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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B3818 - Epigenome-wide association study of depression and antidepressant use - 05/07/2021

B number: 
B3818
Principal applicant name: 
Doretta Caramaschi | MRC IEU
Co-applicants: 
Alex Kwong, Ms Holly Fraser
Title of project: 
Epigenome-wide association study of depression and antidepressant use
Proposal summary: 

At least 7 million adults in the UK are prescribed antidepressants every year. Antidepressant prescriptions in teenagers are rising. In nearly 50% of people on antidepressants the depression symptoms do not improve after the pharmacological treatment. We will investigate the biological pathways that lead to depression by looking at biomarkers in their blood DNA, as well as molecular markers that antidepressant treatments might leave on blood cells in young adults. We will assess antidepressant use in young adults and potential reasons for stopping the medications, with the ultimate aim to explore the possibility of personalized treatment options.

Impact of research: 
Due to the multi-cohort nature of the project (consortium will have a final N of >20000 participants) and the importance of the research questions (depression and antidepressant use) we expect that we will generate conclusive results that will be relevant to a high number of people in the community as well as health professionals.
Date proposal received: 
Monday, 21 June, 2021
Date proposal approved: 
Wednesday, 23 June, 2021
Keywords: 
Molecular genetics and genomics, Mental health, Microarrays, Epigenetics

B3808 - The association between epigenetic prediction signatures of complex traits and health outcomes in ALSPAC - 22/06/2021

B number: 
B3808
Principal applicant name: 
Ryan Langdon | University of Bristol (United Kingdom)
Co-applicants: 
Chloë Fabbricatore, Matt Suderman
Title of project: 
The association between epigenetic prediction signatures of complex traits and health outcomes in ALSPAC
Proposal summary: 

Modelling complex phenotypes using DNA methylation (DNAm) is becoming increasingly common in Epigenetic Epidemiology. This process often includes the use of weighted DNAm “scores” to differentiate between classes of categorical exposures, estimate continuous exposures and/or predict disease outcomes. The reason DNAm can do this is because it bridges the gap between your biology and your environment; one function of DNAm is that it will work to alter gene expression in response to an environmental stimulus. Accordingly, it can be thought of as a “biosocial archive”.

A recent study found that a DNAm proxy of smoking explained more variance in certain mental and physical health outcomes than someone self-reporting their smoking status. This is important because it highlights that DNAm can either augment or improve on how we define self-report traits such as smoking, and could potentially extend to other traits such as alcohol consumption, BMI and educational attainment. Further, using DNAm either in conjunction with, or instead of self-report, may allow researchers to identify targeted interventions for a variety of disease outcomes.

Accordingly, in this project we will be investigating whether DNAm proxies vs self-report smoking, BMI, alcohol consumption and educational attainment, respectively, explain more variance in cardiovascular, mental health, socioeconomic, clinical, metabolic and addiction outcomes in ALSPAC.

Impact of research: 
Generating evidence to support downstream use (or not) of DNA methylation to improve how epidemiologically-relevant phenotypes are defined
Date proposal received: 
Monday, 21 June, 2021
Date proposal approved: 
Tuesday, 22 June, 2021
Keywords: 
Epidemiology, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Diabetes, Hypertension, Mental health, Obesity, Respiratory - asthma, Computer simulations/modelling/algorithms, Metabolomics, Microarrays, Statistical methods, Biological samples -e.g. blood, cell lines, saliva, etc., Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Physical - activity, fitness, function, Statistical methods, Blood pressure, BMI, Cardiovascular, Environment - enviromental exposure, pollution, Epigenetics, Metabolic - metabolism, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Microbiome

B3810 - Birth order and cord blood DNA methylation - 21/06/2021

B number: 
B3810
Principal applicant name: 
Giulia Mancano | IEU, University of Bristol
Co-applicants: 
Dr Gemma Sharp, Sebastian (Shaobo) Li
Title of project: 
Birth order and cord blood DNA methylation
Proposal summary: 

Birth order has strong correlations with developmental and environmental aspects. Birth order is a presumed factor affecting multiple diseases including leukemia (1, 2, 3), atopy (4), type I diabetes (5), non-Hodgkin lymphoma (6) and synovial sarcoma (7). Moreover, first born subjects have unique in utero characteristics including less sufficient placentation, higher estrogen levels, and lower insulin sensitivity. Birth order might therefore play a role in shaping DNA methylation pattern and influence the initiation of the diseases mentioned above.

