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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B4159 - Genome-wide association study GWAS of blood pressure in adults - 11/10/2022

B number: 
B4159
Principal applicant name: 
Qian Yang | University of Bristol
Co-applicants: 
Prof Deborah A Lawlor, Prof Nicholas J Timpson
Title of project: 
Genome-wide association study (GWAS) of blood pressure in adults
Proposal summary: 

The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium invites ALSPAC and Bristol researchers to take part in a large GWAS of blood pressure traits, which include systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP, i.e. SBP-DBP). The main aims of CHARGE's GWAS are to (1) identify novel loci for BP traits separately by sex; (2) identify gene-sleep interaction effects on BP traits by sex. These analyses will follow the most recent analysis plan (currently 'Phase II analysis plan for sleep and blood pressure' version 4.3) provided by CHARGE. Only summary statistics will be shared with CHARGE. Based on the final GWAS results, subsequent analyses (e.g. Mendelian randomization) would be conducted by CHARGE based on the summary statistics.

Impact of research: 
This study will help identify novel genetic variants involved in BP traits and genetic variants affect these traits taking into account potential interaction with a lifestyle factor.
Date proposal received: 
Monday, 3 October, 2022
Date proposal approved: 
Tuesday, 11 October, 2022
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Hypertension, GWAS, Blood pressure

B4160 - Novel implementation of vaccinations against adult respiratory infection and respiratory pathogen surveillance - 04/11/2022

B number: 
B4160
Principal applicant name: 
Catherine Hyams | University of Bristol
Co-applicants: 
Title of project: 
Novel implementation of vaccinations against adult respiratory infection and respiratory pathogen surveillance
Proposal summary: 

Vaccination is currently underutilised in adults, despite the potential for this public health intervention to improve patient outcomes, and reduce healthcare usage and expense. Pre-licensure randomised controlled trials demonstrate vaccine safety and efficacy, but fail to evaluate the impact of these interventions in real-world settings, providing limited insight into outcomes for healthcare systems. Current post-implementation surveillance and safety studies lack detailed clinical outcomes and are limited by methodological constraints. There is therefore an urgent need to undertake well-conducted post-licensure pre-rollout (i.e. vaccine incorporation into national programmes) interventional implementation studies to provide such evidence.

This fellowship will aim to develop the methodology used within this field and undertake research that provides critical evidence for national and international public health decision making. Initially, I aim to undertake this research through an exemplar study of PCV20 (20-valent pneumococcal conjugate vaccine), which may extend into a post-implementation effectiveness study if PCV20 is implemented nationally. This would then provide a pre-existing platform to study RSV or novel influenza vaccine effectiveness.

Impact of research: 
The research proposed in this fellowship aims to improve understanding of human infectious disease and translating these insights into health benefits, thereby ensuring that the UK has the infrastructure, skills and expertise it needs. As such, it falls within the scope of the Infection and Immunity Board. Specific areas of strategic focus covered include: Global Health; Preparedness; Immunity and Infection throughout life; Chronic infection, comorbidity, immunomodulation.
Date proposal received: 
Tuesday, 4 October, 2022
Date proposal approved: 
Tuesday, 11 October, 2022
Keywords: 
Health Economics, Infection, Qualitative study, Cohort studies - attrition, bias, participant engagement, ethics

B4158 - An investigation of the developmental symptom course of chronic pain and mental health Using genetically informative and causal - 03/10/2022

B number: 
B4158
Principal applicant name: 
Ellen Thompson | KCL (United Kingdom)
Co-applicants: 
Title of project: 
An investigation of the developmental symptom course of chronic pain and mental health: Using genetically informative and causal
Proposal summary: 

Chronic pain impacts multiple aspects of the lives of people who experience it with up to 10% of young people experiencing chronic pain into early adulthood, including symptoms of musculoskeletal pain, recurrent abdominal pain, and headaches. Importantly, it is estimated that up to 72% of those who experience chronic pain also experience significant levels of depression and anxiety (also referred to as common mental health problems hereafter). Despite these shocking estimates, few studies have sought to understand the causes, mechanisms, and longitudinal relationship between symptoms of chronic pain and common mental health problems.

The overarching aim of this project is to investigate the direction of the relationship between chronic pain and common mental health across a developmental period, from childhood to young adulthood, and explore potential mechanisms which may elucidate individual differences in the development of symptoms. To do this I will apply advanced statistical methods to large, genetically informative, longitudinal population-based studies to test the relationship between chronic pain symptoms including headaches, backache, and abdominal pain and common mental health problems, including anxiety and depression. Findings will provide a deeper understanding into the causal relationship between symptoms of chronic pain and common mental health across a key developmental period.

Impact of research: 
During the course of my project, I will produce and disseminate academic papers. I will aim to publish, in an open-access form, in high impact journals such as Nature Human Behaviour, The British Journal of Psychiatry, Lancet Psychiatry and Journal of Child Psychology and Psychiatry, which will reach a broad audience. Furthermore, I will address academic and clinical audiences in national and international conferences and departmental seminars across the UK and internationally. Additionally, I will engage public audiences in dialogue about my research and foster public understanding of chronic pain in the development of mental health symptoms and their environmental and genetic underpinnings
Date proposal received: 
Monday, 3 October, 2022
Date proposal approved: 
Monday, 3 October, 2022
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Pain, Statistical methods, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc.

