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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B3394 - Onset of menarche and depressive symptoms from adolescence to adulthood - 11/10/2019

B number: 
B3394
Principal applicant name: 
Abigail Fraser | MRC Integrative Epidemiology Unit (UK)
Co-applicants: 
Miss Claire Prince, Dr Carol Joinson, Dr Jon Heron
Title of project: 
Onset of menarche and depressive symptoms from adolescence to adulthood
Proposal summary: 

During puberty, adolescent girls show a dramatic increase in depressive symptoms, and by mid-teens girls are twice as likely to have depressive symptoms compared to boys. It has been suggested that this increase is controlled by the timing of puberty and, in particular, the onset of menarche; girls who experience puberty earlier may be more likely to experience more depressive symptoms compared to girls who experience it later. Although this link is seen in girls in their mid-teens, it is not clear if this association continues into later teenage years and later on, into adulthood. It is possible that girls who experience late menarche have a decreased risk of depressive symptoms into adulthood and therefore this late menarche may serve as a protective effect. However, girls who experience late menarche may show a 'catch-up' effect and eventually have similar levels of depressive symptoms compared to girls who have an earlier onset of menarche. There is a lack of research investigating the onset of menarche on depressive symptoms beyond teenage years, into adulthood. It is therefore important to investigate whether onset of menarche and the timing puberty explains some of the depressive symptoms seen in adult women. This would also aid in the understanding of the mechanism behind the link between puberty and depression including psychosocial and, hormone and neurological theories.

Impact of research: 
The findings from this research will building on the evidence and understanding of how pubertal timing affects depression in adolescent girls. This could allow the identification of more at-risk groups of depressive symptoms and therefore inform the development of programmes, particularly in schools, to target these at-risk groups and reduce the risk of depression in young girls.
Date proposal received: 
Friday, 11 October, 2019
Date proposal approved: 
Friday, 11 October, 2019
Keywords: 
Epidemiology, Mental health, Statistical methods, Puberty

B3392 - The interplay of maternal and fetal factors in mechanisms of fetal growth birth timing and related adverse outcomes - 18/10/2019

B number: 
B3392
Principal applicant name: 
Rachel Freathy | University of Exeter (UK)
Co-applicants: 
Dr Robin Beaumont
Title of project: 
The interplay of maternal and fetal factors in mechanisms of fetal growth, birth timing and related adverse outcomes
Proposal summary: 

Maternal obesity in pregnancy is increasing worldwide and is associated with adverse pregnancy outcomes for both mother and baby. However, the risks are heterogeneous, with some obese pregnancies leading to preterm birth and reduced fetal growth, and others complicated by high birth weight. Some women who are obese may alternatively have uncomplicated, healthy pregnancies. There is an urgent need to identify those women and babies most at risk of specific outcomes and thus better target healthcare management and interventions. To do this, we first need to better understand the mechanisms underlying how maternal risk factors combine with the fetal response to influence risk. To date, our work using ALSPAC (project B2388) and other studies has identified genetic variation in both mother and baby that is associated with birth weight. We have used these genetic variants to investigate causal associations between maternal modifiable risk factors (e.g. blood pressure, glucose levels) and birth weight of the baby. However, many questions remain unanswered, including whether maternal blood pressure or glucose also influence the timing of birth, the weight of the placenta and the levels of insulin (a key growth factor) produced by the fetus. In addition, the role of the fetal response to the maternal environment is not well defined, and it is not known whether this fetal response influences maternal metabolism. This project will transform our understanding of the mechanisms connecting maternal BMI, glucose and blood pressure, fetal and placental growth, fetal insulin and the timing of birth, using large-scale genetic datasets. By clarifying these mechanistic relationships, the work will pave the way for the identification and targeted management of high-risk obese pregnancies.

Impact of research: 
High impact publications improving understanding of mechanisms of fetal growth in human pregnancy, leading to the basis for (i) intervention on modifiable risk factors to reduce adverse pregnancy outcomes, and (ii) stratification of women according to risk, for more appropriate management and treatment in pregnancy.
Date proposal received: 
Tuesday, 8 October, 2019
Date proposal approved: 
Thursday, 10 October, 2019
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Diabetes, Statistical methods, Growth

B3393 - G1 Addition of lung function to G1 clinic 30 - 18/10/2019

B number: 
B3393
Principal applicant name: 
James Dodd | Southmead Hospital, University of Bristol, MRC IEU (United Kingdom)
Co-applicants: 
Raquel Granell, Seif Shaheen, Sailesh Kotecha, Nic Timpson, George Davey Smith
Title of project: 
G1 Addition of lung function to G1 clinic @30
Proposal summary: 

Obstructive lung diseases are a common cause of disease and disability throughout life.

According to WHO estimates, 65 million people have moderate to severe chronic obstructive pulmonary disease (COPD). More than 3 million people died of COPD in 2005, which corresponds to 5% of all deaths globally.

In 2002 that COPD was the fifth leading cause of death. Total deaths from COPD are projected to increase by more than 30% in the next 10 years unless urgent action is taken to reduce the underlying risk factors, especially tobacco use. Estimates show that COPD becomes in 2030 the third leading cause of death worldwide.

The aim of this research project is to understand factors during childhood that influence the development of peak lung function in early adulthood. We will measure the lung function of around 5,000 young adults who have been intensively studied since before birth as part of a longitudinal birth cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC). Lung function increases with physical growth through childhood, reaching a peak in early adulthood. Following this peak, there is a gradual loss of lung function throughout the rest of life. Therefore, failure to attain maximal lung function during childhood could lead to early onset of respiratory illnesses in adult life. This study will build on previous measurements of lung function in the ALSPAC cohort linked to a wealth of data on early lifestyle and environment to try to find out what factors are associated with slow acquisition of lung function during childhood and low peak lung function in early adulthood.