1. Dockerty JD, Draper G, Vincent T, Rowan SD, Bunch KJ. Case-control study of parental age, parity and socioeconomic level in relation to childhood cancers. Int J Epidemiol. 2001. doi:10.1093/ije/30.6.1428
2. Hjalgrim LL, Rostgaard K, Hjalgrim H, et al. Birth weight and risk for childhood leukemia in Denmark, Sweden, Norway, and Iceland. J Natl Cancer Inst. 2004. doi:10.1093/jnci/djh287
3. Westergaard T, Andersen PK, Pedersen JB, et al. Birth characteristics, sibling patterns, and acute leukemia risk in childhood: A population-based cohort study. J Natl Cancer Inst. 1997. doi:10.1093/jnci/89.13.939
4. Upchurch S, Harris JM, Cullinan P. Temporal changes in UK birth order and the prevalence of atopy. Allergy Eur J Allergy Clin Immunol. 2010. doi:10.1111/j.1398-9995.2009.02312.x
5. Cardwell CR, Stene LC, Joner G, et al. Birth order and childhood type 1 diabetes risk: A pooled analysis of 31 observational studies. Int J Epidemiol. 2011. doi:10.1093/ije/dyq207
6. Grulich AE, Vajdic CM, Kaldor JM, et al. Birth order, atopy, and risk of non-Hodgkin lymphoma. J Natl Cancer Inst. 2005. doi:10.1093/jnci/dji098
7. Wiemels JL, Wang R, Feng Q, et al. Birth characteristics and risk of early-onset synovial sarcoma. Cancer Epidemiol Biomarkers Prev. April 2020:cebp.0093.2020. doi:10.1158/1055-9965.EPI-20-0093

Impact of research: 
Build evidence to elucidate the effect of birth order on neonatal DNA methylation and investigate its possible implication on system development and disease risk.
Date proposal received: 
Tuesday, 15 June, 2021
Date proposal approved: 
Monday, 21 June, 2021
Keywords: 
Epigenetic Epidemiology, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., EWAS, Birth outcomes, Development, Epigenetics, Offspring

B3809 - Comprehensive Prenatal Smoking Assessment and Newborn Methylation - 21/06/2021

B number: 
B3809
Principal applicant name: 
Giulia Mancano | IEU, University of Bristol
Co-applicants: 
Dr Gemma Sharp, Dr Thanh T. Hoang
Title of project: 
Comprehensive Prenatal Smoking Assessment and Newborn Methylation
Proposal summary: 

The detriment of maternal smoking on offspring is well known while the biological mechanism regulating the relationship are not fully understood. Epigenetic profile has emerged as a potential link between the two. Sustained maternal smoking during pregnancy, here defined as smoking past the first trimester, has been associated with deferentially methylated CpG sites in the offspring (1-6) and a dose-response effect might also be plausible (2, 4, 7).

1. Joubert BR, Felix JF, Yousefi P, Bakulski KM, Just AC, Breton C, et al. DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis. Am J Hum Genet. 2016;98(4):680-96.
2. Ladd-Acosta C, Shu C, Lee BK, Gidaya N, Singer A, Schieve LA, et al. Presence of an epigenetic signature of prenatal cigarette smoke exposure in childhood. Environmental research. 2016;144(Pt A):139-48.
3. Lee KW, Richmond R, Hu P, French L, Shin J, Bourdon C, et al. Prenatal exposure to maternal cigarette smoking and DNA methylation: epigenome-wide association in a discovery sample of adolescents and replication in an independent cohort at birth through 17 years of age. Environ Health Perspect. 2015;123(2):193-9.
4. Markunas CA, Xu Z, Harlid S, Wade PA, Lie RT, Taylor JA, et al. Identification of DNA methylation changes in newborns related to maternal smoking during pregnancy. Environ Health Perspect. 2014;122(10):1147-53.
5. Rzehak P, Saffery R, Reischl E, Covic M, Wahl S, Grote V, et al. Maternal Smoking during Pregnancy and DNA-Methylation in Children at Age 5.5 Years: Epigenome-Wide-Analysis in the European Childhood Obesity Project (CHOP)-Study. PLoS One. 2016;11(5):e0155554.
6. Witt SH, Frank J, Gilles M, Lang M, Treutlein J, Streit F, et al. Impact on birth weight of maternal smoking throughout pregnancy mediated by DNA methylation. BMC Genomics. 2018;19(1):290.
7. Richmond RC, Simpkin AJ, Woodward G, Gaunt TR, Lyttleton O, McArdle WL, et al. Prenatal exposure to maternal smoking and offspring DNA methylation across the lifecourse: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC). Hum Mol Genet. 2015;24(8):2201-17.