B4156 - The role of maternal religious belief in adolescent mental health - 18/10/2022

B number: 
B4156
Principal applicant name: 
Isaac Halstead | University of Bristol (United Kingdom)
Co-applicants: 
Carol Joinson, Jon Heron
Title of project: 
The role of maternal religious belief in adolescent mental health
Proposal summary: 

Adolescent mental health issues can have a significant impact on both the individual and their family. Understanding what factors relate to offspring mental health can help identify adolescents at greater risk of mental health issues. Previous research has investigated the role of parental religious belief, with inconsistent results. The aim of the present study was to re-examine whether a parent’s religious belief is related to their offspring’s mental health during adolescence. This is intended to build upon our previous study that looked at childhood mental health and parental religious belief.

Impact of research: 
This study will provide an insight into the way that religious beliefs shapes future generations.
Date proposal received: 
Thursday, 29 September, 2022
Date proposal approved: 
Monday, 3 October, 2022
Keywords: 
Social Science, Mental health, Statistical methods, Social science

B4150 - A Network Approach to Understanding Co-Occurring Mental Health Conditions in People with Autism and High Autistic Traits - 03/10/2022

B number: 
B4150
Principal applicant name: 
Matthew Hollocks | King's College London
Co-applicants: 
Dr Anat Zaidman-Zait, Prof Will Mandy
Title of project: 
A Network Approach to Understanding Co-Occurring Mental Health Conditions in People with Autism and High Autistic Traits
Proposal summary: 

Autism spectrum disorder is a neurodevelopmental condition characterised by difficulties with reciprocal social communication, restricted interests, repetitive behaviours, and sensory difficulties. In addition to these core features autistic people are at extremely high risk of developing additional mental health difficulties. For example, between 40% to 78% of children with autism have at least one anxiety disorder, almost four times the rate observed in children without the diagnosis. In addition, rates of depression and ADHD are extremely high. Adding to this complex picture is the fact that an autistic person will often experience more than one of these additional diagnoses. Current statistical approaches to the study of the co-occurrence of mental health conditions in autism fail to consider of important associations at a symptom level both within and between conditions, potentially preventing vital insights into key problem areas which could be targeted by interventions. To address this, we plan to apply an alternative and novel approach (Network analysis) to understanding the underlying structure of co-occurring conditions in this highly complex and heterogeneous population.

Impact of research: 
The main outcome of this research will be a novel understanding of the nature of co-occurring mental health conditions in autism. Our approach will allow us to identify key symptoms or clusters of symptoms which will guide future research on the assessment, prevention and treatment of the mental health difficulties experienced by autistic people.
Date proposal received: 
Wednesday, 28 September, 2022
Date proposal approved: 
Monday, 3 October, 2022
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Childhood - childcare, childhood adversity, Development, Psychology - personality, Statistical methods

B4154 - The role of genetics in food allergy - 03/10/2022

B number: 
B4154
Principal applicant name: 
Annette Peters | Helmholtz Munich and Ludwig Maximilian University of Munich (Germany)
Co-applicants: 
Lisa Maier
Title of project: 
The role of genetics in food allergy
Proposal summary: 

The prevalence of food allergies has steadily increased in recent decades. This highlights the contribution of environmental and lifestyle factors, which act on the background of individual genetic susceptibility to shape the responsiveness of the immune system to allergenic triggers. A few genetic regions associated with food allergy have been identified but the number of genome-wide association studies (GWAS) on food allergy to date is limited and often restricted to one specific food allergen. Therefore, we aim to conduct a large-scale meta-analysis of GWAS on food allergies.

Impact of research: 
This project aims in particular to identify new risk loci for food allergy, as only a few genes have been identified so far in studies with small sample sizes. Conducting a GWAS meta-analysis on food allergy will expand and improve the understanding of genetic mechanisms of food allergies, which is an essential prerequisite for developing hypothesis-generating approaches to food allergy prevention and therapy.
Date proposal received: 
Thursday, 22 September, 2022
Date proposal approved: 
Monday, 3 October, 2022
Keywords: 
Genetics, Allergy, GWAS, Statistical methods, Biological samples -e.g. blood, cell lines, saliva, etc., Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Cohort studies - attrition, bias, participant engagement, ethics, Genetic epidemiology, Genetics, Genome wide association study, Immunity, Statistical methods

B4151 - The impact of social media reward-learning across development - 19/10/2022

B number: 
B4151
Principal applicant name: 
Amy Orben | University of Cambridge (United Kingdom)
Co-applicants: 
Ms Georgia Turner
Title of project: 
The impact of social media reward-learning across development
Proposal summary: 

Many people feel their emotional wellbeing is affected by their social media use, in positive and/or negative ways. However, scientific research has made little progress in uncovering the mechanisms by which social media could affect mental health. We now know that social media use can be modelled as a reward-learning process, whereby people engage with social media partly in order to gain ‘rewards’ such as ‘Likes’ and followers. However, we do not know which individual differences cause people to pursue and react to these rewards differently, nor whether different responses to these ‘rewards’ might determine the effects of social media on wellbeing.