Impact of research: 
Who will benefit? Academic: The principal beneficiaries of this research will be academics who are working in the field of lung development during childhood. There will be opportunities for cross-disciplinary collaborations through the EC COST Action: Developmental Origins of Chronic Lung Disease and we are working on collaborations across the life course, for example, with the ECRHS study to investigate comparative influence of genetic and lifestyle factors on lung function. ALSPAC is a member of several large-scale consortia working on genetic underpinnings of lung function, COPD and asthma, which will benefit from the additional data generated by this research. Data will be shared more widely through the existing ALSPAC data management and dissemination policy. Patients and Public: Increased recognition and understanding of the childhood origins of obstructive lung diseases will benefit patients, their representative organisation, practitioners and the general public understanding of health and disease. Policy Makers: Identification of factors in childhood that can influence life course lung development and resulting adult lung function has policy implications for early recognition of high risk populations, healthcare advice and public health policy to control exposure to adverse factors where possible. Industry: Increased emphasis on early life factors with demonstrable long term influences on lung function potentially opens pathways to modification of current treatment strategies and new therapeutic targets. Linkage to a large repository of biological data has the potential to discover biomarkers of disease phenotypes that could be amenable to personalised approaches to treatment. How will they benefit? Scientific advancement: This proposal will generate new knowledge through understanding some of the important early life influences on the development of lung function. It will also provide the scientific community with data that can be applied to other research questions concerning the genetic and environmental influences on lung function acquisition. This will stimulate further research to identify pathophysiological mechanisms underpinning these associations, contributing to UK scientific capital. Increased understanding and awareness: Patients and Practitioners will benefit from recognition that early life factors are important contributors to the development of obstructive lung diseases in adults. Clinicians will have evidence-based knowledge on which to advise patients about risk factors and interventions, including lifestyle changes. Public understanding about early life risk factors for COPD may shift their attitudes to research in this area, benefiting charitable organisations by increasing available research funding. This work is important to in order to identify interventions to reduce the risk of poor lung health, COPD and associated mortality.
Date proposal received: 
Thursday, 10 October, 2019
Date proposal approved: 
Thursday, 10 October, 2019
Keywords: 
Epidemiology, Respiratory - asthma, COPD, lung health and development, Ageing, Development, COPD, Asthma, lung development, lung health

B3389 - An investigation of the environmental effect of parental genotypes on offspring behavioural problems - 08/10/2019

B number: 
B3389
Principal applicant name: 
Hannah Sallis | School of Psychological Science, University of Bristol (United Kingdom)
Co-applicants: 
Prof Marcus Munafo
Title of project: 
An investigation of the environmental effect of parental genotypes on offspring behavioural problems
Proposal summary: 

Parental depression is related to internalising as well as externalizing problems, including attention problems, in childhood. These behaviours are heritable, so this association may be due to the transmission of genes from parents to children. However, as parents also provide part of the environment to their children, it is difficult to disentangle the role of nature versus nature in the intergenerational transmission of these behaviours.

One way to investigate the extent to which parental environmental influences exert an effect on offspring behaviour is by looking at the impact of the parental genome. M-GCTA (maternal-effects genome-wide complex trait analysis) estimates the extent to which SNPs in the maternal or paternal genome contribute to variance in offspring behaviour.

Additionally, recent investigations have made use of polygenic scores constructed using non-transmitted DNA from parents to offspring to report associations between parenting and offspring behaviours traits. These studies show that the part of the parental genotype that children do not inherit nonetheless predicts childhood behavior, indicating an effect of genetic nurture. The methodology has not been applied to investigate parental influences on offspring behavioural problems thus far. The aim of this project is to use transmitted and non-transmitted polygenic scores to clarify parental genetic and genetically-mediated environmental influences on offspring internalizing, externalizing and attentional problems. Furthermore, we aim to investigate whether the genetic nurture effect on offspring internalizing, externalizing and attention problems is exacerbated in children of depressed parents.

Impact of research: 
Date proposal received: 
Monday, 7 October, 2019
Date proposal approved: 
Tuesday, 8 October, 2019
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Mental health, Statistical methods, Childhood - childcare, childhood adversity, Genetic epidemiology, Mothers - maternal age, menopause, obstetrics, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Offspring

B3391 - When Sleeping Like a Baby Isnt So Dreamy - 08/10/2019

B number: 
B3391
Principal applicant name: 
Lawrence Katz | Harvard University (USA)
Co-applicants: 
Kirsten Clinton, Natalia Emanuel
Title of project: 
When Sleeping Like a Baby Isn't So Dreamy
Proposal summary: 

Much of the "Motherhood Penalty" that tips women’s wage trajectories lower than men’s trajectories has been attributed to time out of the labor market – either for maternity leave or because of subsequent scaling back of hours. We explore whether lost/interrupted sleep accounts for some of this penalty, either as a proximate cause for scaling back on hours or because of lower productivity upon returning to work.

A baby’s sleep may have lasting consequences on her parents’ earnings if (a) sleep loss continues for several years, (b) sleep loss (of either short of long duration) leads to scaling back of labor force participation, or (c) sleep loss (of either short or long duration) produces worse work and bosses put outsized weight on post-leave work.

The project contains several testable hypotheses:
- Lost/interrupted sleep can account for some of the motherhood penalty
- Lost/interrupted sleep leads to decreased labor force participation
- Lost/interrupted sleep should vary inversely with duration of parental leave since baby sleep is often worse immediately after birth
- If lost/interrupted sleep is particularly important for creative/executive tasks, one may see greater portions of the motherhood penalty explained in jobs that use those faculties.
- The sleep penalty should be smaller if there is paternal/household help

Impact of research: 
We hope that this research will help us understand the causes of the motherhood gap and quantify how important leave policy and paternal involvement are for mitigating this gap. Especially in the US, where the authors are based, the importance of leave and paternal involvement are still hotly debated as there is no national paid leave for mothers, let alone fathers.
Date proposal received: 
Monday, 7 October, 2019
Date proposal approved: 
Tuesday, 8 October, 2019
Keywords: 
Social Science, Statistical methods, Sleep, Social science