Impact of research: 
To expand the portfolio of evidence of the impact of prenatal smoking on offspring DNA-methylation by investigating a series of smoking-related exposures.
Date proposal received: 
Tuesday, 15 June, 2021
Date proposal approved: 
Monday, 21 June, 2021
Keywords: 
Epigenetic Epidemiology, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., EWAS, Epigenetics, Fathers, Smoking

B3799 - Exploratory ML Based Longitudinal Modelling Approaches to Map Genetic-Phenotypic Multi-Trait Predictors of Fibrosis - 28/06/2021

B number: 
B3799
Principal applicant name: 
Nathan Lawless | Boehringer Ingelheim (Germany)
Co-applicants: 
Zhihao Ding, Dr
Title of project: 
Exploratory ML Based Longitudinal Modelling Approaches to Map Genetic-Phenotypic Multi-Trait Predictors of Fibrosis
Proposal summary: 

Global Computational Biology & Digital Sciences (GCBDS) is a department in Boehringer Ingelheim’s Innovation Unit (IU) and is principally engaged in early discovery research programs. In 2020 the IU embarked on a curriculum to more deeply explore healthcare databases and biobank initiatives. The overall objective of the program is to explore advanced analytical methods to harness genomic & phenotypic data in order to better understand causative pathological mechanisms for disease which have the long-term potential to support patients.

Boehringer has a longstanding heritage in a number of unmet areas of medical need we consider our core disease areas; These include cardio-metabolic diseases, central nervous system diseases, immunology, respiratory and oncology as well as fields of active research that are currently covered by Research Beyond Borders (e.g. infectious diseases or regenerative medicines).

As part of BI’s preparatory research, a meta-analysis was undertaken to identify initiatives which focus on longitudinal multi-generational familial analysis in the field of fibrosis research (lung, liver). Two area’s of interest are of high priority (i) developing computational based method development programs focused on accurate and interpretable statistical approaches and (ii) Exploring methods to undertake trans biobank analysis on individuals from diverse ethnic backgrounds, but sharing similar phenotypic traits.

Impact of research: 
As previously outlined, Boehringer has a longstanding heritage in treating patients with a range of heterozygous respiratory diseases often underpinned by fibrosis. In these early exploratory analysis we aim to shed new light on the disease progression underpinning fibrosis and leverage our existing experience to support disease understanding.
Date proposal received: 
Saturday, 19 June, 2021
Date proposal approved: 
Monday, 21 June, 2021
Keywords: 
Bioinformatics, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Allergy, Epilepsy, Gastrointestinal, Hypertension, Incontinence, Infection, Learning difficulty, Mental health, Obesity, Pain, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Respiratory - asthma, Sexually transmitted diseases, chlamydia, gonorrhoea, Developmental disorders - autism, Cancer, Chronic fatigue, Cognitive impairment, Congenital abnormalities, Diabetes, Eating disorders - anorexia, bulimia, Computer simulations/modelling/algorithms, Gene mapping, RNA, Statistical methods, GWAS, Mass spectrometry, Medical imaging, Metabolomics, Microarrays, NMR, Proteomics, Qualitative study, Ageing, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Equipment - MRI, Endocrine - endocrine disrupters, ENT - hearing, Environment - enviromental exposure, pollution, Epigenetics, Expression, Genetic epidemiology, Genetics, Genomics, Genome wide association study, Blood pressure, Immunity, Linkage, Liver function, Mendelian randomisation, Statistical methods, Whole genome sequencing, BMI, Cardiovascular, Cohort studies - attrition, bias, participant engagement, ethics, Childhood - childcare, childhood adversity, Cognition - cognitive function, Communication (including non-verbal), Development

B3815 - Cholesterol trajectories throughout childhood and associations with growth and carotid intima-media thickeness - 28/06/2021

B number: 
B3815
Principal applicant name: 
Laila J Tata | School of Medicine, University of Nottingham (United Kingdom)
Co-applicants: 
Professor Nadeem Qureshi, Professor Steve Humphries
Title of project: 
Cholesterol trajectories throughout childhood and associations with growth and carotid intima-media thickeness
Proposal summary: 

Cholesterol is a type of fat that is essential for our body to work well. Among its roles, it helps the body make use of hormones and vitamins. Our bodies make cholesterol, but we also get cholesterol from food. When we eat too many foods high in fat we can start to have a build-up of cholesterol in our bodies, especially in our blood vessels. We know that having too much bad cholesterol (called Low-Density Lipoprotein or LDL-cholesterol) in our blood can result in forming a layer that sticks to the inside walls of our blood vessels, making them thinner and sometimes blocking them, which can result heart disease, such as having a heart attack.