We propose to investigate, for the first time, reward-learning behaviours as a potential mechanism linking social media and mental health. We intend to use the unique Twitter-data linkage ALPSAC has established for its participants in recent years. We will link the multidimensional questionnaire data regarding interindividual differences and developmental trajectories in the ALSPAC cohort, to data from these individuals’ Twitter profiles. We will then use computational models of reward-learning to model the Twitter data. This will allow us to associate behavioural and emotional trajectories with reward-learning behaviours on Twitter.

We will attempt to answer the following questions:
- Are behavioural and emotional characteristics, and other individual differences, associated with reward-learning behaviours on Twitter?
- Do reward-learning behaviours, such as the extent to which people alter their posting in response to the numbers of ‘Likes’ they receive, predict mental health trajectories over subsequent years?

Impact of research: 
We hope to stimulate avenues for new research which apply a computational psychiatry approach to investigating social media and mental health, and ultimately, to inform interventions. A better understanding of the mechanisms by which social media affects mental health, and the ages at which these mechanisms are most relevant, would enable design of new interventions to improve people’s relationship with social media, which target the relevant psychological mechanisms, for the right people, at the right time. It also has the potential to inform timely policy questions and debates, such as those surrounding social media regulations and design standards.
Date proposal received: 
Sunday, 18 September, 2022
Date proposal approved: 
Tuesday, 27 September, 2022
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Mental health, Computer simulations/modelling/algorithms, Statistical methods, Childhood - childcare, childhood adversity, Cognition - cognitive function, Statistical methods

B4146 - Intimate Partner Violence and Childrens Human Capital - 10/10/2022

B number: 
B4146
Principal applicant name: 
Dan Anderbeg | Royal Holloway University of London (United Kingdom)
Co-applicants: 
Dr Gloria Moroni, Dr Alexander Vickery
Title of project: 
Intimate Partner Violence and Children's Human Capital
Proposal summary: 

A recent EU-wide report by the European Union Agency for Fundamental Rights found that 22 percent of women had experienced Intimate Partner Violence (IPV) in their lifetime, and wide-cited estimates by the WHO suggest that the global incidence is significantly higher. The scale and impact of IPV, have attracted the attention from multiple academic disciplines that -- from different angles -- are trying to provide accurate evidence on this important and devastating phenomenon. Besides the indubitable and widely documented adverse impact of IPV on women’s physical and mental health, children exposed to IPV are also increasingly recognized as victims in their own right. The harm to children exposed to IPV may be both direct through the witnessing of abuse or indirect by affecting the mother-child interactions. Growing up in a family where the mother is abused by her partner might represent a grave shock for the child, potentially hindering the development of their human capital.

This project will provide evidence on the impact of children’s exposure to IPV on their cognitive and socio-emotional development between birth and age seven, and on the role of with mother’s responses to abuse. To this purpose, this project will implement and further develop a methodology recently introduced in economics to study the technology of human capital formation. The focus will be on the dynamics of the accumulation of skills, studying how skills co-evolve, and the role of mother-child interactions in this process. Most importantly, in relation to this highly successful recent literature, we will incorporate, for the first, time IPV as a negative input.

The strength of this method will be fully exploited by using an exceptionally rich source of data –internationally unique in containing all the necessary information for this analysis within a large representative population. The Avon Longitudinal Study of Parents and Children (ALSPAC) is a UK cohort study that includes (i) annual indicators of the incidence of IPV; (ii) high-frequency and reliable measures of children’s cognitive and socio-emotional skills; (iii) extremely detailed set of information on mother-child interactions as well as mother’s mental health.

Specifically, the project will address three research questions that will further the understanding of how children’s development is hampered by exposure to IPV. First, how large are the direct effects of children’s exposure to IPV on their development of cognitive and socio-emotional skills? This in effects casts exposure to IPV as a form of harmful maltreatment. Second, what are the indirect effects generated by change in mother-child interactions as a response to IPV? Such interactions can potentially amplify or compensate for the negative impact of IPV on children witnessing IPV. Third, what interactions between skills, and between skills and mother-child interactions, shape the dynamic effects of IPV on children’s development of socioemotional and cognitive skills over their early life years? Such interactions are crucial for suggesting the optimal nature and timing of policy interventions.
The current project will hence contribute to a highly influential and rapidly growing economic literature studying the importance of early childhood conditions for development and will allow new important insights to be gained by fully exploiting the richness of an existing unique data resource. In developing this analysis, our project will draw on, and contribute, to a research that spans multiple disciplines including sociology, psychology, pediatrics and criminology. The findings of this project respond to the need of thoroughly documenting and further studying the damaging effect of IPV within the family with the purpose of suggesting effective policy recommendations to alleviate its effect.

