Proposal summaries

These are research proposals that have been approved by the ALSPAC exec. The titles include a B number which identifies the proposal and the date on which the proposals received ALSPAC exec approval.

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B3092 - epigenetic heritability of child psychiatric phenotypes - 04/04/2018

B number: 
B3092
Principal applicant name: 
Esther Walton | University of Bristol - IEU
Co-applicants: 
Dr Charlotte Cecil, Alexander Neumann
Title of project: 
epigenetic heritability of child psychiatric phenotypes
Proposal summary: 

Growing evidence points to a role of epigenetic alterations in the development of psychiatric disorders. DNA methylation – an epigenetic mechanism sensitive to both genetic and environmental influences – 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.

Impact of research: 
Findings could lend novel insights into the epigenetic landscape of child psychiatric symptoms.
Date proposal received: 
Thursday, 29 March, 2018
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Mental health, Microarrays, Statistical methods, Cognition - cognitive function, Epigenetics, Genetics, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc.

B3111 - Time-dependent associations between body mass/body composition physical activity diet and lung function in childhood - 08/05/2018

B number: 
B3111
Principal applicant name: 
Annabelle Bédard | Barcelona Institute for Global Health (Spain)
Co-applicants: 
Dr Judith Garcia-Aymerich, Ms Anne-Elie Carsin
Title of project: 
Time-dependent associations between body mass/body composition, physical activity, diet and lung function in childhood
Proposal summary: 

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.

Impact of research: 
Respiratory diseases are global public health concerns, and leading causes of morbidity and mortality in children and adults. This research project could thus lead to potential public health interventions such as dietary, physical activity or weight loss interventions to improve lung function, prevent lung function decline etc. As per the methodological aspect of this project, we will assess the relevance of using novel methods from the causal inference framework to investigate research questions for which standard epidemiological methods are usually used and/or where knowledge is still needed. Through dissemination of its outcomes, this research project will potentially inform study design and methodology to improve causal inference when investigating specific research questions.
Date proposal received: 
Saturday, 5 May, 2018
Keywords: 
Epidemiology, Obesity, Respiratory - asthma, Statistical methods, BMI, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Nutrition - breast feeding, diet, Physical - activity, fitness, function, Statistical methods

B3127 - Maternal caffeine intake during pregnancy An epigenome-wide association study - 06/06/2018

B number: 
B3127
Principal applicant name: 
Gemma Sharp | IEU, University of Bristol (UK)
Co-applicants: 
Miss Laura Schellhas
Title of project: 
Maternal caffeine intake during pregnancy: An epigenome-wide association study
Proposal summary: 

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?

Impact of research: 
Clarifying the association of caffeine intake during pregnancy and offspring methylation at birth in humans
Date proposal received: 
Friday, 1 June, 2018
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., epigenome-wide association study, Biological samples -e.g. blood, cell lines, saliva, etc., Birth outcomes, Development, Epigenetics, Genetic epidemiology, Genetics, Mothers - maternal age, menopause, obstetrics, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Offspring

B3555 - The EU Child Cohort Networks core variables establishing a set of findable accessible interoperable and reusable FAIR data - 10/06/2020

B number: 
B3555
Principal applicant name: 
Angela Pinot de Moira | University of Copenhagen (United Kingdom)
Co-applicants: 
Title of project: 
The EU Child Cohort Network’s core variables: establishing a set of findable, accessible, interoperable and reusable (FAIR) data
Proposal summary: 

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 Network’s 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, mother’s ethnic background, mother’s parity, mother’s 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.

Impact of research: 
Date proposal received: 
Tuesday, 9 June, 2020
Keywords: 
Epidemiology, LifeCycle focuses on cardiovascular, respiratory and mental health outcomes, Data harmonisation, Cross-cohort collaboration, data harmonisation

B3129 - Longitudinal intake of free sugars in ALSPAC children 06-06-2018 - 151010 - 06/06/2018

B number: 
B3129
Principal applicant name: 
Pauline Emmett | CCAH, University of Bristol (United Kingdom)
Co-applicants: 
Dr Caroline Taylor
Title of project: 
Longitudinal intake of free sugars in ALSPAC children (06-06-2018 - 15:10:10)
Proposal summary: 

The current recommendation is that we should limit our intake of free sugars to provide less than 10% of daily energy intake. This study will investigate free sugars intake in ALSPAC children at ages 18 months, 3.5, 5, 7, 10 & 13 years and determine whether those consuming less than 10% energy from free sugars have a more beneficial nutrient and food group intake than those that consuming more free sugars. Then to investigate if there are differences in obesity levels in relation to free sugars intakes.