B3390 - Predictors and patterns of self-harm thoughts and behaviours - 11/10/2019

B number: 
B3390
Principal applicant name: 
Becky Mars | UOB (United Kingdom)
Co-applicants: 
Title of project: 
Predictors and patterns of self-harm thoughts and behaviours
Proposal summary: 

Self-harm in young people is a major problem. As many as 1-in-6 teenagers have self-harmed, but we know little about what happens to them as they get older. We also know little about how much self-harm thoughts and behaviours (SHTB) change from day-to-day, and what factors help to predict this. This project will look at predictors and patterns of SHTB both over long periods of time (from adolescence to adulthood) and over short periods of time (over days/weeks).
Although selfharm is very common in young people, most do not seek help. This makes it difficult to provide support. In this study, I will find out whether young people who self-harm are either (1) not visiting a GP or (2) visiting a GP for other reasons and not telling them about their self-harm. I will also look for factors that will help GPs to better identify young people who have self-harmed.

Impact of research: 
work steam 1 will considerably enhance knowledge of the epidemiology of self-harm and will facilitate effective targeting of early interventions to those who are most likely to show a chronic course. It will also improve understanding of the role of adolescent experiences in shaping future health. The knowledge gained from workstream 2 will be important in the design and targeting of interventions aimed at improving help seeking and detection rates for self-harm. This workstream will also inform the early identification of young people who are likely to engage in serious self-harm in the future; a group known to be at high risk for suicide.
Date proposal received: 
Monday, 7 October, 2019
Date proposal approved: 
Tuesday, 8 October, 2019
Keywords: 
Epidemiology, Mental health, Statistical methods, Cohort studies - attrition, bias, participant engagement, ethics, Development, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc.

B3388 - Dietary intake throughout childhood and adolescence with cardiometabolic health in later life - 04/10/2019

B number: 
B3388
Principal applicant name: 
Kaitlin Wade | MRC-IEU, University of Bristol (United Kingdom)
Co-applicants: 
Dr Emma Anderson, Rosie Fraser
Title of project: 
Dietary intake throughout childhood and adolescence with cardiometabolic health in later life
Proposal summary: 

The aim of this study is to assess the association between dietary intake measured throughout childhood and early adolescence and later cardiometabolic health within a large population.

Impact of research: 
It is currently unclear whether there are sensitive periods during early life that whereby diet has impact cardiometabolic health later in life. Additionally, most studies assessing the impact of childhood nutrition on later health are either of cross-sectional or short-term prospective design, most of which focus on a specific period (e.g., infancy) and are usually restricted to one measure of dietary intake. Repeated measure data is necessary to determine whether there are sensitive periods of early life during which dietary intake is particularly strongly related to later cardiometabolic health to identify suitable target ages for dietary intervention. In parallel, the mechanism by which dietary intake is associated with cardiovascular health requires interrogation, in order to develop more focused strategies aimed to prevent later adverse cardiovascular health.
Date proposal received: 
Thursday, 3 October, 2019
Date proposal approved: 
Friday, 4 October, 2019
Keywords: 
Epidemiology, Obesity, cardiovascular health, Statistical methods, Blood pressure, BMI, Cardiovascular, Childhood - childcare, childhood adversity, Statistical methods

B3387 - Early-life determinants of peak muscle function in adulthood - 22/10/2019

B number: 
B3387
Principal applicant name: 
Alex Ireland | Manchester Metropolitan University (UK)
Co-applicants: 
Prof Jon Tobias, Prof Rachel Cooper
Title of project: 
Early-life determinants of peak muscle function in adulthood
Proposal summary: 

Sarcopenia is defined as the age-related loss of muscle mass and function, occurring in 5-13% of individuals at 60 years of age, leading to increases in premature mortality, functional decline, falls and hospitalisations.

Age-related declines in muscle function are three times greater than those which occur in muscle mass, as changes such as motor unit loss lead to reduced muscle quality. Therefore it is crucial to assess muscle function, mass and quality in order to fully understand the determinants and consequences of sarcopenia.

Studies of sarcopenia to date have focused on identifying factors influencing decline, whereas less well known are the factors which determine peak muscle function. A similar concept of ‘peak bone mass’ is well established in the osteoporosis field, through which several key early-life determinants of bone mass have been identified. Strong relationships exist between muscle and bone, and around a third of individuals with sarcopenia also have osteoporosis. As a result, early-life influences on bone mass accrual may also involve effects on muscle function.

This project will examine whether early-life factors found to influence peak bone mass acquisition, also affect the attainment of peak muscle function. Furthermore, we aim to identify novel factors that contribute to peak muscle function. To do this, we propose to invite attendees to the ALSPAC@30 clinic to undergo a mid-calf peripheral quantitative computed tomography (pQCT) scan, from which muscle mass and density will be derived. We will also use jumping mechanography, a quick, highly-repeatable, sensitive method of assessing muscle function.

Impact of research: 
This application will examine whether early life factors found to influence peak bone mass acquisition, particularly those that are modifiable or amenable to intervention, also affect the attainment of peak muscle function. If true, this would suggest that population based strategies to optimise peak bone mass are likely to be equally effective in optimising peak muscle function, reducing the risk of sarcopenia, osteoporosis and osteosarcopenia in later life. Furthermore, we aim to apply bioinformatics resources such as MR-base (an analytical platform for Mendelian randomisation studies developed by University of Bristol (Hemani et al., 2018)) to identify novel factors and mechanisms that contribute to muscle function.
Date proposal received: 
Wednesday, 2 October, 2019
Date proposal approved: 
Thursday, 3 October, 2019
Keywords: 
Developmental biology, Bone disorders - arthritis, osteoporosis, Sarcopenia, GWAS, Medical imaging, Ageing, Bones (and joints), Development, Physical - activity, fitness, function

B3386 - Impact of parenthood on maternal and paternal neurobiology and subsequent child development - 11/10/2019