Impact of research: 
The goal of the current research is to deepen the understanding of how exposure to IPV affects the accumulation of both socio-emotional and cognitive skills of young children, accounting for both dynamic effects and interactions between these skills, and also the relationship to maternal health and mother-child interactions. The value of such knowledge can be enhanced for positive social impact if it also reaches policy-makers and practitioners.
Date proposal received: 
Tuesday, 13 September, 2022
Date proposal approved: 
Monday, 26 September, 2022
Keywords: 
Social Science, Intimate partner violence Child development, Statistical methods, Childhood - childcare, childhood adversity, Cognition - cognitive function, Parenting

B4155 - Maternal eating of fish during pregnancy antecedents and consequences - 14/12/2022

B number: 
B4155
Principal applicant name: 
Jean Golding | UoB
Co-applicants: 
Dr Joseph Hibbeln, Steven Gregory, Holly Tunstall
Title of project: 
Maternal eating of fish during pregnancy: antecedents and consequences
Proposal summary: 

There is considerable evidence that if the mother eats fish during pregnancy, the developing fetus benefits in a number of ways, including in behaviour intellectual abilities and aspects of vision. However, although a number of confounders have been taken into account there has always been a suspicion of residual confounding. The aim of this study is to use the exposome techniques to determine which features of the maternal
background, including features of her childhood, best predict whether she consumes fish during pregnancy. In parallel, aspects of the father's background will be assessed to determine whether similar factors predict his likelihood of eating fish. The results will be used to determine the features to be taken into account when looking at the possible consequences of eating fish.
The outcomes to be considered will be (a) the mother's physical health; (b) the mother's mental health; (c) the mother's beliefs and behaviours; (d) the child's development; (e) the child's health and behaviour; (f) the child's adolescence and early adulthood; (g) the father's physical and mental health, beliefs and behaviours.
All analyses will take account of the features identified in the exposome, as well as of assessing that the results are not due to the individual eating a healthy diet overall.

Impact of research: 
It will possibly emphasise once more the long-term benefits of eating fish.
Date proposal received: 
Sunday, 25 September, 2022
Date proposal approved: 
Monday, 26 September, 2022
Keywords: 
Developmental biology, Respiratory - asthma, Statistical methods, Childhood - childcare, childhood adversity

B4141 - Comparisons of brain structure and microstructure in individuals with and without clinical or genetic risk for psychosis - 26/09/2022

B number: 
B4141
Principal applicant name: 
Christian K. Tamnes | University of Oslo (Norge)
Co-applicants: 
Nasimeh Naseri, Alexandra Havdahl, Dr.
Title of project: 
Comparisons of brain structure and microstructure in individuals with and without clinical or genetic risk for psychosis
Proposal summary: 

The current project is a student project that is linked to the already approved project: B3840 Developmental pathways to mental health problems. All needed data are available through B3840.

Psychotic disorders are often severe and have high heritability. Despite a small proportion of the population being affected by psychotic disorders, they have the highest disability weight. Beside impairing health in their own, these disorders further increase risks for other health outcomes such as suicide. To understand the mechanistic pathways leading to development of psychotic disorders, it is important to study individuals with at risk, either individuals at clinical risk or individuals with genetic risk. Clinical risk refers to the presence of symptoms, but that the full diagnostic criteria are not met. Genetic risk is in an ALSPAC MRI substudy operazationalied as high polygenic risk for schizophrenia. Further, studying individuals at risk reduces confounding for medication or chronic illness to some extent.

Substantial efforts have been dedicated to identify neural factors associated with risk for psychotic disorders. Despite these efforts, the picture of how psychotic disorders develop is not clear and our knowledge about which factors contribute to this development is limited. There is thus a demand for further research to identify the brain structural and microstructural correlates associated with psychosis risk. Moreover, directly comparing individuals with clinical (symptom-based) risk for psychosis and individuals with genetic risk for psychosis can possibly reveal both shared and distinct neural mechanisms.

Impact of research: 
Date proposal received: 
Tuesday, 20 September, 2022
Date proposal approved: 
Monday, 26 September, 2022
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Neuroimaging, Psychosis, schizophrenia, psychotic disorders

B4147 - Religious or spiritual beliefs/behaviours RSBB and COVID infection - 26/09/2022

B number: 
B4147
Principal applicant name: 
Raquel Granell | MRC Integrative Epidemiology Unit (IEU)
Co-applicants: 
Prof James Dodd, Dr Caitlin Morgan, Prof Jean Golding, Isaac Halstead
Title of project: 
Religious or spiritual beliefs/behaviours (RSBB) and COVID infection
Proposal summary: 

The COVID-19 pandemic has had an irrevocable impact on healthcare both in the UK and worldwide. To date, almost 20 million cases had been recorded in the England and 164,000 deaths[1]. As we make advances in understanding how we manage this disease clinically, it is also important that we use this time to better understand who is more susceptible to COVID infection and why. Understanding the impact of religion and spiritual beliefs/behaviours (RSBB) is a novel assessment of factors that may influence COVID-19 transmission and therefore incidence. In this study we will determine whether (and how) behaviours associated with religion or spiritual beliefs such as attending a place of worship, attending a faith school or belief in a divine power has any impact on COVID incidence in our cohort. Our analysis will be conducted using data collected before and after covid from mothers and partners from the ALSPAC cohort and classes of religiosity determined by latent class analysis on the same population (highly religious, moderately religious, agnostic, and atheist)[2]. These four groups have been determined using a range of religious belief indicators and socioeconomic risk factors. By conducting this analysis, we hope to contribute to the emerging description of COVID populations alongside other known risk factors such as social deprivation and co-morbidity.

