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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B3790 - Atopic disease impact on later educational attainment - 03/06/2021

B number: 
B3790
Principal applicant name: 
Amy Mulick | London School of Hygiene and Tropical Medicine (United Kingdom)
Co-applicants: 
Ms Rita Iskandar, Professor Sinéad Langan
Title of project: 
Atopic disease impact on later educational attainment
Proposal summary: 

The global burden of atopic diseases, in particular atopic dermatitis (AD), is on the rise. While most research is focused on the medical outcomes, a more encompassing approach is needed to highlight the effect of AD on social outcomes which has implications on future interventions and social support.
1 in 5 children in the UK suffers from AD, and to date, data are rather conflicting regarding its effect on educational attainment. A previous study on Swedish men who underwent military conscription at ages 17-20 years showed an association with attending university but no significant association between AD and secondary educational attainment after adjusting for family-related factors. Another cohort study on Dutch children found no association between AD and school performance at age 11.

Since educational attainment predicts future health and wellbeing, it is important to investigate any potential association with AD. AD may impact educational performance due to a multitude of factors: itching, poor sleep efficiency, and the use of sedative antihistamines could lead to absenteeism or poor concentration. AD stigma and comorbidities could increase depression, psychological distress, and the risk of attention deficit hyperactivity disorder, which may also adversely impact educational outcomes in affected children.
Additionally, neither have previous studies explored the effect of AD on exam results nor addressed the effect of the three main atopic diseases (AD, Hay fever, and Asthma) simultaneously. These diseases often co-occur, and it is important to determine the interplay and broader effect of atopic diseases on educational outcomes.

Impact of research: 
This paper will be written up for publication in a peer-reviewed journal, and will likely generate some evidence to encourage further detailed research.
Date proposal received: 
Wednesday, 19 May, 2021
Date proposal approved: 
Monday, 24 May, 2021
Keywords: 
Epidemiology, Allergy, Eczema, Statistical methods, Dermatology

B3771 - Testosterone and polygenic score and sex dimorphisms - 24/05/2021

B number: 
B3771
Principal applicant name: 
Tomas Paus | University of Toronto
Co-applicants: 
Zhijie Liao, MSc
Title of project: 
Testosterone and polygenic score and sex dimorphisms
Proposal summary: 

Testosterone has an influence on social behavior and cognition, such as brain response to faces. Testosterone exposure during puberty can modulate the effects of adult testosterone on brain response to faces. Genetic variants contribute to inter-individual variations in testosterone levels, and a polygenic score can be used as a summary index of such genetic variants. We will use the ALSPAC dataset to investigate (1) the relationship between average testosterone exposure during puberty and polygenic score for testosterone; (2) interplay between the polygenic score for testosterone and adult testosterone in brain response to faces. In addition, we will also explore the relationships between the polygenic score for testosterone and brain structure.

Prenatal testosterone is one of the critical factors influencing sexual dimorphic phenotypes. Stress can alter levels and function of testosterone, and in turn, lead to a reduction in biological effects of testosterone on body and brain function and structure. Thus, we expect that prenatal stress can modulate the levels of prenatal testosterone and, therefore, influence the degree of sexual dimorphism in the brain and body in later life.

Impact of research: 
Date proposal received: 
Tuesday, 4 May, 2021
Date proposal approved: 
Monday, 24 May, 2021
Keywords: 
Neurology

B3783 - An exploration into the links between educational attainment intelligence and wellbeing - 24/05/2021

B number: 
B3783
Principal applicant name: 
Claire Haworth | School of Psychological Science, University of Bristol.
Co-applicants: 
Jessica Armitage , Oliver Davis
Title of project: 
An exploration into the links between educational attainment, intelligence, and wellbeing.
Proposal summary: 

In a recent Mendelian Randomisation (MR) study we found a casual link to suggest an independent positive impact of staying in school on wellbeing, but a negative impact of intelligence on wellbeing. In the current project, we aim to explore further the extent to which either of these effects are moderated by the other. To do this, we will use available data from genome-wide association studies (GWAS) on educational attainment and intelligence to construct polygenic scores. These scores will be used in an interactive model to predict wellbeing in ALSPAC participants. This will allow us to investigate whether the positive effects of educational attainment are driven by those with higher intelligence, and whether negative effects of intelligence are moderated by spending more time in school. We also aim to understand more about the factors driving the main effects of educational attainment and intelligence on wellbeing. We will therefore investigate the potential role of socioeconomic status (SES), personality, and peer relations. Previous findings have shown that children more likely to complete more years of schooling tend to grow up in families with more socioeconomic resources (Krapohl & Plomin, 2016), have certain personality traits (Heckman, Stixrud & Urzua, 2006), and more extensive social networks (Chen, 2012). Thus, we aim to explore the extent to which these factors mediate or moderate associations between educational attainment and wellbeing, and between intelligence and wellbeing.