We know what levels of LDL-cholesterol are considered too high in adults, but we know very little about what normal and high levels of LDL-cholesterol are in children. We know cholesterol is important for brain development, that cholesterol may go up and down at certain ages in children, but there are very few studies of how cholesterol changes normally throughout childhood and adolescence. We also know little about how young people’s cholesterol is related to their growth and health (for example, weight and blood pressure), or whether it is related to early signs of heart disease in early adulthood.

We will answer these questions using this cohort. The results will be important for the general population and for children who have certain conditions that require medications to lower their cholesterol in childhood.

Impact of research: 
We believe this study will provide important information in characterising cholesterol profiles in childhood and that this information will fill an important evidence gap that will be valuable for many studies of cardiovascular health not only in the UK but internationally. As described in the previous section, in addition to providing standalone valuable information for the general population of children and useful information for predicting future risk of cardiovascular health, this ALSPAC analysis will be used to provide more immediate impact for informing a study on the treatment of FH in childhood. We will assess whether cholesterol trajectories in children with untreated FH are similar to those in the general ALSPAC population, or how they differ. We will also use information from the ALSPAC study to model the risk of early evidence of atherosclerosis in children with FH because there are no available following up children with FH long enough to incorporate childhood and early adulthood. The latter will inform our economic models to estimate the benefits of starting statins at different ages in childhood. By the end of the 5-year project on FH, we aim to provide clearer evidence on what age and LDL-C level children with FH should ideally start statins, based on their clinical risk profile. The impact could be changing or strengthening current clinical guidelines in treatment of FH.
Date proposal received: 
Thursday, 17 June, 2021
Date proposal approved: 
Monday, 21 June, 2021
Keywords: 
Epidemiology, Hypercholesterolaemia, cardiovascular disease, Statistical methods, Cardiovascular

B3814 - Polygenic susceptibility in chronic air pollution exposure associated adverse respiratory health in adolescents a meta-analysis - 05/07/2021

B number: 
B3814
Principal applicant name: 
Raquel Granell | MRC Integrative Epidemiology Unit
Co-applicants: 
Dr Tamara Schikowski, Sara Kress, Dr Claudia Wigmann
Title of project: 
Polygenic susceptibility in chronic air pollution exposure associated adverse respiratory health in adolescents: a meta-analysis
Proposal summary: 

Several studies support an association between being exposed to air pollution and having respiratory health problems in adolescence. However, only some of those who are highly exposed to air pollution develop respiratory diseases. Genetics play a role in how an individual respons to air pollution exposure as well as in the probability to develop air pollution induced respiratory health problems. We want to investigate if there is a difference in how air pollution affects our respiratory health, when comparing 'genetic low-risk' and 'genetic high-risk' groups of people.

Impact of research: 
Date proposal received: 
Thursday, 17 June, 2021
Date proposal approved: 
Monday, 21 June, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation)

B3811 - Alcohol Consumption And Hypertensive Disorders Of Pregnancy A Negative Control Analysis In ALSPAC - 14/06/2021

B number: 
B3811
Principal applicant name: 
Luisa Zuccolo | MRC Integrative Epidemiology Unit (United Kingdom)
Co-applicants: 
Miss Florence Martin, Professor Abigail Fraser
Title of project: 
Alcohol Consumption And Hypertensive Disorders Of Pregnancy: A Negative Control Analysis In ALSPAC
Proposal summary: 

Drinking alcohol when pregnant has been shown to be associated with reduced risk of having high blood pressure disorders during pregnancy. However, given that the opposite is true outside of pregnancy, that drinking alcohol is associated with increased blood pressure and risk of stroke and heart attack, the effect in pregnancy may be a result of other factors, not alcohol itself. We aim to use the Avon Longitudinal Study of Parents and Children (ALSPAC) to compare women who drank alcohol during their pregnancy and those who didn't, to see if drinkers were more likely to develop high blood pressure disorders during pregnancy than non-drinkers. We also aim to use information on partner's alcohol use during pregnancy and mum's risk of these disorders, to try and understand if the effect seen in mum is caused by alcohol or whether it is related to other factors shared by mum and her partner. In other words, given that a partner's drinking can't have a physical effect on mum's risk of these disorders, if we see a decreased risk when comparing drinking and non-drinking partner's, we can assume that maybe there are other factors shared by both mum and partner that is causing the reduced risk, not the alcohol itself.

