEASE IGNORE
B3078 - Single SNP Replication of rs71564871 - 08/03/2018
A single mutation within the genome (called rs71564871 near a gene called BEND6) has been previously linked to fat distribution in the body, specifically the proportion of fat stored across the waist compared to the hips, in women of the ORCADES study and UK Biobank. Within this study, we want to assess whether this single mutation is similarly related to the same pattern of fat deposition in the Avon Longitudinal Study of Parents and Children.
B3088 - Metabolic profile of prediabetes using genetic susceptibility and repeat metabolomics to inform early detection - 29/03/2018
Type 2 diabetes develops for many years before it is diagnosed. Using data from ALSPAC offspring, we aim in this study to harness genetic susceptibility to adult type 2 diabetes and detailed metabolic profiling to better understand the early stages of diabetes development that are detectable in blood. This will involve describing associations of a genetic risk score comprised of hundreds of genetic variants for adult type 2 diabetes with hundreds of metabolic traits from targeted metabolomics at four key stages of early life â childhood (age 8y), adolescence (age 15y), early adulthood (age 18y), and formal adulthood (age 25y) â to view subtle changes in metabolism over time which precede the onset of clinical diabetes. Recognizing the early signs of diabetes is vital for early detection and for preventing downstream cardiovascular diseases and cancers.
B3122 - Genome-wide analysis of selection and methylation - 06/06/2018
Human evolution has been associated with drastic changes in environment and lifestyle over time, with each of these changes resulting in selective pressures (Voight et al., 2006). Natural selection is the differential reproductive success of genetically distinct individuals or genotypes within a population. Strongly deleterious mutations will rapidly be eliminated from populations, whereas strongly positive mutations will quickly rise to fixation leading to changes in allele frequency over time. This process leaves signatures on the genome which can then be detected (Sabeti et al., 2006).
Epigenetics refers to heritable changes outside of the DNA sequence itself and provides a potential mechanism by which environmental and lifestyle exposures can impact gene expression over the course of a lifetime. Epigenetic mechanisms can include DNA methylation and histone modifications. DNA methylation is the most widely studied epigenetic change and involves the addition of methyl groups to nucleotide bases (Vocht et al., 2018).
Natural selection is a long term, multigenerational response to environmental factors that can influence the role of genes in human traits (Bamshed and Wooding, 2003) whereas epigenetic inheritance allows stable changes in DNA methylation to be passed from one generation to the next (Feil and Fraga, 2012). Both selection and methylation act in response to environmental exposures but over different timescales. This project will aim to unravel the interplay between selection and methylation to assess whether DNA methylation offers a mechanism to respond to exposures in the short term which may eventually lead to changes in allele frequency.
References
1. Bamshad, M. & Wooding, S.P. Signatures of natural selection in the human genome. Nature Reviews Genetics 4, 99-111A (2003).
2. de Vocht, F. et al. DNA methylation from birth to late adolescence and development of multiple-risk behaviours. Journal of Affective Disorders227, 588-594 (2018).
3. Feil, R. & Fraga, M.F. Epigenetics and the environment: emerging patterns and implications. Nature Reviews Genetics 13, 97-109 (2012).
4. Sabeti, P.C. et al. Positive natural selection in the human lineage. Science 312, 1614-1620 (2006).
5. Stearns, S.C., Byars, S.G., Govindaraju, D.R. & Ewbank, D. Measuring selection in contemporary human populations (vol 11, pg 611, 2010). Nature Reviews Genetics 12, 1 (2011).
6. Voight, B.F., Kudaravalli, S., Wen, X.Q. & Pritchard, J.K. A map of recent positive selection in the human genome (vol 4, pg 154, 2006). Plos Biology 4, 659-659 (2006).
B3554 - Asthma and COVID-19 - 08/06/2020
Asthma affects the lives of 5.4 million people across the UK. COVID-19 attacks the lungs and can trigger asthma symptoms like wheezing, chest tightness and difficulty breathing, which is very distressing for patients and can cause feelings of anxiety. We want to know if participants with asthma at 23-24 years were more likely to report respiratory symptoms, mental health issues, shielding during the COVID-19 lock-down.
We'll also be interested to explore differences between people with asthma and COVID-19 related symptoms and people with asthma and non-related COVID-19 symptoms, e.g. economical status, asthma severity....