Impact of research: 
The current study will advance our understanding of the benefits of staying in school and why this may matter for wellbeing. The importance of education has been heavily emphasised in policy and government, yet little is known about its role in predicting positive aspects of mental health, and the role of factors driving positive effects. Understanding the relative contribution of education and intelligence on wellbeing is of clear importance for devising policy interventions focused on improving wellbeing. If the association between education and wellbeing is largely accounted for by intelligence, SES, or personality, interventions may benefit less from focusing on raising the school leaving age, and more on narrowing the gap to ensure those at risk of completing fewer years in school are supported.
Date proposal received: 
Tuesday, 18 May, 2021
Date proposal approved: 
Monday, 24 May, 2021
Keywords: 
Epidemiology, Polygenic risk scores, Genetic epidemiology

B3788 - Parental depression and young peoples higher education - 24/05/2021

B number: 
B3788
Principal applicant name: 
Amanda Hughes | University of Bristol (United Kingdom)
Co-applicants: 
Prof Laura Howe, Dr Tim Morris, Ms Sally Bowman
Title of project: 
Parental depression and young people’s higher education
Proposal summary: 

Higher education attendance has important implications for individual’s future outcomes with those who attend higher education having higher earnings on average, as well as better health outcomes.
Attendance at higher education is already known to be affected by socioeconomic status, with those from lower socioeconomic backgrounds attending lower quality institutions and courses, relative to their attainment. However less is known about the role maternal depression may play in young person’s attendance at higher education and how it may influence their course and institution. Maternal depression has previously been shown to affect development and wellbeing with maternal distress being associated with worse socioemotional development, as well as being associated with worse educational attainment. This research will build on this existing knowledge by exploring the influence maternal depression has on higher education attendance.

Impact of research: 
Date proposal received: 
Wednesday, 19 May, 2021
Date proposal approved: 
Monday, 24 May, 2021
Keywords: 
Epidemiology, Mental health, Statistical methods, Childhood - childcare, childhood adversity, Parenting, Social science

B3789 - Exploring the associations between ADHD symptoms mental health and higher education - 24/05/2021

B number: 
B3789
Principal applicant name: 
Amanda Hughes | University of Bristol (United Kingdom)
Co-applicants: 
Prof Laura Howe, Deborah Caldwell, Tim Cadman, Natalie Kravtsov
Title of project: 
Exploring the associations between ADHD symptoms, mental health and higher education
Proposal summary: 

This dissertation will explore any associations between ADHD symptoms (exposure), educational attainment (mediator) and mental health (outcome). Previous studies have suggested that severe ADHD symptoms lead to difficulties in university life and have a negative effect on mental health. A literature review found that young people with ADHD are less likely to pursue higher education and those who do are less likely to graduate a the same time as their peers. The majority of studies conducted on this topic are based in North America and use a small sample size from a single university. A study found that the majority of individuals with ADHD have comorbid disorders such as anxiey or mood disorders. This dissertation will attempt to understand what role higher education plays in this equation: does it have a protective or harmful effect on the association between ADHD and mental health. Unlike other studies, this study uses a large UK-based sample size and isn’t focused on a single institution. It aims to assess how partaking in higher education for individuals with ADHD affects their mental health later in life.

Impact of research: 
Date proposal received: 
Wednesday, 19 May, 2021
Date proposal approved: 
Monday, 24 May, 2021
Keywords: 
Epidemiology, Mental health, Attention-deficit hyperactivity disorder, Statistical methods, Social science

B3777 - Air pollution exposure during pregnancy and associations with child gene expression at birth - 24/05/2021

B number: 
B3777
Principal applicant name: 
Stine Marie Ulven | Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo (Norway)
Co-applicants: 
Amanda Rundblad, PhD, Kirsten Bjørklund Holven, Professor, Jason Matthews, Professor, Siddartha Das, Ana Luiza Goncalves Soares, Ahmed Elhakeem
Title of project: 
Air pollution exposure during pregnancy and associations with child gene expression at birth
Proposal summary: 

Exposure to air pollution increases the risk of cardiometabolic diseases. Inhaling air pollution, initiates inflammation, oxidative stress, and receptor activation, which in turn increases the risk of cardiovascular disease (CVD). Although the underlying mechanisms are largely unknown, altered gene expression may be involved in mediating the effects of air pollution on CVD risk. Already before birth, mothers’ exposure to air pollution is associated with foetal growth restriction and low birth weight, which may be caused by epigenetic changes and altered gene expression. In fact, air pollution may have a larger effect on gene expression in children than in adults. In this project, we will investigate the association between air pollution exposure during pregnancy and gene expression in cord blood in ALSPAC. Moreover, we aim to do pathway analyses to get insight into pathways that are associated with air pollution prenatally, and to investigate if the pathways involved have any associations with birth weight and cardiometabolic risk factors such as blood lipids. This work will be a part of the LongITools project, and we aim to do similar analyses in other cohorts, including Generation R (9-year old children) and in the Rotterdam study (adults, 40-100 years). By comparing findings between the different cohorts, we can get insight into biological pathways associated with air pollution throughout the life course.

Impact of research: 
A possible understanding of the underlying mechanisms behind the adverse health effects of air pollution exposure.
Date proposal received: 
Thursday, 6 May, 2021
Date proposal approved: 
Wednesday, 19 May, 2021
Keywords: 
Epidemiology, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Cardiometabolic disease risk, Microarrays, RNA, Biological samples -e.g. blood, cell lines, saliva, etc., Birth outcomes, Cardiovascular

B3784 - The Influence of Genetic Polymorphisms within the DNA Damage Response Pathway on the Age at Natural Menopause - 17/05/2021

B number: 
B3784
Principal applicant name: 
Kimberley Burrows | MRC IEU (United Kingdom)
Co-applicants: 
Dr. Gemma Ford, Alex Shattock
Title of project: 
The Influence of Genetic Polymorphisms within the DNA Damage Response Pathway on the Age at Natural Menopause
Proposal summary: 