Impact of research: 
Adequately powered estimates of the causal effect of alcohol use in pregnancy on hypertensive disorders of pregnancy
Date proposal received: 
Friday, 11 June, 2021
Date proposal approved: 
Monday, 14 June, 2021
Keywords: 
Epidemiology, Hypertension, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., Statistical methods, Blood pressure, Cardiovascular, Cohort studies - attrition, bias, participant engagement, ethics, Fathers, Mothers - maternal age, menopause, obstetrics

B3812 - Trajectories of problematic cannabis use in adolescence and their association with childhood psychological risk factors - 14/06/2021

B number: 
B3812
Principal applicant name: 
Lindsey Hines | University of Bristol
Co-applicants: 
Rachel Lees, Dr Tom Freeman
Title of project: 
Trajectories of problematic cannabis use in adolescence and their association with childhood psychological risk factors
Proposal summary: 

Cannabis is the most commonly used illicit drug worldwide, with use particularly prevalent in adolescents. The number of under-18’s in treatment for cannabis as a primary problem in the UK in 2019-2020 was 11,136, 78% of all treatment entrants in this age group. Whilst this demonstrates a current clear demand for treatment of cannabis problems, the majority of people with cannabis problems do not seek out professional treatment. Further, current psychosocial treatment options lack data on their long-term efficacy, and there are no approved pharmacological treatments. One approach to tackle the global burden of cannabis use disorder (CUD) is to develop early targeted interventions, directed towards reducing the incidence of CUD. Identifying key variables that are associated with development of cannabis problems could help to ascertain which groups are most at risk. Previous research in adolescent and adult populations indicates that cannabis use profile, mental health problems and other drug use are all associated with increased risk of sustained problems related to cannabis use, compared to those with stable-low risk of cannabis problems. However, these studies either did not investigate childhood risk factors, or only assessed these retrospectively, and did not collect data specifically prior to cannabis initiation. This project aims to identify distinct trajectories of cannabis problems, and assess whether mental health and cognition in childhood (8-10 years old), prior to onset of cannabis use, represent potential modifiable risk factors for likelihood of experiencing problems with cannabis use, in order to inform early interventions to potentially reduce the incidence of cannabis problems.

Impact of research: 
The likely impact of this research will be improving our current understanding of how cannabis problems develop and are sustained over time in adolescence and young adulthood. The research should also give insight into whether potentially modifiable risk factors in earlier childhood could help create targeted interventions to reduce incidence of cannabis problems, thus potentially improving mental health for many young people. We intend to disseminate our findings widely, including as a peer-reviewed publication and at conference presentations.
Date proposal received: 
Friday, 11 June, 2021
Date proposal approved: 
Monday, 14 June, 2021
Keywords: 
Mental health - Psychology, Psychiatry, Cognition, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Statistical methods, Cognition - cognitive function, Mental health Substance use

B3801 - HMOX1 imputation testing and impact on outcomes - 10/06/2021

B number: 
B3801
Principal applicant name: 
Nic Timpson | University of Bristol (United Kingdom)
Co-applicants: 
Fergus Hamilton, Ruth Mitchell
Title of project: 
HMOX1 imputation, testing and impact on outcomes
Proposal summary: 

This PhD proposal aims to look at a gene, the HMOX1 gene, that is critical for managing the breakdown of haemoglobin in humans. Previous studies have shown that this gene is critical for management of infection. In animal studies, loss of function of this gene is associated with much worse outcomes in infection (more likely to die). In humans, there is much more uncertainty about the role of this gene and its importance. It has previously been shown that a small region of DNA in this gene is comprised of a dinucleotide repeat, where the two bases guanine and thymine are repeated. This is called a “GT” repeat. In this region, the DNA code is of variable length between patients, with an average of 31 repeats across the whole population, although some people have as little as 20 repeats, and some as high as 45. In previous small studies, the length of this repeat has altered the amount the gene is switched on and off (gene expression), and some studies have shown this has important impacts on lots of diseases, including in infection. Previous studies have shown those with longer repeats are more likely to be diagnosed with Type 2 diabetes, for example. Importantly, multiple studies in malaria have shown that carriage of the longer repeats is associated with much better outcomes, with a large reduction in severe malaria. However, all of the previous studies (in all clinical diseases) have been performed in small cohorts. In this proposal, we aim to measure this repeat using bioinformatic tools in ALSPAC using whole genome sequencing data. We also then plan to measure this repeat using another methodology, by imputing it from array data. These two methods will be compared to test the accuracy of repeat calling from array data. This will also be used to allow confidence in the imputation method so this can be used in other databases (e.g. UK Biobank). Subsequently, we will then look at the relationship between the repeat length and various clinical and bioinformatic measurements. In particular, we will focus on whether repeat length relates to immunological function (e.g. antibody levels, T-cell function (where measured)), clinical outcomes (both self-reported and healthcare linked), and metabolomic outcomes. Finally, we will also look at the impact of this repeat on the transcriptome, to see if gene expression truly changes with the repeat length. Further work will compare results from ALSPAC with other cohorts e.g. UK Biobank. All participants who have genetic data will be included.

