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.

Click here to export results in Word format.

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

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

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

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

B3776 - Association of diet and physical activity with serum metabolites and cardiovascular disease risk in adolescents from the ALSPAC - 13/05/2021

B number: 
B3776
Principal applicant name: 
Laura Johnson | University of Bristol (United Kingdom)
Co-applicants: 
Mr Eduard Martinez
Title of project: 
Association of diet and physical activity with serum metabolites and cardiovascular disease risk in adolescents from the ALSPAC
Proposal summary: 

In this study I am going to look at how different lifestyle factors, like foods eaten, timing or frequency of eating, physical activity, sedentary behaviours and their timing or location, combine together to create an overall behavioural pattern score that indicates whether adolescents have good health. It has been previously found that a combination of factors is more important for health compared with single factors alone. I also plan to use a new, reproducible laboratory technique, known as metabolomics, to record over 220 measures of blood that indicate a range of metabolic processes. This will help to find out in much more detail than ever before how behaviour leads to better cardiovascular health via metabolic pathways. When it is known more about the pathway that leads from lifestyle to disease it will be easier to predict who will stay healthy and who will not from their behaviours.

I will be using information from diet diaries, activity monitors and blood samples that have already been provided by Children of the 90s participants when they were teenagers.

Impact of research: 
Identifying the metabolic intermediates between poor health behaviours and long-term metabolic risk has the potential to offer objective methods for monitoring health, looking at responses to intervention and preventing long-term risk of cardiometabolic disease.
Date proposal received: 
Thursday, 13 May, 2021
Date proposal approved: 
Thursday, 13 May, 2021
Keywords: 
Epidemiology, Diabetes, Hypertension, Obesity, Metabolomics, Biological samples -e.g. blood, cell lines, saliva, etc., Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Sex differences, Blood pressure, BMI, Cardiovascular, Cohort studies - attrition, bias, participant engagement, ethics, Metabolic - metabolism, Nutrition - breast feeding, diet, Physical - activity, fitness, function, Puberty

B3773 - Long COVID and mental health - 07/05/2021

B number: 
B3773
Principal applicant name: 
Alex | UoB (United Kingdom)
Co-applicants: 
Professor Nic Timpson, Dr Kate Northstone, Dr Rebecca Pearson
Title of project: 
Long COVID and mental health
Proposal summary: 

The COVID-19 pandemic and related mitigation measures have had a profound impact of society and wellbeing. Much research (including that of ALSPAC) has focused on the impact of the mitigation measures, rather than the impact of the disease. ALSPAC forms part of larger consortia examining the impact of contracting COVID-19 and Long COVID on later consequences, one of which is mental health.

This project will specifically focus on the impact of COVID-19 status and Long COVID throughout the pandemic, on later mental health by examining depression and anxiety in both generations of ALSPAC.

Impact of research: 
Results will be shared with PHE and HDRUK
Date proposal received: 
Wednesday, 5 May, 2021
Date proposal approved: 
Wednesday, 5 May, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Psychology - personality

B3764 - Assessing and taking account of measurement error using repeat measurements of exposure and outcome variables - 04/05/2021

B number: 
B3764
Principal applicant name: 
Rosie Cornish | University of Bristol (United Kingdom)
Co-applicants: 
Dr Willy Steven Kamgang, Professor Kate Tilling, Professor Deborah Lawlor
Title of project: 
Assessing and taking account of measurement error using repeat measurements of exposure and outcome variables
Proposal summary: 

Most measures in epidemiology are subject to error; despite this, the impacts of measurement error are often overlooked. Measurement error in an outcome variable will generally result in a loss of precision whereas measurement error in an exposure variable (or other covariate) will generally lead to bias in regression coefficients.
In this project we will quantify measurement error in systolic blood pressure, weight and height using repeated measurements made on a subsample of individuals attending ALSPAC clinics. We will then assess the impact of measurement error in these variables on regression coefficients and their standard errors.