The menopause is a significant event in the life of any woman, marking the end of their reproductive life. However, the timing of the menopause is not only associated with the end of fertility, but also the increased risk of mortality and developing serious morbidity, including cardiovascular disease; osteoporosis; and breast and endometrial cancer (Carty et al., 2013). Previous studies have concluded that the heritability of the age at natural menopause (ANM) is approximately 30-90% (Murabito, Yang, Fox and Cupples, 2005; Murabito, Yang, Fox, Wilson, et al., 2005; Long et al., 2006); therefore, understanding the precise pathways, genes and individual polymorphisms that affect the ANM, and therefore the risk of developing menopause-related disease, is important. The DNA damage response (DDR) pathway, and many genes within it, has been identified in several genome-wide association studies as significantly linked to the timing of the menopause (Stolk et al., 2012; Chen et al., 2014; Day et al., 2015; Wang et al., 2019). The mechanism behind this is theorised to be an increased rate of follicular atresia due to accumulating DNA damage, leading to earlier menopause in women with mutations that reduce the efficiency of genes within the DDR pathway (Stolk et al., 2012; Titus et al., 2013; Perry et al., 2014; Day et al., 2015).
Menarche is another reproductive milestone within a woman’s life, and the age at menarche (AAM) could theoretically influence the ANM (Parazzini, 2007). The duration of the reproductive years - between the AAM and ANM – is associated with oestrogen exposure which can increase or reduce the risks of developing certain diseases, such as atherosclerosis (Cui et al., 2006).

In this project, we aim to investigate the associations between single nucleotide polymorphisms (SNPs) within genes of the DDR pathway and the ANM and AAM in mothers from the Avon Longitudinal Study of Parents and Children (ALSPAC). This will form part of the research project component of my MSc degree in Reproduction and Development at the University of Bristol.
This proposal forms the basis of a multidisciplinary, collaborative MSc student research project which is being jointly supervised by research groups in Population Health Sciences and Translational Health Sciences, and financially supported by the MSc in Reproduction and Development within the Bristol Medical School. As part of this postgraduate taught MSc (https://www.bristol.ac.uk/study/postgraduate/2021/health-sciences/msc-re...), the 60-credit research project encompasses a student-led topic of interest, composed of a detailed literature review and a novel research dissertation which can be in the form of a data analysis project (this proposal) or a paper-based project.
As such, data extraction will be performed by an ALSPAC direct user (Kimberley Burrows) and this dataset will be sent to the ALSPAC data team for ID recoding prior to forwarding on to the primary analyst (Alex Shattock, RED MSc student 2020-21).

References
Carty, C. L., Spencer, K. L., Setiawan, V. W., et al. (2013) ‘Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study.’, Human reproduction (Oxford, England), 28(6), pp. 1695–1706.
Chen, C. T. L., Liu, C.-T., Chen, G. K., et al. (2014) ‘Meta-analysis of loci associated with age at natural menopause in African-American women.’, Human molecular genetics, 23(12), pp. 3327–3342.
Day, F. R., Ruth, K. S., Thompson, D. J., et al. (2015) ‘Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair.’, Nature genetics, 47(11), pp. 1294–1303.
Cui, R., Iso, H., Toyoshima, H., et al. (2006) ‘Relationships of age at menarche and menopause, and reproductive year with mortality from cardiovascular disease in Japanese postmenopausal women: the JACC study.’, Journal of epidemiology, 16(5), pp. 177–184.
Long, J.-R., Shu, X.-O., Cai, Q., et al. (2006) ‘Polymorphisms of the CYP1B1 gene may be associated with the onset of natural menopause in Chinese women.’, Maturitas, 55(3), pp. 238–246.
Murabito, J. M., Yang, Q., Fox, C. S. and Cupples, L. A. (2005) ‘Genome-wide linkage analysis to age at natural menopause in a community-based sample: the Framingham Heart Study.’, Fertility and sterility, 84(6), pp. 1674–1679.
Murabito, J. M., Yang, Q., Fox, C. S., Wilson, P. W. F., et al. (2005) ‘Heritability of age at natural menopause in the Framingham Heart Study.’, The Journal of clinical endocrinology and metabolism, 90(6), pp. 3427–3430.
Parazzini, F. (2007) ‘Determinants of age at menopause in women attending menopause clinics in Italy’, Maturitas, 56(3), pp. 280–287.
Perry, J. R. B., Hsu, Y.-H., Chasman, D. I., et al. (2014) ‘DNA mismatch repair gene MSH6 implicated in determining age at natural menopause.’, Human molecular genetics, 23(9), pp. 2490–2497.
Stolk, L., Perry, J. R. B., Chasman, D. I., et al. (2012) ‘Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.’, Nature genetics, 44(3), pp. 260–268.
Titus, S., Li, F., Stobezki, R., et al. (2013) ‘Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans’, Science translational medicine, 5(172), p. 172ra21.
Wang, G., Lv, J., Qiu, X. and An, Y. (2019) ‘Integrating genome-wide association and eQTLs studies identifies the genes associated with age at menarche and age at natural menopause.’, PloS one, 14(6), p. e0213953.