Impact of research: 
The question of HMOX1 repeat length variability and clinical outcome is hotly debated. A previous systematic review identifying links with clinical outcomes has been cited >400 times[2]. However, no biobank scale analysis has ever been performed looking at this locus. It is likely that regardless of the findings, there will be significant clinical interest in whether HMOX1 repeat length variability has impact on clinical outcomes or on the transcriptome in ALSPAC. 2 Exner M, Minar E, Wagner O, et al. The role of heme oxygenase-1 promoter polymorphisms in human disease. Free Radic Biol Med 2004;37:1097–104
Date proposal received: 
Tuesday, 8 June, 2021
Date proposal approved: 
Thursday, 10 June, 2021
Keywords: 
Immunology, Infection, DNA sequencing, Genetic epidemiology, Genetics, Genomics, Immunity, Whole genome sequencing

B3800 - Body Mass Index trajectories across childhood and young adulthood and risk for disordered eating in young adulthood - 07/06/2021

B number: 
B3800
Principal applicant name: 
Naomi Warne | University of Bristol
Co-applicants: 
Eleanor Wade, Dr Helen Bould, Professor Golam Khandaker, Dr Ben Perry
Title of project: 
Body Mass Index trajectories across childhood and young adulthood and risk for disordered eating in young adulthood.
Proposal summary: 

Disordered eating behaviours (such as fasting, purging, binge-eating and excessive exercise) are common in young adulthood, and have the potential to cause serious long-term harm. Identifying risk factors that precede the onset of disordered eating in young adulthood is important for our understanding of how disordered eating develops. Furthermore, these risk factors may be useful for identifying individuals at high risk of developing disordered eating and for designing effective treatments.
Although diagnosis for an eating disorder often depends on Body Mass Index (BMI) and this can be a barrier for treatment, there is less evidence on whether changes in BMI across childhood and adolescence precede later disordered eating. Previous research using the ALSPAC sample (Perry et al. 2021) has found 5 different BMI trajectories from 1-24 years: stable average, gradually decreasing, puberty-onset minor increase, puberty-onset major increase and persistently high BMI. Compared to those with a stable average BMI, those with a puberty-onset major increase trajectory had higher risk of a depressive episode and depressive symptoms. However it is unclear whether these BMI trajectories are differentially associated with subsequent disordered eating.
This study investigates the associations between BMI trajectories across childhood up to age 24 with disordered eating behaviours at age 24. This study will improve our understanding of how BMI can lead to the development of disordered eating behaviours.

Impact of research: 
This project will lead to a greater understanding of how differences in BMI across childhood and adolescence are associated with disordered eating behaviours in young adulthood.
Date proposal received: 
Tuesday, 1 June, 2021
Date proposal approved: 
Monday, 7 June, 2021
Keywords: 
Epidemiology, Eating disorders - anorexia, bulimia, BMI

B3802 - Intimate partner violence and mental health of parents children - 07/06/2021

B number: 
B3802
Principal applicant name: 
Rebecca Lacey | UCL (UK)
Co-applicants: 
Prof Gene Feder, Prof Laura Howe, Prof Ruth Gilbert
Title of project: 
Intimate partner violence and mental health of parents & children
Proposal summary: 

In any two year period, almost one quarter of children were exposed to maternal mental illness. Mother’s mental health problems are associated with problems in children’s cognitive development, physical and mental health. We also know that exposure to intimate partner violence (IPV) and parental substance misuse during childhood increases the risk of negative mental health outcomes. There is some evidence that parental mental health problems may reduce children’s resilience to the impact of IPV. However we do not yet fully understand the relationships between IPV, parental mental health and children’s mental health. We also know little about factors that promote resilience in children exposed to IPV.