Impact of research: 
Will help other users of ALSPAC data understand the extent of measurement error in these key variables and its likely impact on analyses.
Date proposal received: 
Wednesday, 21 April, 2021
Date proposal approved: 
Tuesday, 4 May, 2021
Keywords: 
Epidemiology, Statistical methods, Blood pressure, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Statistical methods

B3766 - An exploration into the impact of social contact on the risk of depressive symptoms during COVID-19 findings from a prospective - 04/05/2021

B number: 
B3766
Principal applicant name: 
Jessica Armitage | Co-Supervisor
Co-applicants: 
Professor Claire Haworth, Eunhee Kim
Title of project: 
An exploration into the impact of social contact on the risk of depressive symptoms during COVID-19: findings from a prospective
Proposal summary: 

COVID-19 has resulted in significant increases in psychological distress, concerns, and depressive symptoms. This increased vulnerability may have resulted from environmental and social changes caused by the pandemic crisis. Social contact modalities changed drastically due to lockdown restrictions throughout the COVID-19 pandemic. Stay at home and social distancing orders resulted in a decrease in in-person social contact, and a resulting increase in distant social contact via video calls, phone calls, and texts. Our study will explore whether these different forms of social contact influenced the levels of depression, and the possible factors driving this. Additionally, gender difference in the usage of social contact methods can have an association with the elevation of loneliness. Females are more susceptible to loneliness while keeping social distance due to COVID lockdown. Since females are more dependent on in-person social engagement, females could feel lonelier by the changes in social contact forms than males, which can further trigger depression. Hence, we will also consider whether the gender contributes to increasing depressive symptoms in relation to changes in social contact modalities caused by social distancing. Understanding how symptoms of depression may be predicted by different modes of social contact will prove key to ensuring those most at risk are supported to help prevent further increases in depression.

Impact of research: 
The research is extremely timely due to recent changes in social contact restrictions in the UK. By exploring possible benefits of in-person social contact, the present study could facilitate a crucial insight into its importance for mental health. By investigating predictors of symptoms of depression, our findings could also be used to help prevent later occurrences of depression by enforcing the importance of different forms of social contact. By also exploring the extent to which increases in depressive symptoms resulting from social contact may be explained by gender differences, increases in loneliness, and other COVID-related circumstances, our study will provide insight into how different forms of social contact may impact mental health.
Date proposal received: 
Thursday, 22 April, 2021
Date proposal approved: 
Tuesday, 4 May, 2021
Keywords: 
Immunology, Statistical methods, Statistical methods

B3769 - Investigating inflammation as a targetable mechanism in depression suicide and self-harm - 04/05/2021

B number: 
B3769
Principal applicant name: 
Hannah J Jones | University of Bristol (United Kingdom)
Co-applicants: 
Professor Golam Khandaker, Professor Stan Zammit, Dr Jon Heron, Professor Caroline Relton, Dr Carol Joinson, Dr Becky Mars, Professor Robert Yolken
Title of project: 
Investigating inflammation as a targetable mechanism in depression, suicide and self-harm
Proposal summary: 

Depression is common, devastating, disabling, and a major risk factor for suicide. About a third of individuals with depression are unresponsive to antidepressant treatment, suggesting that other mechanisms are involved in the onset and progression of the disorder. Emerging evidence implicates inflammation as a risk factor for depression and suicidal behaviour. However, little is known about the role inflammation plays in causing or worsening these mental health outcomes. As such, we aim to investigate whether inflammation represents a relevant and therapeutically targetable mechanism for depression and suicidal behaviour in young people.

Using repeated measures of inflammation (taken from blood samples collected over time), we will first define robust patterns of inflammation during childhood and adolescence in ALSPAC. Second, we will test whether early-life risk factors associated with both depression and suicidal behaviour, specifically adversity during childhood, infection, and timing of puberty, relate to patterns of inflammation during adolescence. Third, we will investigate if inflammation mediates the relationship between these early-life risk factors and depression, self-harm and suicide in young people.

Findings from this research will inform whether inflammation could be a target for treatment, prediction and prevention of depression, self-harm and suicidal behaviour in young people.