Impact of research: 
The impact of individual SNPs within these genes on the ANM has been estimated by previous studies to be quite sizable, with the potential to alter the timing of menopause by more than 5 years. This would have a large impact on women’s risk of menopause-related disease. It is also important to understand the effect of SNPs with smaller effects that may still contribute to a large additive effect. There is conflict in the literature regarding the size of effect, significance and even the direction of effect of certain SNPs on the ANM and AAM. This project will help to understand the results of previous genome-wide association studies (GWAS’s), as well as potentially uncovering new associations in a smaller-scale association study. Although this MSc project is unlikely to result in a publication, it has the potential to be presented at a conference that would spread awareness of ALSPAC to a wider audience. In addition, results may inform additional projects furthering the collaboration between THS and PHS.
Date proposal received: 
Thursday, 13 May, 2021
Date proposal approved: 
Monday, 17 May, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Contraception, Genetic epidemiology, Genetics, Genomics, Hormones - cortisol, IGF, thyroid, Mothers - maternal age, menopause, obstetrics, Puberty, Reproduction Fertility Age of natural menopause

B3785 - Modelling longitudinal BMI and height over childhood for GWAS - 17/05/2021

B number: 
B3785
Principal applicant name: 
Kimberley Burrows | MRC IEU (United Kingdom)
Co-applicants: 
Professor Debbie Lawlor, Professor Sylvain Sebert, Dr. Nicole Warrington, Dr Mickaël Canouil, Dr. Anni Heiskala , Dr Jonathan Bradfield
Title of project: 
Modelling longitudinal BMI and height over childhood for GWAS
Proposal summary: 

GWAS have been enormously successful in uncovering novel genetic variants associated with a range of complex human diseases, but the majority have used cross-sectional data and relatively simplistic statistical tests. Longitudinal studies are advantageous for investigating genetic associations as they: 1) facilitate the detection of genetic variants that influence change in a trait over time; and 2) allow the detection of genes that are associated with the age of onset of a trait. Improving analytic techniques for conducting longitudinal GWAS offers the opportunity to advance our understanding of the aetiology of health and disease.

To test statistical methods for modelling trajectories, we have selected two growth traits: height and body mass index (BMI). These traits were selected as most cohorts within EGG (The Early Growth Genetic consortium) have data available for analysis, therefore maximizing our sample size. Height was chosen as its trajectory has a relatively simple (linear) shape, whereas BMI is more complex but is of interest to a large number of groups within the consortium. Ideally, the methods we define will be transferable to other traits of interest across the consortium.

Childhood obesity is associated with poor mental and physical health and is one of the strongest predictors of adult obesity. BMI, the most commonly used quantitative measure of adiposity, follows a well-characterised trajectory throughout childhood: a rapid increase soon after birth until approximately 9 months, the adiposity peak, followed by a gradual decline until around 4–6 years of age, the adiposity rebound, followed by an increase again until the end of puberty. Although the community has identified a large number of genetic variants associated with adult BMI, relatively little is known about the genetic determinants of BMI throughout infancy and childhood, or the rate of growth across early life.

Distinct height growth patterns, particularly during puberty, have also been linked with adverse health outcomes such as poor cardio-metabolic health. Analysis in the EGG consortium using SITAR growth curve analysis has shown that velocity of height growth throughout puberty is genetically correlated with adult health, including glycemic traits, metabolites, bone density measures, lung function and lung cancer. By investigating height growth across childhood, rather than just puberty, we will be able to investigate whether these genetic correlations are more generally related to early life growth.

Impact of research: 
To contribute to the wider understanding of the genetic contribution to growth throughout childhood and adolescence. This work will not only potentially contribute novel findings to help understand wider mechanisms involved in child growth, but will also contribute to designing and implementing efficient methodologies for genetic studies of longitudinal trait analysis.
Date proposal received: 
Monday, 17 May, 2021
Date proposal approved: 
Monday, 17 May, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Obesity, GWAS, BMI, Development, Genetic epidemiology, Genetics, Genomics, Genome wide association study, Growth, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Statistical methods

B3786 - application of co-occurrence networks to the discovery of preeclampsia risk - 17/05/2021

B number: 
B3786
Principal applicant name: 
Brian J Cox | UNIVERSITY OF TORONTO (Canada)
Co-applicants: 
Abigail Fraser, Andreea Obersterescu
Title of project: 
application of co-occurrence networks to the discovery of preeclampsia risk
Proposal summary: 

Typical analysis of genetic data to find a gene with a risk for a disease is designed to look for single gene/allele relationships. While multiple relationships can be found they assume independence. We have developed novel methods that assess allele-allele interactions. Normally in biology genes interact and abnormal changes in gene expression or functions in two or more members of an interacting set of genes may lead to disease. OUr novel methods can build netwoks of allels that combine to increase risk of preeclampsia and potentially other diseases of pregnancy.

Impact of research: 
Our analysis of an unrelated cohort of preeclampsia cases and controls suggest that our methods can identify networks of co-occurring polymorphic variant enriched to specific pathways linked to the pathophysiology of preeclampsia. Our method is more statistically robust than typical GWAS and can use a smaller sample size. The identification of associated co-occurring alleles with the risk of preeclampsia will establish new genetic-based diagnostic tests.
Date proposal received: 
Friday, 14 May, 2021
Date proposal approved: 
Monday, 17 May, 2021
Keywords: 
Bioinformatics, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Computer simulations/modelling/algorithms, GWAS, Statistical methods, Birth outcomes, Blood pressure, BMI, Cardiovascular, Genetic epidemiology, Genetics, Genomics, Genome wide association study, Statistical methods

B3780 - Is lung function a determinant of cognitive ability in children An analysis of a British birth cohort - 24/05/2021

B number: 
B3780
Principal applicant name: 
James Dodd | University of Bristol (United Kingdom)
Co-applicants: 
Raquel Granell, Jack Grenville
Title of project: 
Is lung function a determinant of cognitive ability in children? An analysis of a British birth cohort
Proposal summary: 

Multiple studies have found an association between decline in lung function and cognitive ability in later life such as memory and problem solving, but the relationship in childhood remains unknown. If an independent association between lung function and cognitive ability can be identified, the possibility arises that interventions to reduce pre-birth or early life risk factors for poor lung function could improve children’s life chances.