Impact of research: 
This project will provide a more nuanced understanding of the interplay between parental mental health, substance misuse, IPV and child mental health. The analysis of why some children fare better than expected will inform interventions for children exposed to IPV. This project also has a qualitative component, working with Early Intervention Foundation, which looks at the weak points and blind spots in current practices, including routine data records, that need to be addressed to ensure effective early identification and intervention in vulnerable families. The quantitative ALSPAC and CPRD-HES analyses will inform the qualitative work.
Date proposal received: 
Thursday, 3 June, 2021
Date proposal approved: 
Monday, 7 June, 2021
Keywords: 
Epidemiology, Mental health, Statistical methods, Childhood - childcare, childhood adversity, Parenting

B3803 - Inflammation and Health The causes and consequences of GlycA and its role in the inflammatory system - 07/06/2021

B number: 
B3803
Principal applicant name: 
Abigail Fraser | University of Bristol (UK)
Co-applicants: 
Miss Daisy Crick
Title of project: 
Inflammation and Health: The causes and consequences of GlycA and its role in the inflammatory system
Proposal summary: 

Inflammation is known to be associated with adverse non-communicable diseases (NCDs). However, the most commonly used biomarkers in inflammation research (namely C-Reactive Protein and Interleukin-6) are potentially not valid measures of chronic and cumulative inflammation. This is because they respond to short-term, acute inflammatory changes in the body. This therefore limits our knowledge of the true association between chronic inflammation and NCDs, but also limits our understanding of the role certain exposures (such as adverse childhood experiences; ACEs) have on levels of chronic inflammation.
A novel biomarker GlycA may be a more reflective of chronic inflammation because it is not affected by short-term inflammatory changes, given that it is a composite biomarker. Therefore GlycA may be a more valid measure compared to previously used biomarkers. This project aims to use GlycA to investigate the causes and consequences of chronic inflammation more accurately, with a focus on mental health (such as depression). The project will collaborate with the work being done by Debbie Lawlor’s group investigating the association between GlycA and cardiovascular disease.

Impact of research: 
In many Western populations, the lifetime prevalence of NCDs such as mental health disorders is approaching 50%, creating societal, health and economic impacts. However, the pathway of their development is still not fully understood. My research will build on previous literature to understand one of the potential pathways leading to such negative outcomes. We hope to provide evidence that the novel biomarker GlycA is a useful tool for measuring cumulative and chronic inflammation and investigate its application in the relationship with NCDs such as depression.
Date proposal received: 
Thursday, 3 June, 2021
Date proposal approved: 
Monday, 7 June, 2021
Keywords: 
Epidemiology, Mental health, Metabolomics, Childhood - childcare, childhood adversity

B3806 - Examining the genetic architecture of depression in and around pregnancy in the ALSPAC study - 07/06/2021

B number: 
B3806
Principal applicant name: 
Alex Kwong | University of Bristol
Co-applicants: 
Ruxin Luo, Dr Rebecca Pearson, Dr Hannah Sallis, Ms Holly Fraser
Title of project: 
Examining the genetic architecture of depression in and around pregnancy in the ALSPAC study
Proposal summary: 

Depression is a common and complex disease, influenced by both genetic and environmental factors, with heritability estimated to be from 31% to 42%. However, a recent genome-wide association study meta-analysing data on 807,553 individuals from three largest GWAS studies identified 102 independent variants and 269 genes associated with depression. This result suggests that depression is a polygenetic trait and enables researchers to use these polygenic risk scores to investigate how genetic liability for depression manifests over the life course.

Depression is more common in women during childbearing age, but it has particular importance during pregnancy and after birth due to additional potential consequences for the child. There are many women worldwide suffering from perinatal depression, and according to a meta-analysis, the prevalence of it ranges from 6.5% to 13% at different time points during pregnancy. Perinatal depression has been reported to be associated with many complications, such as hypertension, preeclampsia, and gestational diabetes for mothers and premature birth, low birth weight, fetal growth restriction for foetuses. Furthermore, some pregnant women with depression are reported to have suicidal ideation and thoughts of harming their child. It is clear that perinatal depression is important for both the mother and the child, and thus it is important to examine its aetiology in order to identify potential treatments and interventions. The role of genetics in perinatal presentation of depression is one particular path that could further enhance our understanding of the disease.

There are many studies on heritability of depression, but few about the genetic architecture of perinatal depression. This study will use the polygenetic risk score based on GWAS study on broad depression and examine the association between greater genetic liability to depression and depression across the perinatal period.