B3087 - INTIMATE PARTNER VIOLENCE PERPETRATORS THE ORIGINS - 29/03/2018
Intimate Partner Violence (IPV) is defined as any violent behavior within an intimate relationship or any other controlling behavior that is conducted by a current or former partner. It is the most common form of violence in women which constitutes a major public health problem worldwide. The current explanatory theories of IPV perpetration can be summarized as feminist/sociocultural, social learning theory-based intergenerational transmission and psychological/psychosocial. According to the feminist/sociocultural theory, domestic violence is a consequence of âpatriarchyâ. From this view, violence is used as a form of power and control of women by men. The intergenerational transmission theory asserts that domestic violence is based on the exposure to, or observation of, violence in the family of origin. Psychological theories propose that there are psychological, psychiatric, behavioural and neurological risk factors for domestic violence perpetration. In the study of IPV perpetration, it is important to consider the variables addressed by such theories as a whole and from a developmental perspective and there is no study that simultaneously considers all the variables of these explanatory theories. The general aim of our study is to identify those etiological mechanisms linking risk factors for IPV perpetration across development. This study will be the first one that sheds light on which the origins of IPV perpetration are by knowing how IPV perpetration develops. Implications in terms of prevention and treatment will be of a great relevance for public health.
B3106 - Does the effect of eating patterns at night on childhood weight status differ between the UK and China - 08/05/2018
It has been suggested that night eating is related to increased fat storage and therefore increased body weight. There is also no clear definition of what is meant by night eating. The potential effects of night eating on obesity have primarily been examined in adults to date and any studies in childhood have been cross-sectional, with none in the UK. Based on information collected in diet diaries at the age of 7, this project will aim to examine different definitions of night eating and examine the effects on childhood weight status and it's change over time. This will be carried in two different cohort studies - one based in the UK and one based in China.
B3124 - Using the power of DPUK cohorts to explore childhood adversity and adult behavioural psychological physical cognitive and b - 06/06/2018
Childhood adversity could cover many things including extreme difficulties and adverse experiences during childhood such as sexual, physical and emotional abuse, deprivation, and family dysfunction. Experiencing adversity during childhood may have a dramatic effect on a child's life. It has been linked to a number of poor outcomes in adulthood such as worse health outcomes, poor mental health, reduced life satisfaction and dementia. One in three adults diagnosed with mental health conditions are reported to have experienced childhood adversities therefore, there is the potential for life-long associations between childhood adversity and health, which need to be evaluated and accounted for. The proposed project will examine childhood adversity in three different UK populations and in a birth cohort and associations with a number of different outcomes including physica and mental health, poor lifestyle choice such as unhealthy diet, smoking and binge drinking and antisocial behaviours.
B3081 - Helicobacter pylori - Association with cardiovascular disease and cancer - 13/03/2018
Helicobacter pylori (H. pylori) is a gram-negative bacterium that colonises on the gastric epithelium, and there is clear evidence for its role in causing gastrointestinal diseases. Studies in the United Kingdom have demonstrated the prevalence of H. pylori infection status ranging from 26-66% of the population. There is increasing evidence of the role H. pylori in the development of other diseases, including cardiovascular disease and cancer. Given the relatively high prevalence of infection, this is potentially an important disease risk factor that merits causal investigation. Studies have suggested that infection with H. pylori may affect lipid metabolism, especially with the cardiovascular risk factors: HDL-cholesterol, triglyceride and apolipoproteins. By this mechanism, this could increase the risk of developing atherosclerosis and coronary artery disease. Additionally, studies have postulated that H. pylori could be involved in the development of atherosclerosis by causing vascular inflammation and endothelial dysfunction. H. pylori has also been shown to be involved in gastric carcinogenesis. Through the disruption of epithelial cell functions by H. pylori cytotoxin-associated antigen A (CagA), this oncogenic factor activates oncogenic pathways in these cells and induces epigenetic modifications which play a significant role in initiating carcinogenesis.
B3094 - A novel genetic instrument for lifetime smoking indicates that smoking is a causal risk factor for depression and schizophrenia - 04/04/2018
Smoking is highly co-morbid with several psychiatric conditions, but understanding the causal nature of this relationship is complicated by well-described issues of confounding and reverse causality. Mendelian randomisation uses genetic variants associated with an exposure (e.g., smoking) to examine causal pathways between the exposure and outcomes. Previous genetic instruments for smoking have only captured discrete aspects (e.g., initiation, heaviness of smoking), limiting power and requiring individual level data on smoking status for analyses of heaviness of smoking. To overcome these issues, we are developing a novel genetic instrument for comprehensive smoking exposure, which takes into account duration of smoking, heaviness of smoking, time since cessation, and a simulated half-life constant to capture the exponentially decreasing effect of smoking on health over time. Our instrument includes both smokers and non-smokers, removing the need to stratify on smoking status.
We have begun work on this instrument by conducting a genome-wide association study (GWAS) of our comprehensive smoking measure in the UK Biobank (N=463,003) and identified 124 independent SNPs associated at the genome-wide level of significance. Our two-sample Mendelian randomisation validation analysis confirmed that smoking causes lung cancer and coronary heart disease. To further establish the validity of the instrument we need to check that it predicts smoking in an independent sample. Here we hope to use ALSPAC, checking whether a polygenic risk score for lifetime smoking exposure predicts actual smoking behaviour. Secondly, we need to check that the instrument is not spuriously associated with any traits other than smoking. We can do this by checking for associations with other outcomes in ALSPAC.