Impact of research: 
Improve our understanding of 2 of the word's leading long term condition of chronic lung disease and cognitive dysfunction.
Date proposal received: 
Tuesday, 11 May, 2021
Date proposal approved: 
Monday, 17 May, 2021
Keywords: 
Epidemiology, Cognitive impairment, Respiratory - asthma, Statistical methods, Environment - enviromental exposure, pollution

B3765 - Metabolomics of Asthma Chronic Obstructive Pulmonary Disease Lung Function and Allergy Phenotypes with COMETS - 17/05/2021

B number: 
B3765
Principal applicant name: 
Laura Corbin | MRC Integrative Epidemiology Unit, University of Bristol (United Kingdom)
Co-applicants: 
Neil Goulding, Raquel Granell, Deborah Lawlor, Jessica Lasky-Su, Dr Rachel Kelly
Title of project: 
Metabolomics of Asthma, Chronic Obstructive Pulmonary Disease, Lung Function and Allergy Phenotypes with COMETS
Proposal summary: 

Metabolomics, the systematic profiling of the small molecules in a biological system, represents a powerful tool to increase the understanding of the mechanisms of respiratory health. Several studies have used metabolomics to explore diseases including asthma and chronic obstructive pulmonary disease (COPD), suggesting there are alterations in the metabolome that reflect changes in the respiratory system. However, few studies have validated their findings in independent populations and few studies have investigated the metabolome of forced expiratory volume in one second (FEV1) or the ratio of FEV1 to forced vital capacity (FEV1/FVC), two key indicators of pulmonary function in both children and adults. Furthermore, large scale studies of allergic phenotypes that are relevant to respiratory disorders such as asthma are lacking. Consequently, metabolomic profiling of lung function and related allergic phenotypes warrants further investigation.
In this work we will evaluate relationships between metabolite concentrations with lung and allergic phenotypes, including asthma, Chronic Obstructive Pulmonary Disease (COPD) and lung function measurements (FEV1, FVC, FEV1/FVC, etc.) in ALSPAC. Our findings will be combined with those from other cohorts by analysts of the COMETS Lung Working Group within the Consortium of Metabolomics Studies.

Impact of research: 
A contribution to the identification of validated metabolomic biomarkers of lung function and disease (including asthma).
Date proposal received: 
Wednesday, 12 May, 2021
Date proposal approved: 
Monday, 17 May, 2021
Keywords: 
Epidemiology, Allergy, Respiratory - asthma, Metabolomics, NMR, Metabolic - metabolism

B3781 - Identifying risk factors for adverse mental health outcomes in orofacial cleft and optimising interventions to avoid these - 17/05/2021

B number: 
B3781
Principal applicant name: 
Gemma Sharp | MRC IEU, UoB
Co-applicants: 
Dr Evie Stergiakouli
Title of project: 
Identifying risk factors for adverse mental health outcomes in orofacial cleft and optimising interventions to avoid these
Proposal summary: 

Children born with a cleft (gap) in the lip and/or palate face tough challenges throughout their lives. They undergo multiple operations and attend numerous clinical appointments, creating significant stress on children and their families. Many children experience facial disfigurement and difficulties making themselves understood, which can lead to teasing and low self-esteem. These children are particularly vulnerable to mental health issues, but it’s currently unclear how many children are at risk and how to identify them. With the COVID-19 pandemic introducing additional difficulties with delaying surgeries and disrupting schooling, we urgently need to develop a better understanding of which children are likely to need additional psychological support. Therefore, this research project aims to shed light on the pathways linking clefts to mental health problems. We will capitalise on our existing access to large-scale population-wide and clinical cohort studies, including the Cleft Collective cohort study, which is the world’s largest and most detailed longitudinal cohort study of children and families affected by cleft. In this established cohort, we will send additional questionnaires to collect more information as the children grow up and enter puberty, which is when mental health problems tend to emerge. Using these data, we will provide the first detailed description of mental health outcomes in children born with a cleft, and compare this to the same outcomes in children without a cleft IN THE ALSPAC COHORT and the Millennium Cohort Study. We will use state-of-the-art statistical approaches to study the contribution of genetic and environmental factors to shaping mental health in children born with a cleft, and we will use data from the Cleft Collective cohort study’s COVID-19 questionnaire to study the impact of the pandemic on these particularly vulnerable children, many of whom experienced delays in their surgeries. Finally, we will use our existing strong links to the NHS cleft teams and cleft charities to feed our findings directly into clinical decision making and policy to enable clinicians to plan provision to improve mental health outcomes for these children.

Impact of research: 
By capitalising on our access to large-scale population-wide and clinical cohort studies, our project will provide the first detailed description of neurodevelopmental and mental health outcomes in children born with CL/P. Using our expertise in genetic epidemiology and causal inference, we will explore the contributions of genetic, prenatal environmental, and downstream factors associated with having CL/P on mental health outcomes. Using existing data collected before and during the COVID-19 pandemic, we will study whether and how the COVID-19 situation has affected the mental health and wellbeing of this paediatric population. Finally, through our established, strong network of NHS and charity stakeholders, our scientific insights will be fed directly into clinical decision making and policy. Therefore, our research will make a valuable contribution to improving mental health and neurodevelopmental outcomes for this vulnerable population of children.
Date proposal received: 
Tuesday, 11 May, 2021
Date proposal approved: 
Monday, 17 May, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, child behaviour and mental health

B3782 - Genome-wide association study of menstruation-related traits - 17/05/2021