[1]coronavirus.data.gov.uk.(n.d.).Official UK Coronavirus Dashboard. [online]Available at: https://coronavirus.data.gov.uk/details/deaths?areaType=nation&areaName=....
[2]Halstead I, Heron J and Joinson C. Identifying patterns of religiosity in adults from a large UK cohort using latent class analysis[version 1; peer review: awaiting peer review].Wellcome Open Res 2022, 7:192(https://doi.org/10.12688/wellcomeopenres.17969.1)

Impact of research: 
High impact journal publication, presentations at national/international conferences
Date proposal received: 
Tuesday, 13 September, 2022
Date proposal approved: 
Monday, 26 September, 2022
Keywords: 
Epidemiology

B4148 - Examining the bidirectional association between emotion recognition and social wellbeing and school outcomes - 26/09/2022

B number: 
B4148
Principal applicant name: 
Zoe Reed | University of Bristol
Co-applicants: 
Dr Angela Attwood, Professor Marcus Munafò
Title of project: 
Examining the bidirectional association between emotion recognition and social, wellbeing and school outcomes
Proposal summary: 

Emotion recognition is an important part of social interaction, and difficulties in recognising others’ emotions can have a negative impact on this. In addition, these difficulties may subsequently impact social function and mental health. It is also possible that difficulties in this area e.g., social anxiety, could disrupt school attendance in children. Previous studies which have examined these relationships tend to be small and cross-sectional. We propose using a large existing cohort with data at multiple timepoints to overcome these limitations and allow the direction of association to be examined as well. It is important to further understand these relationships particularly given that poorer emotion recognition is observed in autistic individuals, or those with more autistic traits, and therefore these relationships will be particularly relevant for autistic individuals with emotion recognition difficulties.

We will examine the bidirectional association between emotion recognition and outcomes related to social traits, wellbeing/mental health and school attendance. Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) will be used for this. Data will be used from different time points to attempt to understand the direction of any associations found. This work would be useful in informing what downstream effects there may be with interventions targeting emotion recognition, for example, in autistic individuals.

Impact of research: 
This research will lead to a better understanding of relationship between emotion recognition and social, wellbeing and school attendance outcomes. We hope to use this information to strengthen the evidence base around these relationships which will be useful for other work we are doing around emotion recognition interventions for autistic children, in terms of identifying potential downstream effects.
Date proposal received: 
Thursday, 15 September, 2022
Date proposal approved: 
Monday, 26 September, 2022
Keywords: 
Epidemiology, Mental health, Statistical methods, Childhood - childcare, childhood adversity, Communication (including non-verbal), Emotion recognition

B4149 - Identifying the genetic markers associated with within-individual variability in blood pressure mini-project - 26/09/2022

B number: 
B4149
Principal applicant name: 
Richard Parker | University of Bristol (UK)
Co-applicants: 
Dr April Hartley, Prof Kate Tilling, Dr Jessica Barrett, Helen Natukunda
Title of project: 
Identifying the genetic markers associated with within-individual variability in blood pressure (mini-project)
Proposal summary: 

Evidence suggests that erratic (highly-variable) blood pressure, as well as high mean average blood pressure, could be associated with cardiovascular disease (CVD). As such, a better understanding of the associations of genes with blood pressure variability could provide further insight into the development of CVD. However, whilst there has been considerable research identifying the genetic factors associated with mean average blood pressure, little is known about the associations of genetic factors with blood pressure variability. The project aims to address this by analysing data from ALSPAC to investigate associations between blood pressure variability and genes.

Impact of research: 
Identify genetic variants associated with within-individual blood pressure variability, which could provide insight into the development of cardiovascular disease.
Date proposal received: 
Thursday, 15 September, 2022
Date proposal approved: 
Monday, 26 September, 2022
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Hypertension, GWAS, Statistical methods, Blood pressure, Cardiovascular, Genetic epidemiology, Genome wide association study, Statistical methods

B4143 - LoF MC3R coding mutations in cohorts of patients with delayed puberty - 20/09/2022

B number: 
B4143
Principal applicant name: 
Stephen O'Rahilly | Wellcome MRC Institute of Metabolic Science (UK)
Co-applicants: 
Professor Nicholas Timpson, Dr Ahmed Elhakeem, Laura Corbin, Ruby Tsang
Title of project: 
LoF MC3R coding mutations in cohorts of patients with delayed puberty
Proposal summary: 

We are currently writing a follow-up MC3R paper where we have found and characterised LoF MC3R coding mutations in cohorts of patients with delayed puberty, in collaboration with Dr Yee-Ming Chan, a member of the Delayed Puberty Genetics Consortium based in Boston, and Prof Peter Clayton from Manchester University. 
 
We have found 3/268 heterozygous individuals total in these cohorts carrying LoF MC3R mutations and we have compared this to the number of individuals in ALSPAC carrying both partial or complete LoF MC3R mutations, to see if there is any enrichment in the delayed puberty cohorts compared to ALSPAC as a control cohort.
 
We currently have an estimate (from previous sequence data in ALSPAC) of the number of carriers in ALSPAC for the pLoF R220S mutation - 29 het individuals - based on the frequency of coverage of this variant within the pooled target capture sequencing data performed for MC3R. However as we never broke these pools we do not have a validated number of carriers for this variant (chr20_56249501_C_A).