B number: 
B3386
Principal applicant name: 
Elanor Hinton | University of Bristol (United Kingdom)
Co-applicants: 
Professor Iain D Gilchrist, Nicholas Timpson
Title of project: 
Impact of parenthood on maternal and paternal neurobiology and subsequent child development
Proposal summary: 

Parenthood is one of the most important events in an adult’s life. Yet there is much to learn about how becoming a parent for the first time influences underlying biology. Researchers have begun to study changes in brain structure and function, as well as functioning of the heart, and pattern of fat and muscle in the body. These changes may help to prepare for the transition to parenthood, but also may have positive and negative consequences for future health. This project aims to study these changes in more detail using magnetic resonance imaging (MRI) by studying adults before and after having their first child. ALSPAC (Avon Longitudinal Study of Parents and Children) is a long-term health project that has studied parents and their children since the early 1990s. The ‘Children of the 90s’ are now having their own children; these births represent an unparalleled time limited opportunity to study the health consequences of pregnancy and parenthood. We will use records collected since birth from the Children of the 90s to predict how their bodies might cope with the challenge of parenthood. There is also much to understand about infant development. By collecting MRI data on the brain and body early in lives of the Children of the Children of the 90s, we will gain greater understanding of how the body develops. By comparing the data from parents with their children, this project will provide a unique opportunity to study the influence of parental biology on their child’s development.

Impact of research: 
Novel and important findings will be made possible through this project by further understanding the changes in body composition and the structure and functioning of the brain and heart during the perinatal period. Thus far, this has been understudied in the literature using small sample sizes. This project has the potential for high impact in this field due to the retrospective analyses made possible by the three generational nature of the dataset and existing detailed phenotypic and genetic records on participants therein. Such analyses will allow us to predict who may be at risk of negative outcomes and to give the possibility of early intervention. Beyond the specific hypotheses specified here, the newly acquired imaging data has huge potential for impact in numerous subject areas through prospective analyses. For example, by imaging the G2 babies early in life, precursors of many health and disease outcomes can be elucidated, including obesity and depression.
Date proposal received: 
Tuesday, 1 October, 2019
Date proposal approved: 
Tuesday, 1 October, 2019
Keywords: 
Neuroscience, Mental health, Obesity, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Medical imaging, Combining medical imaging data with data already collected on the G1 participants, as well as future data collected on G1 and G2 during clinics., BMI, Cardiovascular, Parenting, Psychology - personality, Childhood - childcare, childhood adversity, Equipment - MRI, Fathers, Genetic epidemiology, Mothers - maternal age, menopause, obstetrics, Neurology, Nutrition - breast feeding, diet, Offspring

B3385 - Spatial Analytics to Prevent Population Health Inequalities in Residential Environments The SAPPHIRE study - 10/10/2019

B number: 
B3385
Principal applicant name: 
James Kirkbride | UCL (United Kingdom)
Co-applicants: 
Prof Eirini Flouri, Prof David Osborn, Prof Gianluca Baio, Prof Ed Manley
Title of project: 
Spatial Analytics to Prevent Population Health Inequalities in Residential Environments: The SAPPHIRE study
Proposal summary: 

Adverse built, social and physical environments are associated with worse mental health outcomes which first emerge in adolescence, offering potentially modifiable population-level targets for prevention. While early detection has become the cornerstone of UK and Australian youth mental health provision, which has led to improved downstream clinical and social outcomes for young people, primary prevention remains an elusive goal, resulting in lifelong physical and mental health disparities which affect whole communities. Hitherto, most studies of the environment and mental health have considered selected indicators from a single domain (built, social or physical), making unobserved and residual confounding major obstacles to causal inference and primary prevention. Methods to characterise the way in which the exposome affects mental health and well-being are now required.

We will address this in two phases.

First, by linking large, geocoded epidemiological and clinical data from ALSPAC with a comprehensive set of built, social and physical environmental exposures via the ALSPAC-PEARL/ALGAE linkage, we will identify the pathways through which these factors affect various mental health outcomes. We will also consider how physical health and activity in childhood may mediate the relationship with later mental health, and vice versa. Environmental data will be linked from multimodal sources available in PEARL/ALGAE and via integration of other available environmental data to characterise the built (building quality, indoor air quality, density, land use, overcrowding, transportation links), social (population density, social isolation and cohesion, inequality, deprivation, ethnic diversity, homelessness, crime) and physical (air, light & noise pollution; accessibility to and quality of green or blue spaces, walkability) environment.

Second, we will develop a simulation platform (SAPPHIRE) to evaluate putative intervention strategies in the built environment to prevent selected adverse mental health outcomes and physical health comorbidities. We will develop a simulation approach based on the ALSPAC sample and the wider population of the Bristol region. We will synthesise theoretical and empirical evidence to build this platform via a hybrid Dynamics/Agent-Based Modelling approach, consistent with capturing the interplay between geospatial, household and individual factors which affect mental health. SAPPHIRE will be open-source, so that decision makers can readily adapt, deploy and test prevention strategies in different contexts based on parameter values representing their local circumstances. This has the potential to unlock primary or secondary prevention strategies in the built environment, which would otherwise be prohibitively expensive, time-consuming or impossible to deploy in the wild.