B number: 
B3782
Principal applicant name: 
Gemma Sharp | MRC IEU, UoB
Co-applicants: 
Dr Rebecca Richmond, Bethan Whiddon
Title of project: 
Genome-wide association study of menstruation-related traits
Proposal summary: 

Female reproductive health and research into menstruation disorders/traits is an incredibly underfunded area of medical research. It is commonplace for data to be collected as part of questionnaires, yet much of the data collected by UK Biobank and the ALSPAC cohort has had little attention to date. Conducting a Genome-wide association study (GWAS) would be a promising approach to improve the knowledge and understanding of the genetic contribution and variants associated with these phenotypes. Heavy menstrual bleeding and painful periods are considered common conditions, yet the prevalence is unclear, with studies reporting between 16-91% for painful periods and 20-54% for heavy menstrual bleeding in different populations(1, 2). It is clear further research is needed within this field to better understand the genetic architecture of menstrual disorders. In this student project, the student will conduct GWAS of menstrual conditions in UK Biobank and seek replication in ALSPAC.

Impact of research: 
We plan to publish results of this novel GWAS and the results will also inform future genetic epidemiological studies to explore causal associations between risk factors, menstrual traits and outcomes.
Date proposal received: 
Tuesday, 11 May, 2021
Date proposal approved: 
Monday, 17 May, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Women's health, GWAS

B3778 - Understanding the experiences of young parents during the COVID pandemic a qualitative study - 24/05/2021

B number: 
B3778
Principal applicant name: 
Louise Dalton | University of oxford (United Kingdom)
Co-applicants: 
Dr Elizabeth Rapa, Dr Rebecca Pearson
Title of project: 
Understanding the experiences of young parents during the COVID pandemic: a qualitative study
Proposal summary: 

The peak onset of psychological disorders is during adolescence and early adulthood. Simultaneously, many young people start a family during this time; pregnancy and parenting are major risk factors within this already vulnerable age group, both for parents’ mental health, and their children’s emotional and developmental outcomes.

COVID-19 has compounded the situation by disrupting both informal and professional support networks for these young people. Young families find themselves isolated from their extended family and support networks who might otherwise be able to offer both practical help, but also model sensitive early interactions with infants. This isolation during such an intense and demanding period is likely to negatively impact on parents’ mental health.

The aim of this project is to explore the experiences of young parents’ during the pandemic and identify their specific needs regarding parenting and mental health. This will help us understand how they and their children can be better supported by services post-pandemic.

Impact of research: 
Our research will document parents' qualitative feedback about their experiences during the pandemic. This understanding is vital to understand parental needs and make evidence-based recommendations about service configuration and delivery post-pandemic.
Date proposal received: 
Thursday, 6 May, 2021
Date proposal approved: 
Thursday, 13 May, 2021
Keywords: 
Parenting , Mental health, Qualitative study, Parenting

B3772 - Incorporating a developmental perspective into gene identification models for alcohol outcomes - 13/05/2021

B number: 
B3772
Principal applicant name: 
Jessica Salvatore | Department of Psychology, Virginia Commonwealth University (United States)
Co-applicants: 
Mr. Nathaniel Thomas
Title of project: 
Incorporating a developmental perspective into gene identification models for alcohol outcomes
Proposal summary: 

Studies that aim to identify genes associated with alcohol use outcomes in longitudinal datasets often average across timepoints or examine lifetime measures, constructing phenotypes that disregard developmental variability in genetic effects. Predictive models of genetic influences on alcohol use may be improved if they measure genetic effects that are unique to different developmental periods and, subsequently, leverage these unique effects for the prediction of alcohol use outcomes throughout the lifespan. The proposed research will implement novel methods to conduct a longitudinal gene-identification study of alcohol use and use the resulting genetic effects to predict alcohol use throughout the lifespan in an independent sample.

Impact of research: 
This project provides an analytic approach for developmentally-informed genetic prediction of alcohol use outcomes. These novel methods will advance the field of genetics beyond the study of aggregated longitudinal phenotypes and represents an important step towards the goal of advancing precision medicine strategies for alcohol use outcomes.
Date proposal received: 
Tuesday, 4 May, 2021
Date proposal approved: 
Thursday, 13 May, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., GWAS, Development, Genetic epidemiology, Genome wide association study

B3774 - Selection bias in epigenome-wide association studies - 13/05/2021

B number: 
B3774
Principal applicant name: 
Matthew Suderman | Population Health Sciences, Bristol Medical School (UK)
Co-applicants: 
Title of project: 
Selection bias in epigenome-wide association studies
Proposal summary: 

Selection bias is pervasive in human studies and even more so for epigenome-wide association studies (EWAS) due to the relatively high costs of measuring DNA methylation. Although this bias is often acknowledged, its impact on findings has not been evaluated. We aim to perform such an evaluation for EWAS performed in ALSPAC. We will characterise selection by comparing the characteristics of ALSPAC participants measured at baseline with and without DNA methylation profiles and then estimate the resulting bias using simulations informed by the data.