Impact of research: 
Better understanding of rare variants in the MC3R locus.
Date proposal received: 
Monday, 5 September, 2022
Date proposal approved: 
Tuesday, 20 September, 2022
Keywords: 
Genetics, Growth, development, maturation., DNA sequencing, Development

B4144 - Ability of adult blood pressure-related CpGs to predict blood pressure in childhood and adolescence - 20/09/2022

B number: 
B4144
Principal applicant name: 
Hannah Elliott | University of Bristol (UK)
Co-applicants: 
Dr Paul Yousefi, Mr Mohammed el Sharkawy, Dr Leanne Kupers
Title of project: 
Ability of adult blood pressure-related CpGs to predict blood pressure in childhood and adolescence
Proposal summary: 

Hypertension is one of the strongest risk factors for cardiovascular disease, which is the leading cause of death worldwide (1). Early-life exposures have been associated with blood pressure and the development of hypertension (2), with differential DNA methylation suggested as a potential underlying mechanism (3). Two large epigenome-wide association studies (EWAS) on systolic and diastolic blood pressure in adults have identified associations with DNA methylation (DNAm) levels of multiple Cytosine-phosphate-Guanine (CpG) sites (4,5). In the CHARGE consortium, one large-scale multi-ethnic EWAS on blood pressure in n=9,828 adults identified 13 CpGs annotated to 8 genes that were associated with blood pressure (4). A DNAm risk score based on these CpGs explained 1.4% and 2.0% of the inter-individual variation in systolic and diastolic BP, respectively. Another, more recent, EWAS on 4,820 multi-ethnic adults (6), identified 33 CpGs that explained an additional 3.3% and 4.0% of the inter-individual variation in systolic and diastolic blood pressure, respectively, beyond the traditional blood pressure risk factors age, sex, and body mass index (BMI), with 3 CpGs overlapping with the CHARGE study. The majority of the discovered CpG sites have been linked with other metabolic phenotypes including obesity, lipids, CRP, insulin resistance, and type 2 diabetes mellitus by previous epigenome-wide association studies (6), indicating that DNAm may be one of the common factors related to the concurrence of multiple cardiometabolic abnormalities.

Much less is known about the associations between DNAm and blood pressure in children. It is also not known if blood pressure associations with DNAm found in adults are already apparent in early childhood, late childhood and adolescence. Therefore, in this project, we aim to test the ability of a methylation risk score, developed using CpGs previously identified to be associated with SBP and DBP in adult EWAS meta-analysis by Richard (4) and Huang (6), to predict blood pressure at multiple timepoints in childhood and adolescence, and its added value compared to a risk score constructed only from the basic covariates age, sex and BMI.
This weighted methylation risk score was developed using the CpGs from the adult studies that survived a penalized elastic net regression in the ALSPAC adult data.

1. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, et al. A comparative risk assessmentof burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet (London, England).2012;380(9859):2224-60.
2. Lackland DT. Fetal and Early Life Determinants of Hypertension in Adults. Hypertension. 2004;44(6):811-2.
3. Wang X, Falkner B, Zhu H, Shi H, Su S, Xu X, Sharma AK, Dong Y, Treiber F, Gutin B, et al.. A genome-wide methylation study on essential hypertension in young African American males. 2013; 8:e53938.
4. Richard MA, Huan T, Ligthart S, Gondalia R, Jhun MA, Brody JA, Irvin MR, Marioni R, Shen J, Tsai PC,Montasser ME, Jia Y, Syme C, Salfati EL, Boerwinkle E, Guan W, Mosley TH Jr, Bressler J, Morrison AC,Liu C, Mendelson MM, Uitterlinden AG, van Meurs JB; BIOS Consortium, Franco OH, Zhang G, Li Y, Stew-art JD, Bis JC, Psaty BM, Chen YI, Kardia SLR, Zhao W, Turner ST, Absher D, Aslibekyan S, Starr JM,McRae AF, Hou L, Just AC, Schwartz JD, Vokonas PS, Menni C, Spector TD, Shuldiner A, Damcott CM,Rotter JI, Palmas W, Liu Y, Paus T, Horvath S, O'Connell JR, Guo X, Pausova Z, Assimes TL, SotoodehniaN, Smith JA, Arnett DK, Deary IJ, Baccarelli AA, Bell JT, Whitsel E, Dehghan A, Levy D, Fornage M. DNAMethylation Analysis Identifies Loci for Blood Pressure Regulation. Am J Hum Genet. 2017 Dec7;101(1):888-902.
5. Kazmi N, Elliott HR, Burrows K, Tillin T, Hughes AD, Chaturvedi N, et al. (2020) Associations between highblood pressure and DNA methylation. PLoS ONE 15(1): e0227728.
6. Huang Y, Ollikainen M, Muniandy M, Zhang T, Dongen Jv, Hao G, et al. Identification, Heritability, and Re-lation With Gene Expression of Novel DNA Methylation Loci for Blood Pressure. Hypertension.2020;76(1):195-205.
7. Gervin, K., Salas, L.A., Bakulski, K.M. et al. Systematic evaluation and validation of reference and library selection methods for deconvolution of cord blood DNA methylation data. Clin Epigenet 11, 125 (2019).