Impact of research: 
We will identify the most plausible, modifiable targets for prevention of mental health disorders associated with the built environment. We will also produce an open-source spatial analytics simulated environment so that decision makers can readily adapt, deploy and test prevention strategies in different contexts based on parameter values representing their local circumstances. This has the potential to unlock primary or secondary prevention strategies in the built environment, which would otherwise be prohibitively expensive, time-consuming or impossible to deploy in the wild.
Date proposal received: 
Monday, 30 September, 2019
Date proposal approved: 
Monday, 30 September, 2019
Keywords: 
Epidemiology, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Mental health, Computer simulations/modelling/algorithms, Childhood - childcare, childhood adversity, Cognition - cognitive function, Environment - enviromental exposure, pollution, Physical - activity, fitness, function, Sleep, Social science

B3384 - Variants trait-causal via their effect on VDR binding - 13/10/2019

B number: 
B3384
Principal applicant name: 
Chris Ponting | MRC Institute of Genetics & Molecular Medicine (Midlothian)
Co-applicants: 
Dr. Neil Clark
Title of project: 
Variants trait-causal via their effect on VDR binding
Proposal summary: 

Genome-wide association studies (GWAS) do not pinpoint the disease-causal variant, and genomics experiments do not pinpoint which molecular events influence disease risk. What is needed are methods that combine GWAS and functional genomics to infer disease risk-altering causal variants. We aim to identify the variants that have a causal effect on trait via their effect on the binding of the Vitamin D Receptor (VDR). Two-sample Mendelian randomization is limited by unobserved pleiotropic effects of candidate variants which may explain trait effects independently of VDR binding. This project addresses this problem by adding the cis-acting DNA variants that explain Vitamin D (25OHD) Serum level in specific tissues to the model. This allows us to infer variants that are causal for physiological/disease trait variation via their effect on VDR binding.

Impact of research: 
Our research addresses a central problem in genetic epidemiology - the pleiotropic bias of the inferred causal effects. Separating the causal from the pleiotropic effects will allow us to identify variants that are causal via their effect on the binding of the Vitamin D Receptor. Identifying the causal effects at individual loci will reveal causal effects of Vitamin D that may be lost in studies examining the overall level of Vitamin D. Furthermore, our estimates of the size and direction of the causal effects may facilitate a translation into genotype and trait dependent therapeutic role for Vitamin D supplementation.
Date proposal received: 
Friday, 27 September, 2019
Date proposal approved: 
Friday, 27 September, 2019
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), This project is trait agnostic but aims to test any traits that overlap with UK-Biobank as we aim to compare the summarised results with the aim of replication of our analysis results., Computer simulations/modelling/algorithms, Statistical methods, Genetic epidemiology, Genetics, Genomics, Genome wide association study, Mendelian randomisation

B3383 - Environment-wide association study for adiposity in ALSPAC - 27/09/2019

B number: 
B3383
Principal applicant name: 
Jie V Zhao | The University of Hong Kong (Hong Kong)
Co-applicants: 
Dr. C Mary Schooling, Prof. Debbie Lawlor, Dr. Ahmed Elhakeem
Title of project: 
Environment-wide association study for adiposity in ALSPAC
Proposal summary: 
Impact of research: 
The increased prevalence of obesity and related comorbidities is a major public health problem. Identifying the potential drivers of adiposity will be helpful for providing dietary recommendations, and identifying a healthy diet and lifestyle. Examining the underlying pathways will improve risk prediction for adiposity and chronic diseases, provide new insights into the prevention and treatment strategies, with direct relevance to clinical practice and population health.
Date proposal received: 
Thursday, 26 September, 2019
Date proposal approved: 
Thursday, 26 September, 2019
Keywords: 
Epidemiology, Obesity, Statistical methods, BMI, Nutrition - breast feeding, diet

B3382 - Eating disorders and anxiety Mapping developmental trajectories and their genetic underpinnings - 27/09/2019

B number: 
B3382
Principal applicant name: 
nadia micali | University of Geneva, Switzerland; UCL, UK
Co-applicants: 
Cynthia M Bulik, Zeynep Yilmaz, Dr, Katherine Schaumberg, Dr, Yufeng Liu
Title of project: 
Eating disorders and anxiety: Mapping developmental trajectories and their genetic underpinnings
Proposal summary: 

Eating disorders (ED) such as anorexia nervosa (AN), bulimia nervosa (BN), and binge-eating disorder (BED) are debilitating and costly with few effective treatments. Comorbidity between ED and anxiety (ANX) and obsessive-compulsive disorder (OCD) is typical, with about two-thirds of individuals with ED also reporting lifetime ANX (including OCD). Comorbidity adversely impacts prognosis and time to recovery. Most ED and ANX phenotypes onset during adolescence, and evidence points to shared risk at the genetic level. ED and ANX phenotypes are moderately heritable. Genetic risk scores (GRS), which combine weighted risk from common variant single-nucleotide polymorphisms (SNPs) across the genome, are effective in defining psychiatric risk, although the focus has typically been on diagnoses. Integrating genetic risk information across multiple ED- and ANX- phenotypes could enhance predictive power of GRS while also specifying whether this genetic risk is best understood through a single factor vs. multiple factors. For instance, multiple metabolic, anthropometric, and psychiatric traits share genetic risk with AN. ANX also shows significant genetic overlap with psychiatric traits but less so with anthropometric and metabolic traits, suggesting shared risk between ED and ANX with psychiatric traits, but differential risk with metabolic and anthropometric traits. We will investigate this empirically using genomic structural equation modeling (GSEM) to identify genomic factors associated with ED and ANX phenotypes.
Additionally, we propose a fine-grained investigation of the association between ED and ANX by examining ED and ANX symptom trajectories across adolescence and into adulthood; to hone in on the biology that underlies ED and ANX change over time. At present, little is known about how ED and ANX symptoms affect each other across development, and how genetic risk influences their onset and course, though it is likely that genetic risk affects onset and course differently in adolescence vs. adulthood. Studying how ED and ANX are associated, both genetically and phenotypically, across development will advance early identification and targeted prevention and treatment of these conditions before threshold diagnoses crystallize.