If the instrument predicts smoking in ALSPAC and is not associated with other unexpected traits, we hope to go onto use our novel genetic instrument to explore bi-directional effects between smoking and mental health, focusing on schizophrenia and major depressive disorder.
B3108 - Longitudinal patterns and predictors of multiple cancer-risk behaviours among UK adolescents - 08/05/2018
Using two British cohort studies, the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Millennium Cohort Study (MCS), this fellowship will explore the longitudinal patterns and predictors of multiple cancer-risk behaviours (MCRB). MCRB are modifiable behaviours including tobacco smoking, alcohol consumption, physical inactivity, overweight and obesity, unhealthy diet and risky sexual behaviour that are associated with cancer incidence and mortality. Rather than focusing on specific cancers this research will cover a wide range of cancers that are associated with these behaviours.
B3125 - Trajectories of Weight and Obesity From Birth to Adulthood According to Polygenic Susceptibility - 06/06/2018
We want to quantify what the impact of genetics across the whole genome has on weight and risk of severe obesity from birth to middle adulthood.
B3092 - epigenetic heritability of child psychiatric phenotypes - 04/04/2018
Growing evidence points to a role of epigenetic alterations in the development of psychiatric disorders. DNA methylation â an epigenetic mechanism sensitive to both genetic and environmental influences â has been linked to a wide range of emotional and behavioral problems in childhood, including anxiety, depression, conduct problems and attention-deficit hyperactivity. However, findings to date have been primarily drawn from candidate gene studies, or EWAS studies investigating single sites across the genome. As a result, how much of the variance in psychiatric phenotypes is collectively explained by the methylome as a whole is currently unknown.
B3111 - Time-dependent associations between body mass/body composition physical activity diet and lung function in childhood - 08/05/2018
The large increase in the prevalence of respiratory diseases over the last decades, in the West more particularly, cannot be explained by genetics only. It has been hypothesized that these increases are a consequence of changing environmental and/or lifestyle factors. Given the multifactorial aspect of these diseases, it is thus important to take into account the interrelations between these factors and respiratory health. The interrelations between body mass/body composition, physical activity, diet and lung function in childhood and adulthood have been incompletely addressed, likely because their time-dependent and bidirectional nature represent a methodologically challenging research question. Marginal structural models (MSMs) allow estimation of causal effects in observational studies by addressing time-dependent confounding (Robins JM et al. Epidemiology 2000). This approach has still limited application in respiratory epidemiology. We aim to investigate the joint and independent causal effects of body mass/body composition, physical activity and diet on lung function during childhood and early adulthood using MSMs in children from the ALSPAC study.
B3127 - Maternal caffeine intake during pregnancy An epigenome-wide association study - 06/06/2018
Rationale: Animal studies have provided some evidence that maternal caffeine consumption can influence offspring DNA methylation (PMIDs: 22970234, 24475304, 25354728, 25868845, 25868845), but what about humans?
B3555 - The EU Child Cohort Networks core variables establishing a set of findable accessible interoperable and reusable FAIR data - 10/06/2020
LifeCycle is a cross-cohort collaboration which brings together data from pregnancy and child cohorts from across Europe and also Australia to facilitate studies on the influence of early-life exposures on cardio-metabolic, respiratory and mental health outcomes. The end product of this collaboration is a sustainable data resource known as the EU Child Cohort Network.
In the proposed paper we provide a detailed description of the EU Child Cohort Networkâs core variables; a set of basic variables, derivable by the majority of participating cohorts and frequently needed as covariates in life-course research. We firstly describe the process adopted to establish a list of core variables and the protocol developed to harmonise these core data, thus making them interoperable. This protocol also defines the harmonisation process adopted generally within LifeCycle. Secondly, we describe the catalogue developed to ensure that all EU Child Cohort Network data are both findable and reusable. Finally, we describe the core data themselves, including the proportion of variables harmonised by each cohort and the number of children with harmonised data.
We would also like to provide some summary statistics (N and % for categorical variables, and N, mean, standard deviation for continuous variables) on some key variables (namely, sex, maternal education at baseline, motherâs ethnic background, motherâs parity, motherâs smoking in pregnancy, size for gestational age, whether the index child was ever breastfed, age of the mother at birth, birth weight and gestational age). These variables have already been harmonised as part of the LifeCycle project. To obtain the requested summary statistics, we have prepared some R code for individual cohorts to run on their harmonised datasets.
The paper is already written and we hope to submit it to the Journal of Epidemiology in the summer.