Impact of research: 
This research will improve our understanding of the role of early-life stressors in priming patterns of inflammation during childhood and adolescence, as well as the impact of these patterns on later mental-health outcomes. The longitudinal inflammatory patterns derived by this study may serve as a useful resource for other researchers interested in inflammation levels during the life-course. More specifically, findings from this research will inform whether inflammation could be a target for treatment, prediction and prevention of depression, self-harm and suicidal behaviour in young people. Findings could be used to direct future work investigating characteristics of inflammation-related depression and clinical trials of immuno-modulating therapies for depression and suicidal behaviour.
Date proposal received: 
Wednesday, 28 April, 2021
Date proposal approved: 
Tuesday, 4 May, 2021
Keywords: 
Epidemiology, Infection, Mental health, Inflammation, Statistical methods, Childhood - childcare, childhood adversity, Epigenetics, Immunity, Statistical methods

B3770 - Can neuroprotective strategies reduced cerebral visual impairment CVI - a pilot study into genetic susceptibility to CVI - 06/05/2021

B number: 
B3770
Principal applicant name: 
Cathy Wlliams | University of Bristol (United Kingdom)
Co-applicants: 
Dr Silvia Pregnolato, Professor Karen Luyt, Dr Santi Rodriguez, Dr David Odd, Dr Alexandra Creavin, Professor Jeremy Guggenheim
Title of project: 
Can neuroprotective strategies reduced cerebral visual impairment (CVI)? - a pilot study into genetic susceptibility to CVI
Proposal summary: 

Paediatric cerebral visual impairments (CVIs) are vision problems caused by damage to the brain rather than the eyes. Injuries to the newborn brain are by far the most common causes, including injuries associated with prematurity, hypoxia-ischemia and/or infections in the perinatal period. Many of these children have multiple neurodevelopmental impairments affecting movement, cognition and/or behaviour, and require extra educational support. There is concern that in some of these children CVIs go unnoticed or mistaken for other problems. Recent work by our group has shown that CVIs might be more prevalent than previously appreciated in the population, highlighting the need for a panel of biomarkers/predictors which can promote earlier and more accurate identification of high-risk children.
Genetic variants may affect how the newborn brain responds to perinatal stresses capable of causing brain injury. Compared to other neurodevelopmental disorders, research into the genetic contributions to CVIs is lacking, although a few genetic associations have been reported (1, 2).
This study aims at evaluating whether candidate genetic variants in the main candidate pathways involved in perinatal brain injuries (glutamate signalling and inflammation) are associated with CVIs. This hypothesis has derived partly from work carried out by two of the applicants (CW and KL) in the DRIFT study(3), in which children were assessed 10-years after a new intervention to treat brain bleeds. A high proportion of these children had CVIs and the number of CVIs correlated with the degree of structural damage to the brain that the children sustained in infancy. The genetic variants we will investigate have been identified both from the wider literature and from our own previous work (4). This includes preliminary findings within the Bristol Neonatal Gene Study, implicating candidate genetic variants in the glutamate signalling and inflammation pathways in childhood motor and cognitive outcomes. For some of these variants, us and others have explicitly shown functional effects on glutamatergic and inflammatory regulation in in vivo models relevant to brain injuries.
Associations between candidate genetic variants and vision outcomes in children from the general population will be explored within ALSPAC. By combining research from the Bristol Neonatal Gene Study with the rich database of visual function data within ALSPAC, we will be able to consider of a range of potentially important perinatal factors (e.g. prematurity, birth complications, evidence of brain injuries during the neonatal stay in the hospital) that may modify the effect of genotype on visual outcomes. We will also examine the associations between the same SNPs with (a) cognitive and (b) motor findings. From the existing literature we expect there is to be associations and we will compare the effect sizes (ES) in analyses of associations between the vision data and the SNPs of interest, with those obtained when using the motor and cognitive data. These results will be used to onform designs for future powered studies.
Additionally, we will collect new prospective data for children at risk for CVIs, enrolled by the PI at the Bristol Eye Hospital. This new clinical data will include additional more in-depth vision assessments compared to those routinely offered in the standard clinic, which will be evaluated as novel biomarkers for CVIs. Genetic profiles of these children with clinical diagnoses of CVIs will be compared to those from ALSPAC representing the general population.
This work is a collaboration between research groups in Bristol and is complementary to a proposal already approved, submitted in 2019 by SR. Some of the work proposed here is already approved as part of that proposal - however use of the vision data is unique to this proposal