Impact of research: 
This is extremely topical and will contribute to an current EFSA review
Date proposal received: 
Wednesday, 6 June, 2018
Keywords: 
Nutrition, Diabetes, Statistical methods, Nutrition - breast feeding, diet

B3113 - NIHR Bristol BRC - Exploring Mental Health and Cognition using Mendelian randomisation - 24/05/2018

B number: 
B3113
Principal applicant name: 
Robyn Wootton | University of Bristol (United Kingdom)
Co-applicants: 
Professor Marcus Munafò, Professor Ian Penton-Voak, Sarah Peters, Steph Suddell, Caroline Skirrow
Title of project: 
NIHR Bristol BRC - Exploring Mental Health and Cognition using Mendelian randomisation
Proposal summary: 

Treatment for mental illness often focuses on changing cognitive patterns (for example, cognitive behavioural therapy). There is much evidence to suggest that cognition is different in those with mental illness but whether change in cognition is a causal risk factor has not yet been established. Classic observational studies of cognitive patterns and mental illness do not get around the problems of reverse causation and residual confounding. That is to say that the change in cognition might instead emerge as a result of the mental illness, or both might be the result of other unmeasured factors.

One way to get around this is using Mendelian randomisation. Here we take genetic variants associated with the trait of interest: cognition and use them to naturally randomise individuals to levels of the exposure. Therefore, analogous to a randomised control trial, we can make conclusions about whether or not the relationship is causal. In this study, we will be looking at the cognitive traits of emotion recognition, working memory, cognitive styles and impulsivity. This research could inform the development of cognitive training tasks as interventions for mental illness.

Impact of research: 
This research could inform the development of cognitive training tasks as interventions for mental illness.
Date proposal received: 
Monday, 14 May, 2018
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Mental health, GWAS, Genetic epidemiology

B3559 - Does the Timing of Menarche Affect the Development of Eating Disordered Behaviour - 16/06/2020

B number: 
B3559
Principal applicant name: 
Helen Bould | University of Bristol (UK)
Co-applicants: 
Ms Sneha Nicholson, Dr Carol Joinson, Dr Jon Heron, Dr Naomi Warne
Title of project: 
Does the Timing of Menarche Affect the Development of Eating Disordered Behaviour
Proposal summary: 

Disordered eating behaviour remains a widespread and persistent problem among adolescent girls. The various changes associated with puberty have been implicated in the development of these behaviours (Senia 2018). The link between timing of menarche, as a proxy for pubertal development, and psychological distress more generally has been previously established (Mendle 2007, Joinson 2013). However, many questions remain about the relationship between eating disordered behaviours and pubertal development during adolescence. Previous studies have not adequately assessed the age of menarche due to recall bias. This study examines if early menarche could be relevant in the development of eating disordered behaviour using prospective measures from ALSPAC. Furthermore, this study interrogates if the link between early menarche and disordered eating behaviour holds through late adolescence, when early developers’ peers have caught up. In other words, does the association between early pubertal development and disordered eating result from the discord between a child and their peers or does it have more to do with the actual development itself?

Using questionnaire data collected through ALSPAC, this study assesses various markers relating to puberty as well as identifying timing of menarche and any disordered eating behaviour.