Impact of research: 
A better understanding of the effects of selection bias in epigenome-wide association studies as well as advice for identifying and mitigating these effects in future studies.
Date proposal received: 
Thursday, 6 May, 2021
Date proposal approved: 
Thursday, 13 May, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), No specific diseases will be investigated., Computer simulations/modelling/algorithms, Statistical methods, Cohort studies - attrition, bias, participant engagement, ethics, Epigenetics, Statistical methods

B3649 - Estimated Prevalence and Stability of Nonverbal Learning Disability - 24/05/2021

B number: 
B3649
Principal applicant name: 
Amy Margolis | Columbia University Medical Center (USA)
Co-applicants: 
Ena Selmanovic, Bruce Ramphal, David Pagliaccio, Jordan Dworkin, Katherine Keyes , Ava Hamilton, Alan Emond
Title of project: 
Estimated Prevalence and Stability of Nonverbal Learning Disability
Proposal summary: 

Nonverbal Learning Disability (NVLD) is a disorder characterized by deficits in visual-spatial, but not verbal reasoning, as well as impairment in two of four areas: math calculation, visual executive functioning, fine motor skills, or social skills. Prior findings established the population prevalence of NVLD to be 3% - 4% in children and adolescents.(1) We aim to establish the stability of NVLD over time, using children’s test scores at two time points (age 7 to 9 and again at age 11 to 15). This project also identifies indicators and risk factors of NVLD, such as child temperament and environmental exposures, and studies NVLD's long term outcomes.

References

1. Margolis AE, Broitman J, Davis JM, Alexander LM, Hamilton A, Liao Z, Banker S, Thomas L, Ramphal B, Salum GA, Merikangas KR, Goldsmith J, Paus T, Keyes K, Milham MP. Estimated Prevalence of Nonverbal Learning Disability Among North American Children and Adolescents. JAMA Network Open. 2020;3(4):e202551-e202551.

Impact of research: 
We are conducting this study to support our submission to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) to consider NVLD as a discrete clinical entity. We and others have already begun to establish the pathophysiology and prevalence of NVLD.(1-5) We are now working to document the stability, risk factors, and life course of NVLD to support this submission. Inclusion in the DSM-5 will have a large impact on the millions of children in the U.S. alone who, according to our prevalence study, will meet criteria for the disorder. Inclusion in the DSM-5 could potentially improve identification of individuals with NVLD and thus communication among treating professionals, provide access to care by allowing for billing for treatment, and encourage and support research on treatment by having a clear set of diagnostic criteria. Currently individuals with NVLD tend to receive diagnoses that capture some of their functional impairments but do not signal the hallmark feature of NVLD, a visual-spatial deficit. References 1. Margolis AE, Broitman J, Davis JM, Alexander LM, Hamilton A, Liao Z, Banker S, Thomas L, Ramphal B, Salum GA, Merikangas KR, Goldsmith J, Paus T, Keyes K, Milham MP. Estimated Prevalence of Nonverbal Learning Disability Among North American Children and Adolescents. JAMA Network Open. 2020;3(4):e202551-e202551. 2. Banker SM, Ramphal B, Pagliaccio D, Thomas L, Rosen E, Sigel AN, Zeffiro T, Marsh R, Margolis AE. Spatial Network Connectivity and Spatial Reasoning Ability in Children with Nonverbal Learning Disability. Sci Rep. 2020;10(1):561. 3. Margolis AE, Pagliaccio D, Thomas L, Banker S, Marsh R. Salience network connectivity and social processing in children with nonverbal learning disability or autism spectrum disorder. Neuropsychology. 2019;33(1):135-143. 4. Fine JG, Musielak KA, Semrud-Clikeman M. Smaller splenium in children with nonverbal learning disability compared to controls, high-functioning autism and ADHD. Child Neuropsychol. 2014;20(6):641-661. 5. Semrud-Clikeman M, Fine JG, Bledsoe J, Zhu DC. Regional Volumetric Differences Based on Structural MRI in Children With Two Subtypes of ADHD and Controls. J Atten Disord. 2014.
Date proposal received: 
Friday, 7 May, 2021
Date proposal approved: 
Thursday, 13 May, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Developmental disorders - autism, Cognitive impairment, Learning difficulty, Mental health, Nonverbal Learning Disability , Statistical methods, Biological samples -e.g. blood, cell lines, saliva, etc., Childhood - childcare, childhood adversity, Environment - enviromental exposure, pollution, Intelligence - memory

B3775 - Anxiety symptoms and eating patterns during COVID-19 for young UK adults with different eating behaviour traits - 13/05/2021

B number: 
B3775
Principal applicant name: 
Laura Johnson | Centre for Exercise, Nutrition and Health Sciences, School for Policy Studies, University of Bristol (United Kingdom)
Co-applicants: 
Miss Esther Curtin
Title of project: 
Anxiety symptoms and eating patterns during COVID-19 for young UK adults with different eating behaviour traits.
Proposal summary: 

This study will investigate the relationship between anxiety and eating patterns during COVID-19. At this stage in the research, eating patterns are defined by three variables: number of snacks consumed per day, number of meals consumed per day, and dietary intake. We also wish to find out whether individuals with different eating behaviour traits show variable effects. It will entail a secondary data analysis of the Avon Longitudinal Study of Parents and Children (ALSPAC), a large ongoing study that recruited approximately 14,000 pregnant women from one geographical area in the UK in 1991. Specifically, we will look at their now young adult children (aged approximately 28 years) and their responses on three questionnaires over the course of the COVID-19 pandemic from April 2020 to March 2021.