Impact of research: 
This research will improve knowledge of the relationship between DNA methylation and BP across the lifecourse. This research will will improve current risk scores to predict blood pressure in children.
Date proposal received: 
Monday, 12 September, 2022
Date proposal approved: 
Tuesday, 20 September, 2022
Keywords: 
Epidemiology, Hypertension, Statistical methods, Methylation analysis, Blood pressure, Cardiovascular, Epigenetics

B4145 - Fatigue among adolescents and young people with psychotic experiences Results from the ALSPAC birth cohort - 20/09/2022

B number: 
B4145
Principal applicant name: 
Trudie Chalder | King's College London (United Kingdom)
Co-applicants: 
Ms Kim Poole-Wright, Fiona Gaughran, Mr Ismail Guennouni
Title of project: 
Fatigue among adolescents and young people with psychotic experiences: Results from the ALSPAC birth cohort
Proposal summary: 

The experience of psychotic-like experiences (PLE), such as hallucinations and delusions, are not uncommon in the general population. Previous studies have indicated that adolescents reported higher rates of approximately 13% for at least one symptom (Horwood et al., 2008) and 4.9% for ‘definite’ symptoms among 18 year olds. Research shows that those with PLE have lower global and social functioning outcomes (Pontillo, De Luca, Pucciarini, Vicari, & Armando, 2018), which become progressively impaired on the course to schizophrenia (Addington, 2003). Among these impairments, is a ‘marked lack of energy’. Fatigue becomes a factor in the prodrome phase of psychosis (Chen et al., 2019), and for those with a psychotic diagnosis (Poole-Wright, Gaughran, Murray, & Chalder, 2022). Although it is an important factor in these phases, not much is known about fatigue in those experiencing attenuated symptoms. Some research into sub-types of PLE, such as unusual perceptual experiences or ideas of reference, has been related to fatigue. For example, fatigue was found to mediate the relationship between adverse experiences with caregivers and ideas of reference in non-clinical participants (León-Palacios, Garrido-Fernández, Senín-Calderón, Perona-Garcelán, & Rodríguez-Testal, 2019). Young people at ultra-high risk were found to manage their fatigue by various strategies (Carney, Cotter, Bradshaw, & Yung, 2017). However, fatigue and its associations in those with PLE remain under-explored in the literature. This research will address this gap in the literature by examining the prevalence and associations of fatigue in adolescents and young people who experience psychotic-like symptoms.

Impact of research: 
This research is intended to extend current understanding of fatigue symptoms in psychosis by investigating whether fatigue is implicated in adolescents with psychotic-like experiences, and if tiredness is an important factor in PLE. This could be significant in the continuum to a psychosis diagnosis by indicating that fatigue is a factor in the early alterations in functioning (alongside cognitive, social and communication declines) in those with PLE.
Date proposal received: 
Monday, 12 September, 2022
Date proposal approved: 
Tuesday, 20 September, 2022
Keywords: 
Epidemiology, Chronic fatigue, Statistical methods, psychotic experiences, fatigue, depression, anxiety, physical activity

B4138 - Financial difficulties and the cost of living crisis - 13/09/2022

B number: 
B4138
Principal applicant name: 
Nic Timpson | UoB
Co-applicants: 
Prof Kate Northstone
Title of project: 
Financial difficulties and the cost of living crisis
Proposal summary: 

With the current cost of living crisis, it is important to include relevant questions on financial difficulties in the next questionnaires going out to both G0 and G1 in order to understand the impact this will have on their lives.

Impact of research: 
Date proposal received: 
Friday, 2 September, 2022
Date proposal approved: 
Tuesday, 13 September, 2022
Keywords: 
Social Science, Social science

B4139 - Childhood predictors of later-emerging ADHD among women - 13/09/2022

B number: 
B4139
Principal applicant name: 
Jessica Agnew-Blais | Queen Mary University London (UK)
Co-applicants: 
Title of project: 
Childhood predictors of later-emerging ADHD among women
Proposal summary: 

Until recently, attention deficit hyperactivity disorder (ADHD) was thought of as a childhood disorder that mostly affected boys; thus the majority of ADHD research neglects ADHD among girls, and to an even greater extent, ADHD among adult women. While in childhood, ADHD has a strong male preponderance (10:1 to 2:1 male:female ratio), by adulthood this imbalance has disappeared and women make up 50% of the adult ADHD population. One explanation for this change could be that girls with ADHD are missed in childhood and only join the ADHD population in adulthood when they are asked to report their own symptoms, rather than relying on parent or teacher report. This is supported by research that finds teachers are less likely to identify ADHD symptoms among girls, and that girls are more likely to present with symptoms of inattention than hyperactivity/impulsivity, which may cause them to ‘fly under the radar’ of parents and teachers. Alternatively, some girls may not the exhibit the full disorder in childhood, but their symptoms may be exacerbated by the challenges of adolescence and young adulthood, such that they begin to meet full ADHD criteria in adulthood. To better understand what characterizes these cases of missed/subthreshold ADHD among girls, this proposal seeks to identify childhood risk factors among girls across socioenvironmental, behavioural and cognitive domains that predict later-emerging adult ADHD.