Impact of research: 
important novel findings in risk for eating disorders
Date proposal received: 
Tuesday, 24 September, 2019
Date proposal approved: 
Wednesday, 25 September, 2019
Keywords: 
Epidemiology, Eating disorders - anorexia, bulimia, GWAS, Development

B3380 - Dissect the interaction of age at first marriage and associated sociological traits with a genetic approach - 24/09/2019

B number: 
B3380
Principal applicant name: 
Qiongshi Lu | University of Wisconsin-Madison (United States)
Co-applicants: 
Tianchang Li, Jason Fletcher, PhD
Title of project: 
Dissect the interaction of age at first marriage and associated sociological traits with a genetic approach
Proposal summary: 

Marital behaviours are important human traits of great interest in sociology, psychology, and related fields. Sociological factors (e.g. educational attainment) have been demonstrated to strongly associate with AFM, especially for women. However, little is known about the genetic basis of marriage. Due to the growing interest in understanding the genetic basis of marriage and how it interacts with environmental factors, this proposed research will study the sociological factors associated with people’s age at first marriage (AFM) using a genetic approach. More specifically, this research aims to identify common genetic variants associated with AFM through a genome-wide association meta-analysis approach. In addition, we will quantify the genetic correlation between AFM and a variety of human traits such as personality and cognitive behaviour, assess the predictive accuracy of AFM using genetic information, and investigate how genetic and environmental factors interact to influence AFM. This research will potentially provide fundamental new insights into the genetic basis of marital behaviour in general and AFM in particular.

Impact of research: 
This research will provide fundamental new insights into the genetic basis of marital behaviour in general and AFM in particular. In addition, the proposed research will generate polygenic scores for AFM which allows us to dissect the interaction between genetic and life-course environmental factors underlying AFM.
Date proposal received: 
Monday, 23 September, 2019
Date proposal approved: 
Tuesday, 24 September, 2019
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Behaviour - e.g. antisocial behaviour, risk behaviour, etc., GWAS, Genome wide association study

B3381 - Early Childhood Shyness Psychosocial Experiences and Trajectories of Cardiovascular Risk Factors across the Life-Course - 24/09/2019

B number: 
B3381
Principal applicant name: 
Alva Tang | University of Maryland (United States)
Co-applicants: 
Natalie Slopen
Title of project: 
Early Childhood Shyness, Psychosocial Experiences, and Trajectories of Cardiovascular Risk Factors across the Life-Course
Proposal summary: 

Shyness is a temperamental trait characterized by an anxious preoccupation with the self and heightened reactivity in social situations. This trait is moderately stable across the childhood to adulthood [1]. Shy children often express social withdrawal and internalizing problems (i.e., loneliness, anxiety and depressive symptoms), if they have experienced negative peer experiences, such as peer rejection and victimization [2-6]. In contrast, mutual and high-quality friendships [6, 7] as well as parenting styles characterized by high warmth and autonomy [4, 8-10] buffer against social withdrawal and internalizing problems among shy youth. While the link between shyness and later socioemotional problems is well-documented, little is known about physical health outcomes of shy children even though epidemiologic studies suggest that childhood social withdrawal/isolation, an outcome of childhood shyness, is an independent risk factor for increased cardiovascular disease (CVD) risk in adulthood [11-13]. Similarly, studies using animal models show that rodents and dogs with stable neophobic/inhibited traits have shorter lifespan, dampened immune response, and elevated glucocorticoid production [14-17]. Yet, no studies in humans have identified whether early temperamental shyness plays a role in increased CVD risk in adulthood and how temperamental shyness, peer and parental relationships shape the development of physiological systems linked to CVD risk across the lifespan to confer later health risks. This research proposal aims to address these knowledge gaps by considering a broad range of negative and positive peer-experiences in relation to CV risk factors measured from childhood to adulthood, and the potential role of child mental health within this relationship. Using the ASLPAC cohort, we will address the following questions:

References
1. Pérez-Edgar, K. and N.A. Fox, Temperament and anxiety disorders. Child and Adolescent Psychiatric Clinics, 2005. 14(4): p. 681-706.
2. Boivin, M., S. Hymel, and W.M. Bukowski, The roles of social withdrawal, peer rejection, and victimization by peers in predicting loneliness and depressed mood in childhood. Development and Psychopathology, 1995. 7(4): p. 765-785.
3. Gazelle, H. and G.W. Ladd, Anxious solitude and peer exclusion: A diathesis–stress model of internalizing trajectories in childhood. Child development, 2003. 74(1): p. 257-278.
4. Booth-LaForce, C. and M.L. Oxford, Trajectories of social withdrawal from grades 1 to 6: Prediction from early parenting, attachment, and temperament. Developmental psychology, 2008. 44(5): p. 1298.
5. Tang, A., et al., Shyness trajectories across the first four decades predict mental health outcomes. Journal of abnormal child psychology, 2017. 45(8): p. 1621-1633.
6. Oh, W., et al., Trajectories of social withdrawal from middle childhood to early adolescence. Journal of Abnormal Child Psychology, 2008. 36(4): p. 553-566.
7. Fordham, K. and J. Stevenson-Hinde, Shyness, friendship quality, and adjustment during middle childhood. The Journal of Child Psychology and Psychiatry and Allied Disciplines, 1999. 40(5): p. 757-768.
8. Booth-LaForce, C., et al., Parent and peer links to trajectories of anxious withdrawal from grades 5 to 8. Journal of Clinical Child & Adolescent Psychology, 2012. 41(2): p. 138-149.
9. Kiel, E.J. and K.A. Buss, Prospective relations among fearful temperament, protective parenting, and social withdrawal: The role of maternal accuracy in a moderated mediation framework. Journal of abnormal child psychology, 2011. 39(7): p. 953-966.
10. Lewis‐Morrarty, E., et al., Infant attachment security and early childhood behavioral inhibition interact to predict adolescent social anxiety symptoms. Child development, 2015. 86(2): p. 598-613.
11. Caspi, A., et al., Socially isolated children 20 years later: risk of cardiovascular disease. Archives of Pediatrics & Adolescent Medicine, 2006. 160(8): p. 805-811.
12. Danese, A., et al., Adverse childhood experiences and adult risk factors for age-related disease: depression, inflammation, and clustering of metabolic risk markers. Archives of pediatrics & adolescent medicine, 2009. 163(12): p. 1135-1143.
13. Lacey, R.E., M. Kumari, and M. Bartley, Social isolation in childhood and adult inflammation: evidence from the National Child Development Study. Psychoneuroendocrinology, 2014. 50: p. 85-94.
14. Cavigelli, S.A., Behavioral Inhibition in Rodents: A Model to Study Causes and Health Consequences of Temperament, in Behavioral Inhibition. 2018, Springer. p. 35-58.
15. Cavigelli, S.A. and M. McClintock, Fear of novelty in infant rats predicts adult corticosterone dynamics and an early death. Proceedings of the National Academy of Sciences, 2003. 100(26): p. 16131-16136.
16. Corsetti, S., et al., Bold personality makes domestic dogs entering a shelter less vulnerable to diseases. PloS one, 2018. 13(3): p. e0193794.
17. Cavigelli, S.A., J.R. Yee, and M.K. McClintock, Infant temperament predicts life span in female rats that develop spontaneous tumors. Hormones and Behavior, 2006. 50(3): p. 454-462.