Impact of research: 
This study will advance current understanding of the change in eating patterns over the course of the pandemic by combining distinct variables that have not yet been examined concurrently. Our analyses may help to elucidate psychometric traits that exacerbate or protect against poor eating patterns during environmental stressors. This could in turn inform screening procedures leading to tailored nutrition interventions for vulnerable populations.
Date proposal received: 
Thursday, 6 May, 2021
Date proposal approved: 
Thursday, 13 May, 2021
Keywords: 
Social Science, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Eating disorders - anorexia, bulimia, Mental health, Obesity, Statistical methods, Cohort studies - attrition, bias, participant engagement, ethics, Physical - activity, fitness, function, Sleep, Social science, Eating architecture Diet Eating behaviour traits

B3779 - To what extent has increased anxiety levels from COVID-19 influenced obesogenic dietary patterns - 13/05/2021

B number: 
B3779
Principal applicant name: 
Laura Johnson | Supervisor
Co-applicants: 
Miss Lauren Cleghorn
Title of project: 
To what extent has increased anxiety levels from COVID-19 influenced obesogenic dietary patterns
Proposal summary: 

Since the coronavirus disease (COVID-19) outbreak in December 2019, changes to societies have been observed globally due to rising infection rates and fatalities. Despite economic risk, public health measures have been enforced, including lockdown(s), social distancing, self-isolation, shielding, and the closure to schools and businesses. We already understand that participants from the ALSPAC cohort have shown higher rates of anxiety. Therefore, this study hopes to determine what influence anxiety has had on obesogenic dietary patterns (energy-dense, high-fat and low-fibre diets).

Impact of research: 
Through the statistical methods outline above, I anticipate that I will be able to expand on the known impact COVID-19 has had on anxiety by showing the influence this has had on obesogenic dietary patterns. In addition, I expect that I will be able to outline the role (mediator/moderator etc) of demographic/ quality of life variables. Thereby, I predict that inferences towards necessary public health policies and interventions will be made.
Date proposal received: 
Friday, 7 May, 2021
Date proposal approved: 
Thursday, 13 May, 2021
Keywords: 
Public Health, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Mental health, Obesity, Statistical methods, Ageing, BMI, Sex differences, Sleep, Social science, Statistical methods, Cohort studies - attrition, bias, participant engagement, ethics, Development, Fathers, Mothers - maternal age, menopause, obstetrics, Nutrition - breast feeding, diet, Offspring, Parenting, Physical - activity, fitness, function

B3767 - Biological markers to study genetics environment and how they influence mental health - 13/05/2021

B number: 
B3767
Principal applicant name: 
Elvira Bramon | University College London (United Kingdom)
Co-applicants: 
Dr Eirini Zartaloudi
Title of project: 
Biological markers to study genetics, environment, and how they influence mental health.
Proposal summary: 

WHAT ARE THE CAUSES OF PSYCHOSIS?
Psychotic disorders including schizophrenia and bipolar disorder are potentially severe conditions affecting about 3% of the population, and constitute a major economic challenge throughout the world. A range of effective antipsychotic medications and psychological therapies are available, but about one in every three patients do not benefit from them. Antipsychotics can cause a range of common and serious side effects such as sleepiness, shaking, sexual dysfunction, obesity and diabetes.

Psychotic disorders emerge because of environmental as well as genetic factors. Established environmental risks include pregnancy and birth complications affecting a baby's brain development, the use of cannabis (especially if starting young), migration, growing up in a city and other factors. However, psychosis also runs in families and genetic factors (we will refer to them as "genetic variants") are important. There are many genetic variants, which are common in the population, but only convey small increases in risk for the disease. We know there are also a few genetic variants that are very rare (found only in 1 or 2 of every 1000 people), but when present, the risk of developing schizophrenia is increased between two and thirty-fold. Some of these rare genetic variants also increase the risk for learning disabilities, autism, epilepsy and a range of physical health problems. These rare genetic variants constitute the strongest known risk factors for schizophrenia and are the focus of this project.

STUDY OBJECTIVES
1. Investigate the influence that these rare high-risk genetic variants have on brain function and structure.
2. Understand why some carriers of the same high-risk variant develop different neurological or mental disorders and why some carriers remain well. Explore how other genetic as well as environmental factors modulate the impact of the high-risk variants: Can any of them reduce risks?
3. Investigate genetic and environmental influences on response to antipsychotic medications.
4. Combine or compare data from ALSPAC with our study at University College London (UCL).

HOW WILL WE DO THE RESEARCH?
We will analyse a large sample of volunteers who participated in our study in UCL including people with schizophrenia, bipolar or other psychotic disorders and controls without these conditions. More than 14,000 participants have already had their DNA examined with the latest genetic technology. Many study participants have completed brain scans, electroencephalograms (EEG tests similar to those used in epilepsy), cognitive and clinical assessments. To our knowledge, this is one of the largest and most thoroughly characterised studies of biomarkers and genetics of psychosis.

The ALSPAC project is similar to our study in London. Because some of the genetic variants we are investigating are very uncommon, it is best to combine the two studies and analyse them together. Where the genetic variants and traits are common and we have large samples already, then we will compare the findings from our study and from ALSPAC. This approach (combine or compare information) enhances the accuracy of the research.

WHY IS THIS IMPORTANT?
This project will offer new insights into how genetic variants predisposing to schizophrenia can influence brain anatomy, physiology and cognitive abilities. A better understanding of the genetics of psychosis will provide leads for the development of new medications and psychological interventions. Genetic advances will also help to identify people at high risk of developing psychosis who will benefit from earlier access to treatments, leading to a better recovery.

Impact of research: 
Understanding the neurobiological mechanisms underlying psychotic disorders is key to develop new treatments. Understanding better the genetic and environmental influences on response to antipsychotic drugs will help us optimise how we prescribe these medications.
Date proposal received: 
Friday, 7 May, 2021
Date proposal approved: 
Thursday, 13 May, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, DNA sequencing, GWAS, Microarrays, Biological samples -e.g. blood, cell lines, saliva, etc., Birth outcomes, BMI, Cognition - cognitive function, Equipment - MRI, Genetics, Genome wide association study, Intelligence - memory

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