Impact of research: 
Several lines of research point to under-recognition and underdiagnosis of ADHD among girls compared to boys; and even when girls are diagnosed, it tends to occur at older ages than boys. Women are also more likely to have received other diagnoses prior to their ultimate diagnosis of ADHD, and this later and potential misdiagnosis can result in years of poorer functioning, feelings of low self-worth, and higher risk for depression and anxiety. It is critical to identify factors in childhood that increase risk for adult ADHD among girls, to support earlier identification and intervention.
Date proposal received: 
Friday, 2 September, 2022
Date proposal approved: 
Tuesday, 13 September, 2022
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Psychology - personality

B4142 - Decision-Making Dashboard for Designing Diabesity Prevention Programmes for Children and Young People - 13/09/2022

B number: 
B4142
Principal applicant name: 
Jackie Blissett | Institute of Health and Neurodevelopment, Aston University (UK )
Co-applicants: 
Krishnarajah Nirantharakumar
Title of project: 
Decision-Making Dashboard for Designing ‘Diabesity’ Prevention Programmes for Children and Young People
Proposal summary: 

Obesity and Type 2 diabetes (T2D) (together, called 'diabesity') has an extensive economic burden, a negative impact on healthy life expectancy and is linked to lower quality of life particularly in children and young people (CYP). Diabesity is also strongly linked to health inequity: CYP who are from ethnic minorities, with lower socio-economic position, have much higher risk of diabesity and the poor health associated with it. We have recently shown, using data from primary care records, sharp rises in pre-diabetes and T2D in CYP; incidence rates of T2D in CYP have increased almost threefold from 2005 to 2019. There is an urgent need to invest in diabesity prevention and the development and implementation of specific plans to improve the care of CYP with diabesity. Obesity is the main risk factor for T2D which we are able to modify. Risk of T2D rises with increasing BMI, and only 1.5% of children with T2D have a healthy weight. Interventions to manage weight and physical activity have the potential to reduce T2D risk. Whilst we have identified a number of risk factors for diabesity, we do not know enough about how these multiple factors interact together and across time. This is known as a complex system, with multiple factors interacting and developing together across time. Complex systems make it difficult to identify prevention or intervention strategies that will work for everyone, because of the wide variation of possibilities in the system. This means that, for complex health problems like diabesity, we need to better understand and map the complex system before we can determine what prevention or intervention services would work for who, and when, and at what cost. This would also us to 'tailor' prevention programmes to specific groups to make them as effective as possible as well as estimating their economic costs and benefits.

In this project we will map the complex system of diabesity in CYP, integrating the existing literature with data collected in primary care and birth cohort studies (ALSPAC, Born in Bradford and the Millennium cohort), as well as expert stakeholder input. We will then use a simulation technique called agent-based modeling, which is used to study complex systems and allows us to use artificial intelligence to model what would happen if we introduce a prevention programme with specific features at specific time points to specific groups of people. We will also include health economic data in the model so that economic costs and benefits of programs can be modelled.

The final output of the project will be an open access decision making 'dashboard': a state-of-the-art multi-agent systems simulation tool for Type 2 diabetes prevention in children and young people with which policy makers, commissioners, service providers and clinicians can simulate tailored prevention programmes and strategies for their target population. We will produce training and support materials to maximise usability and uptake. The 'Diabesity Dashboard' will support commissioning of real-life programs tailored for specific groups that are most likely to work and be cost effective.

Impact of research: 
Our analysis of the ALSPAC data is one fundamental aspect of the broader 'Diabesity Dashboard' programme, which has the potential for significant impact to the provision of diabesity prevention services for children and young people. Data analysis from ALSPAC will contribute to the modelling which will allow us to predict which prevention strategies would work for which groups and at what point in development these should be targeted for maximum efficacy to prevent T2D in CYP. Such a model will facilitate informed decision making by stakeholders invested in T2D prevention and will result in reduction of the substantial health inequalities associated with T2D.
Date proposal received: 
Monday, 5 September, 2022
Date proposal approved: 
Tuesday, 13 September, 2022
Keywords: 
Public health, medicine, computer science, psychology., Diabetes, Computer simulations/modelling/algorithms, BMI

B4137 - How and why does ADHD lead to depression in young people - 12/09/2022

B number: 
B4137
Principal applicant name: 
Lucy Riglin | Cardiff University (Wales)
Co-applicants: 
Title of project: 
How and why does ADHD lead to depression in young people?
Proposal summary: 

Depression is the leading mental health cause of disability in the world and has become more common in young people in the last few years. Young people with attention deficit/hyperactivity disorder (ADHD) are around five-times more likely to experience depression than those without ADHD. Depression in those with ADHD is especially serious – for example with a higher risk of suicide compared to either condition alone. However, standard interventions for depression do not seem to be as effective for young people with ADHD. To be able to advise future depression interventions, we need to understand the link between ADHD and depression. This project will examine (i) how the link between ADHD and depression develops across childhood, adolescence and young adulthood, (ii) cognitive and clinical factors that link ADHD and depression, and (iii) interpersonal relationship problems that link ADHD and depression.

Impact of research: 
Date proposal received: 
Sunday, 28 August, 2022
Date proposal approved: 
Monday, 12 September, 2022
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods

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