References

1. Bosch DG, Boonstra FN, de Leeuw N, Pfundt R, Nillesen WM, de Ligt J, et al. Novel genetic causes for cerebral visual impairment. European journal of human genetics : EJHG. 2016;24(5):660-5.
2. Bosch DG, Boonstra FN, Reijnders MR, Pfundt R, Cremers FP, de Vries BB. Chromosomal aberrations in cerebral visual impairment. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2014;18(6):677-84.
3. Luyt K, Jary SL, Lea CL, Young GJ, Odd DE, Miller HE, et al. Drainage, irrigation and fibrinolytic therapy (DRIFT) for posthaemorrhagic ventricular dilatation: 10-year follow-up of a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2020;105(5):466-73.
4. Pregnolato S, Chakkarapani E, Isles AR, Luyt K. Glutamate Transport and Preterm Brain Injury. Front Physiol. 2019;10:417.
5. Williams C, Northstone K, Sabates R, Feinstein L, Emond A, Dutton GN. Visual perceptual difficulties and under-achievement at school in a large community-based sample of children. PLoS One. 2011;6(3):e14772.

Impact of research: 
No studies yet have reported on whether genetic vulnerability to neurotoxic damage can lead to CVIs, despite these being the leading cause of childhood blindness in high-income settings. We propose to collect pilot data to see whether children with CVI do have such vulnerabilities, by investigating whether known genetic markers for vulnerability to neurological damage are overrepresented in children with vision problems and CVI. Therefore, this pilot study may contribute to our understanding of the role that genetic factors play in these debilitating impairments, promoting further research in this field. Genetic biomarkers supported by robust evidence may find clinical utility by promoting earlier and more accurate identification of high risk newborns, especially in combination with sensitive and specific neuroimaging biomarkers. Genetic biomarkers may also provide a tool to identify affected babies who are more likely to respond to neuroprotective treatments. Both glutamate signalling and inflammation are ideal candidates for a pharmacogenomics approach for existing and novel drugs targeting these pathways. We expect that a better understanding of the genetic contributions to CVIs will enable improvements in early identification, diagnosis, and treatment. This has the potential not only to improve prognosis for these newborns, but also to help mothers, families and clinicians making more informed and personalised decisions when planning pregnancy, childbirth, and child follow-up. The subsequent push of neonatal care towards prediction and prevention may have impactful consequences on health and wellbeing in childhood. Finally, CVI occurs more frequently than neurodevelopmental impairments also caused by newborn brain injuries, such as cerebral palsy. Therefore, the study may also assist in evaluating whether vision outcomes reflecting perinatal brain injuries (e.g. visual function, clinical CVI diagnosis or RNFL thickness) are a more sensitive outcome measure for future clinical trials of neuroprotective interventions.
Date proposal received: 
Monday, 3 May, 2021
Date proposal approved: 
Tuesday, 4 May, 2021
Keywords: 
Ophthalmology, Developmental disorders - autism, Cognitive impairment, Congenital abnormalities, Learning difficulty, Statistical methods, Biological samples -e.g. blood, cell lines, saliva, etc., Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Birth outcomes, Cognition - cognitive function, Development, Environment - enviromental exposure, pollution, Genetics, Injury (including accidents), Vision

B3762 - Young peoples barriers to mental health services - 26/04/2021

B number: 
B3762
Principal applicant name: 
Corine Driessens | ARC-Wessex @ University of Southampton (UK)
Co-applicants: 
Peter W Smith, Fiona Lacey
Title of project: 
Young people's barriers to mental health services
Proposal summary: 

Research has discovered that on any given day in England, 28.5% of young people experience mental health problems, and that as little as one in four of them receive formal support for these problems. There is a lack of knowledge of what happens to those young people not receiving mental health services. For those individuals receiving mental health services, mental health problems have been shown to limit economic, vocational, and social functioning. International studies suggest that 50 to 70% of young people who receive services for their mental health problems continue to experience these problems in adulthood.