Impact of research: 
This project will lead to a greater understanding of the development of eating disorders in young adolescent girls. As eating disorders have the highest fatality of any mental health disorder, we believe this research is pertinent and salient.
Date proposal received: 
Monday, 15 June, 2020
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Eating disorders - anorexia, bulimia, Statistical methods, eating disorders; puberty

B3082 - Adaptations to Inequality and the Perpetuation of Disadvantages An Evolutionary Developmental Approach - 16/03/2018

B number: 
B3082
Principal applicant name: 
Callie Burt | University of Washington, Department of Sociology (King)
Co-applicants: 
Esther Walton
Title of project: 
Adaptations to Inequality and the Perpetuation of Disadvantages: An Evolutionary Developmental Approach
Proposal summary: 

Socioeconomic disparities in health across the life-course are well-documented, long-standing, and consequential. Research suggests that a significant proportion of the social gradient in health is due to SES differences in health-risk behaviors. Scholarship investigating the underlying mechanisms whereby lower SES increases health-risk behavior points to the mediating role of risk-increasing (or ‘riskogenic’) psychosocial schemas. Specifically, evidence suggests that social context and experiences in development, which are patterned by one’s social position, calibrate psychosocial orientations, including impulsivity or self-control, sensation seeking, and hostile views of relationships, which influence health-risk behaviors and health outcomes. Although the past decade has seen a spate of published GE-health research, few studies have focused on the role of G-E interplay in shaping psychosocial schemas as mechanisms through which SES adversity shapes health disparities. This project will investigate the effects of SES adversity on changes in psychosocial schemas, conceived as socially-calibrated and genetically-influenced endophenotypes which link SES adversity to increased health risk-behaviors. Additionally, although we know that social experiences “get under the skin” to have enduring effects on health outcomes, we lack knowledge on the biological pathways through which such effects persist. Thus, second, and more innovatively, we will engage with the nascent field of social epigenetics to examine DNA methylation (DNAm) as a biological mechanism through which SES-adversity calibrates psychosocial schemas. In this project, we will investigate the DNAm patterns underlying psychosocial adaptations to SES adversity that increase health-risk behaviors, building on work that identifies DNAm as an important molecular underpinning of experience-dependent changes in cognitions, decision-making, and behavior.

Impact of research: 
The rationale for this research is the need to better understand what, when, and how social adversity increases ‘riskogenic’ psychosocial schemas influencing health-risk behaviors in the context of G-E interplay. In addition to enhancing scientific knowledge, findings may identify biomarkers of exposure or response to SES adversity to enhance risk assessments or targeted interventions to improve health. Findings will enhance knowledge on G-E interplay and can improve theorizing about the role of G-E interplay at different developmental periods, especially questions about adolescence as a second sensitive period for (epigenetic) change. e the groundwork for an R01 application longitudinally tracking the effects of SES and racial-ethnic disadvantage in an ethnic-racial minority sample.
Date proposal received: 
Wednesday, 14 March, 2018
Keywords: 
Sociogenomics, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Statistical methods, Childhood - childcare, childhood adversity, Cognition - cognitive function, Statistical methods, Development, Environment - enviromental exposure, pollution, Epigenetics, Genetics, Parenting, Psychology - personality, Sex differences, Social science

B3080 - Micronutrients in Mood Disorders - 24/05/2018

B number: 
B3080
Principal applicant name: 
Richard Martin | University of Bristol
Co-applicants: 
Dr Rebecca Carnegie, Dr Jonathan Evans, Dr Giles Greene
Title of project: 
Micronutrients in Mood Disorders
Proposal summary: 

Depression and anxiety disorders are becoming increasingly common. There is some research suggesting that our diet, (what we eat) might make us more likely to become depressed and anxious. This type of research is called 'Nutritional Psychiatry' research. Many research studies have shown that people with depression and anxiety disorders do not have enough of certain 'micronutrients' either in their food, or in their blood. One example is magnesium, which is contained within green leafy vegetables, and is lacking in processed foods. It is possible that our society is not consuming enough magnesium, which could be increasing the number of people with depression and anxiety. However, it is difficult to say whether a low magnesium in depressed people was the cause of their depression. It may be because people with depression eat less healthily, or because people with other problems (alcohol use or long term illnesses) are more likely to get depressed.

This research will aim to get around these difficulties by using our DNA or genetic code to look at whether genetic changes that cause us to have lower magnesium, are also linked to us having depression.