Impact of research: 
Date proposal received: 
Monday, 23 September, 2019
Date proposal approved: 
Tuesday, 24 September, 2019
Keywords: 
Social Science, Diabetes, Hypertension, Obesity, Statistical methods, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Cardiovascular, Development, Hormones - cortisol, IGF, thyroid, Immunity, Psychology - personality, Social science

B3378 - Lectin Histochemistry and Glycocalyx Measurement of the ALSPAC Placentas - A Feasibility Study - 04/10/2019

B number: 
B3378
Principal applicant name: 
Simon Satchell | University of Bristol
Co-applicants: 
Dr Colin Down, Dr Victora Bills, Dr Rebecca Foster
Title of project: 
Lectin Histochemistry and Glycocalyx Measurement of the ALSPAC Placentas - A Feasibility Study
Proposal summary: 

Pre-eclampsia is a common pregnancy complication and is one of the leading causes of death and injury to mothers and their babies worldwide. Pre-eclampsia occurs in the second half of pregnancy and is characterised by high blood pressure and protein in the urine. We do not fully understand why some women get this condition, but the function and leakiness of small blood vessels (capillaries) is important.

The glycocalyx, is a very thin gel-like layer which is found on the wall of all blood vessels. It seems to act as a barrier, controlling how much water remains inside the blood vessel. Researchers have recently started looking at the glycocalyx and have found in other conditions which cause leaky blood vessels (e.g. diabetes and kidney disease), the glycocalyx appears damaged.

Recently we have completed work to show that glycocalyx is not only present in blood vessels, but also the human placenta. We have done this by staining placenta with different proteins called lectins. These bind to the sugary glycocalyx, and when labelled with a fluorescent dye glow green under the microscope. We compare this green stain to a red membrane stain and can measure the depth of the glycocalyx.

We suspect that the glycocalyx is damaged in pre-eclampsia, like in other diseases.

ALSPAC offers an excellent resource of placental tissue, however, many of these specimens have been stored for a number of years and we know the glycocalyx can be a fragile structure. We propose a feasibility experiment, whereby the research team could look a small selection of ALSPAC placentas to examine if the glycocalyx has been preserved and can still be measured.

Impact of research: 
If it can be confirmed that glycocalyx has been preserved in the ALSPAC placentae, this would provide excellent provisional data for a grant application for further work with the ALSPAC placentas. A larger study could investigate differences in the placental glycocalyx in health and disease and help further elucidate the pathophysiology of pre-eclampsia. The translational potential is exciting and could include glycocalyx as a biomarker, diagnostic tool or even a therapeutic target in pre-eclampsia.
Date proposal received: 
Thursday, 19 September, 2019
Date proposal approved: 
Friday, 20 September, 2019
Keywords: 
Biochemistry/structural biology, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Medical imaging, Biological samples -e.g. blood, cell lines, saliva, etc., Blood pressure

B3377 - Is genetic predisposition to osteoarthritis associated with musculoskeletal pain in adolescents - 20/09/2019

B number: 
B3377
Principal applicant name: 
Aliya Sarmanova | MRC Integrative Epidemiology Unit, PHS/Musculoskeletal Research Unit Translational Health Sciences, Bristol University (United Kingdom)
Co-applicants: 
Professor Jonathan Tobias, Professor George Davey Smith, Professor Nicholas Timpson, Prof. Dr. Eleftheria Zeggini, Dr Monika Frysz, Miss April Hartley
Title of project: 
Is genetic predisposition to osteoarthritis associated with musculoskeletal pain in adolescents?
Proposal summary: 
Impact of research: 
Date proposal received: 
Wednesday, 18 September, 2019
Date proposal approved: 
Friday, 20 September, 2019
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Bone disorders - arthritis, osteoporosis, Statistical methods, Bones (and joints), Genetic epidemiology

B3376 - Evaluating diet at age 30 ALSPAC-G1 - 19/09/2019

B number: 
B3376
Principal applicant name: 
Eleanor Winpenny | MRC Epidemiology Unit, University of Cambridge
Co-applicants: 
Dr Esther van Sluijs, Polly Page
Title of project: 
Evaluating diet at age 30 (ALSPAC-G1)
Proposal summary: 

Poor quality diet is associated with increased risk of heart disease, stroke, type 2 diabetes, many forms of cancer and mental illness. Poor quality diet is the top contributor to mortality globally, and is estimated to cost the NHS £6billion per year.
The period of adolescence to early adulthood is the time when prevalence of overweight and obesity develops most rapidly, making this an important time to understand the contribution of diet to these developing risk factors. Adolescence and early adulthood is a time of rapid personal development and changing lifestyles. It also is the time when adult behaviours, including adult dietary patterns, are developed and established. Understanding the factors that influence development of adult diet is an important first step in developing strategies to change behaviour.
However, there has been little assessment of diet in young adults. Online tools (INTAKE24) are now available that make reporting on nutritional intake easier, allowing online completion of recalls of daily intake, and automated data processing. These validated tools make the collection of diet data in large samples more feasible, and are now being implemented in large-scale dietary surveys across many countries by researchers at the MRC Epidemiology Unit.
This application focusses on assessing the diet of young adults (age 28-30) in the ALSPAC cohort. This data will then be used together with other data collected within ALSPAC, or from linked datasets, to understand (1) the changes in environment and lifestyle which help to explain why individuals have adopted their current diets, and (2) the relationships between diet and measures of heart and blood health. The data will also be available for further research studying associations between diet at age 30 years and longer term measures of health and disease.