The proposed project will learn from cohort data which young people are less likely to receive professional support for their mental health problems and what the characteristics are of those young people not receiving mental health services for their problems. It will also be determined how many young people who do not receive mental health services for their problems continue to experience mental health problems in young adulthood and how resilient these young people were during the COVID pandemic.

The feedback provided by Young People will help direct the course of the project. While researchers from the University of Southampton will share the findings with the academic community, YOUNGMINDS will spread the word about our research and findings to their members and followers, young people, mental health service providers and policy makers using a variety of different media. Output activities will increase awareness and promote discussion among the stakeholder groups and ease the way for more effective mental health support for young people.

Impact of research: 
By focusing our research on causative ameliorating childhood factors of young people’s mental health and focus special attention on those young people not accessing formal mental health services we hope to contribute to the identification of at-risk adolescents, barriers for accessing mental health services, and need for public awareness campaigns, while also spark professional and political interest for those young people not accessing services for their mental health problems. The information gathered can stimulate young people’s mental health campaigns aimed at adolescents at risk. The Young People recruited from Young Minds to advise on this project will have an ‘advisory’ work contract with Young Minds. They will be trained by Young Minds to lead workshops with their peers to discuss our project and will feed information back to research team regarding development of project, adjustments to existing analyses, and interpretation of findings. The staff at Young Minds will lead on the dissemination to the public and Young People by posting updates of the study on their website, post information on social media, and mail information to their members. They will also lead on professional and policy dissemination by organizing a round table with mental health professionals at the NHS and other charities, as well as policy makers. Birth cohort studies are best placed to gather evidence relating to development and management of mental health. Although their representativeness tends to diminish over time as different groups drop out of the study differentially, this bias can be controlled statistically. By successfully applying a nonignorable missing data model to the field of mental health research, we further advance a missing data approach that can be promoted within the wider field of applied health care research.
Date proposal received: 
Monday, 19 April, 2021
Date proposal approved: 
Tuesday, 20 April, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health, Statistical methods, Statistical methods

B3759 - Are poorer attendance and oral hygiene behaviours associated with greater dental anxiety in adolescents - 16/04/2021

B number: 
B3759
Principal applicant name: 
Kate Northstone | University of Bristol (United Kingdom)
Co-applicants: 
Dr Tom Dudding, Jenny Clow
Title of project: 
Are poorer attendance and oral hygiene behaviours associated with greater dental anxiety in adolescents?
Proposal summary: 
Impact of research: 
Understanding which oral health behaviours (attendance and oral hygiene) are most strongly associated with dental anxiety may help focus prevention initiatives.
Date proposal received: 
Monday, 12 April, 2021
Date proposal approved: 
Friday, 16 April, 2021
Keywords: 
Dentistry, Dental health, Dental

B3760 - The impact of the COVID-19 pandemic on OCD symptoms in young adults - 15/04/2021

B number: 
B3760
Principal applicant name: 
Kate Northstone | University of Bristol, UK (United Kingdom)
Co-applicants: 
Beca Morrell, Dr Alex Kwong, Dr Rebecca Pearson
Title of project: 
The impact of the COVID-19 pandemic on OCD symptoms in young adults
Proposal summary: 

Obsessive compulsive disorder (OCD) symptoms have increased over the COVID-19 pandemic in the ALSPAC cohort compared to pre-pandemic reported levels. As an anxiety disorder, it is probable that anxiety induced by fear of contamination and illness has contributed to additional or heightened obsessive behaviours during the pandemic, but it is unclear who has been most affected.

Impact of research: 
Understanding which sub-groups of the population have suffered detrimental changes in OCD may help in providing appropriate support.
Date proposal received: 
Monday, 12 April, 2021
Date proposal approved: 
Thursday, 15 April, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Mental health

Pages