Impact of research: 
A causative association between magnesium and depression/ anxiety would have potential public health implications, as well as provide evidence for the development of non-pharmacological interventions
Date proposal received: 
Monday, 14 May, 2018
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Nutrition - breast feeding, diet

B3132 - Genetic and epigenetic variation in the newborn brain in relation to neurodevelopmental outcomes in childhood - 14/06/2018

B number: 
B3132
Principal applicant name: 
Santi Rodriguez | Integrative Epidemiology Unit, Bristol Medical School (UK)
Co-applicants: 
Dr Karen Luyt, Dr David Odd, Silvia Pregnolato, Emily Jamieson
Title of project: 
Genetic and epigenetic variation in the newborn brain in relation to neurodevelopmental outcomes in childhood
Proposal summary: 

This study aims at exploring the possible influence of genetic and epigenetic variants in the newborn brain on neurologic and mental traits and outcomes. This project aims to combine research from the Bristol Neonatal Gene Study and from ALSPAC. This will represent an interesting opportunity to study in detail the effect of specific genetic and epigenetic variants both in newborns and in childhood. We specifically aim to study the main candidate pathways involved in perinatal brain injuries (glutamate signalling and inflammation) and long-term motor, cognitive and behavioural outcomes. We have produced interesting preliminary findings within the Bristol Neonatal Gene Study, which support the involvement of candidate genetic variants in the glutamate signalling and inflammation pathways. The ALSPAC cohort provides a unique opportunity to validate and add to these findings in a large sample with genetic, epigenetic and phenotypic data collected longitudinally from birth to childhood. With the availability of maternal data, it also offers the opportunity to expand the analysis to maternal-neonatal gene-gene and gene-environment interactions. We have the appropriate expertise in genetic and epigenetic research required for this project. In addition, we are coupling this approach with in vivo work on animal models of newborn brain injuries, exploring the (dys)regulation of key genes involved in glutamate transport and inflammation during perinatal insults.

Impact of research: 
Genetic and epigenetic biomarkers may provide invaluable tools to predict the risk of brain injuries at birth and potentially long before the onset of labour. They may also provide a tool to identify babies who are more likely to respond to treatment, both in the short- and long-term. Both glutamate signalling and inflammation are ideal candidates for a pharmacogenomics approach for existing and novel drugs targeting these pathways. The study may also generate hypotheses about manipulating DNA methylation to achieve neuroprotection. We expect that through a better understanding of the molecular mechanisms of injury it will be possible to improve early identification, diagnosis and treatment, ultimately providing a better prognosis for these newborns. This is likely to help mothers, families and clinicians making more informed and personalised decisions when planning pregnancy, childbirth and child follow-up, contributing to the push of neonatal care towards prediction and prevention.
Date proposal received: 
Tuesday, 12 June, 2018
Keywords: 
Genetics, Neurodevelopmental outcomes in childhood, Gene mapping, GWAS, Statistical methods, Cognition - cognitive function, Epigenetics, Genetic epidemiology, Genetics, Genome wide association study, Mendelian randomisation, Neurology, Statistical methods

B3560 - Relationship between serum sclerostin and cardiovascular disease - 19/06/2020

B number: 
B3560
Principal applicant name: 
Jon Tobias | University of Bristol (United Kingdom)
Co-applicants: 
Monika Frysz, George Davey Smith
Title of project: 
Relationship between serum sclerostin and cardiovascular disease
Proposal summary: 

Anti-sclerostin antibody treatment has recently been licensed as a monthly injection for treating osteoporosis (Evenity), a condition in which bones become fragile and more susceptible to fracture. Though effective at treating osteoporosis, concerns have been raised that Evenity increases the risk of developing cardiovascular disease (CVD) and stroke, either via a direct effect on arteries, or by modifying associated risk factors. This project aims to examine this question, by studying whether circulating levels of sclerostin are related to CVD end-points, related phenotypes and risk factors. This will be achieved by examining these relationships in a range of independent cohorts, including ALSPAC. Furthermore, we aim to triangulate our findings by Mendelian Randomisation, using a genetic instrument for circulating sclerostin which we recently published and are currently refining.

Impact of research: 
Understanding the relationship between sclerostin and CVD risk is important in identifying patient groups in whom anti-sclerostin treatment should be used with caution. This question is particularly important as patients requiring osteoporosis treatment often have co-morbidities such as CVD due to advanced age.
Date proposal received: 
Wednesday, 17 June, 2020
Keywords: 
Epidemiology, Bone disorders - arthritis, osteoporosis, Statistical methods, Cardiovascular

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