Impact of research: 
There is limited robust data available on dietary intake during early adulthood, both globally and in the UK. Collection of this data will allow research which helps us to understand the role of diet within pathways which lead from socioeconomic determinants to cardiovascular and metabolic disease. In particular this research will provide information on the populations at risk for development of poor diet during early adulthood, and suggest opportunities for public health intervention. For example research based on this data could identify particular population groups or particular early adulthood life transitions that increase risk of a poor quality diet, suggesting a particular target for intervention. In the future this data will allow for further research addressing associations between diet in early adulthood and later health and disease, for example to understand whether diet in early adulthood plays an independent role in future disease risk.
Date proposal received: 
Tuesday, 17 September, 2019
Date proposal approved: 
Tuesday, 17 September, 2019
Keywords: 
Epidemiology, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Cancer, Diabetes, Hypertension, Obesity, Nutrition - breast feeding, diet

B3372 - Changes in metabolomic measures attributable to body composition during puberty and young adulthood - 16/09/2019

B number: 
B3372
Principal applicant name: 
Inge Verkouter | Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands (Netherlands)
Co-applicants: 
Dr Joshua Bell, Prof Nicholas Timpson, Dr Linda O'Keeffe, Dr Raymond Noordam, Dr Renée de Mutsert, Dr Dennis Mook-Kanamori, Prof Frits R Rosendaal
Title of project: 
Changes in metabolomic measures attributable to body composition during puberty and young adulthood
Proposal summary: 

Body weight gain during adulthood is known to be associated with a higher risk of cardiometabolic diseases, such as type 2 diabetes and cardiovascular diseases. In addition, body weight gain contributes to higher (mostly abdominal) body fat later in life, as compared with body weight maintenance. Body fat that is stored in the abdomen (android body fat) is strongly associated with the risk of cardiometabolic disease, whereas peripheral body fat (gynoid body fat) is believed to be less detrimental for cardiometabolic health. Cardiometabolic disease is accompanied by changes in the blood metabolic profile, such as changes in cholesterol, fatty acids, amino acids and factors related to inflammatory processes. It is not known whether body fat measures, such as total body fat, trunk fat, leg fat and arm fat, measured during childhood and adolescence are associated with changes in the metabolite profile at young adulthood. Additionally, it is not known whether or how the metabolite profile changes following the onset of puberty, and whether these changes can be attributed to prior changes in body composition.
Therefore, we will examine the change in the metabolite profile following the onset of puberty, and we will examine the relation between fat indices at different stages of development (e.g. before and after puberty) and changes in the metabolite profile. In addition, it is known that men and women have a different body fat distribution, with men having more trunk fat, and women having more leg fat. We will examine whether the regional fat indices in men and women differentially associate with changes in the metabolic profile during childhood and adolescence.

Impact of research: 
Metabolites are important intermediates of phenotypes and disease, and therefore contribute to research on the underlying mechanisms of disease. However, there is lack of longitudinal studies in metabolomics, therefore little is known about changes in metabolite profiles. This research will contribute to unravelling the metabolic changes before, during and after puberty, and whether these metabolic changes are attributable to changes in body composition with use of repeated measures of metabolites in ALSPAC. Thereby, this research will contribute to elucidating the critical periods when the first indications of cardiometabolic disease later in life (as changes in metabolite levels) will develop.
Date proposal received: 
Thursday, 12 September, 2019
Date proposal approved: 
Monday, 16 September, 2019
Keywords: 
Epidemiology, Obesity, Metabolomics, Metabolic - metabolism

B3373 - Prenatal Hg exposure and DNA methylation consortium analysis - 16/09/2019

B number: 
B3373
Principal applicant name: 
Paul Yousefi | MRC Integrative Epidemiology Unit, University of Bristol (United Kingdom)
Co-applicants: 
Gemma Sharp, Caroline Relton
Title of project: 
Prenatal Hg exposure and DNA methylation consortium analysis
Proposal summary: 

Mercury (Hg) is an environmental pollutant that can persist and bio-accumulates as methylmercury (MeHg) through the food chain. Foetuses are especially vulnerable to prenatal exposure since mercury can cross the placental barrier and the blood brain barrier is not fully developed until several months after birth. Prenatal exposure to Hg has been associated with impaired foetus development, such as reduced placental functioning and foetal growth. Prenatal exposure to Hg has also been associated with effects on child neuropsychological development. The specific mechanisms of toxicity related to these associations remain unclear, although some research has suggested that dramatic DNA methylation changes and epigenetic remodelling during early embryogenesis could be involved. Thus, cells and tissues acquire new methylation patterns that may persist in foetal development and childhood. To date, only three studies have been conducted relating Hg and epigenome-wide DNA methylation in cord blood with sample sizes between 138 and 321. These studies have identified altered expression in unique genomic regions as well as methylation changes in specific CpG sites. This study proposes to to investigate the association between prenatal Hg exposure and epigenome-wide methylation.

Impact of research: 
The primary academic beneficiaries of this project will be environmental and biological scientists who will gain insight into the role of the epigenome and environmental Hg exposures. Researchers in the field of life course epidemiology will benefit from a clearer understanding of the role of epigenetic mechanisms in the programming of later health and behaviors. Academics at all career stages, from PhD students to senior academics will have the opportunity to engage with and benefit from the research proposed.
Date proposal received: 
Thursday, 12 September, 2019
Date proposal approved: 
Monday, 16 September, 2019
Keywords: 
Epidemiology, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Microarrays, Environment - enviromental exposure, pollution

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