Impact of research: 
Further understanding of the aetiology of depression
Date proposal received: 
Friday, 4 June, 2021
Date proposal approved: 
Monday, 7 June, 2021
Keywords: 
Epidemiology, Mental health, Statistical methods, Genetic epidemiology

B3804 - Is there a shared genetic aetiology between autism and asthma - 07/06/2021

B number: 
B3804
Principal applicant name: 
Dheeraj Rai | Population Health Sciences, Bristol Medical School, University of Bristol (United Kingdom)
Co-applicants: 
Christina Dardani, Alec McKinlay
Title of project: 
Is there a shared genetic aetiology between autism and asthma?
Proposal summary: 

Autism and asthma are two common but seemingly unrelated conditions. Autism is a chronic neurodevelopmental condition, characterised by difficulties in social communication as well as repetitive behaviours/restricted interests. On the contrary, asthma is a chronic respiratory condition characterised by periods of wheezing, shortness of breath and chess tightness. Despite the distinct features, there is some evidence suggesting an increased prevalence of asthma in individuals with autism, while maternal history of asthma has been associated with autism in the offspring. The reasons underlying these observational associations are currently unknown. One possible explanation could be that there is a shared genetic aetiology between the two conditions. Testing this hypothesis will be an important first step towards understanding the reasons of their co-occurrence.

Impact of research: 
Date proposal received: 
Monday, 7 June, 2021
Date proposal approved: 
Monday, 7 June, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Developmental disorders - autism, Statistical methods, Genetic epidemiology

B3807 - Sexuality and Family Dynamics - 10/06/2021

B number: 
B3807
Principal applicant name: 
Noam Angrist | Blavatnik School of Government, University of Oxford (UK)
Co-applicants: 
Title of project: 
Sexuality and Family Dynamics
Proposal summary: 

Exploring the relationship between family structure (e.g. number of siblings, gender), and sexuality / beliefs towards sexuality.

Impact of research: 
Exploring dynamics of contact theory which can explain one of the most radical transformation of social norms ever observed, with potentially substantial implications for other related issues, such as racial integration/segregation, immigration policy around assimilation, etc.
Date proposal received: 
Saturday, 5 June, 2021
Date proposal approved: 
Monday, 7 June, 2021
Keywords: 
Social Science, Behaviour - e.g. antisocial behaviour, risk behaviour, etc., Computer simulations/modelling/algorithms, Statistical methods, Birth outcomes, Cohort studies - attrition, bias, participant engagement, ethics, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Sex differences, Siblings, Social science, Twins

B3805 - Lfestyle and genetic predictors of maculopathy in the ALSPAC G0 generation - 10/06/2021

B number: 
B3805
Principal applicant name: 
Cathy Williams | University of Bristol (United Kingdom)
Co-applicants: 
Jez Guggenheim, Prof Andrew Lotery, Clare.Bailey@bristol.ac.uk, Dr Kate Northstone, Professor Jean Golding, Prof Tunde Peto
Title of project: 
Lfestyle and genetic predictors of maculopathy in the ALSPAC G0 generation
Proposal summary: 

Maculopathy is a term describing a group of diseases of the retina which together are the leading cause of blindness in developed countries. Treatment is at best only able to stabilize progression in some individuals and for many there is no effective therapy and irreversible sight loss cannot be avoided.

The most widespread form of macular disease is associated with ageing and is known as age-related maculopathy (ARM).The incidence of this rises with age (1). In the Beaver Dam study in USA (2), severe blinding macular changes were seen in 1%-2% of the overall population aged 50-80yr, with mild signs in 8-10% of people aged 43-54, rising to 14% in people aged 55-64y and 30% in people aged 75 or more. Subsequent population-based studies report similar findings.

A number of factors that we know are associated with ARM such as diet and smoking, are also associated with other diseases of ageing including cardiovascular disease and inflammatory conditions. These conditions are themselves more frequent in people with maculopathy and so the specific causal pathways that lead to ARM are still unclear and we are unsure how best to prevent the condition. By contrast myopic maculopathy (MM) is related mainly just to age and degree of myopia, although raised blood pressure is a risk factor. As myopia is increasing in prevalence across the world, so is the prevalence of MM and it is becoming a leading cause of blindness (3).

Treatment trials involving lifestyle changes such as dietary supplements have yet to show strong results in reducing ARM and there are no known lifestyles thought to protect against MM. It is likely that we have not yet identified either the correct pathways that lead to these diseases or the groups of people who are genetically more or less likely to be helped by lifestyle modifications.

We propose to make use of a unique opportunity - to “piggyback” onto a soon-to-start data collection sweep within the most detailed cohort study in the world- the Avon Longitudinal Study of Parents and Children, (ALSPAC, http://www.bristol.ac.uk/alspac). This sweep will involve 7000 very well-documented adults aged approximately 50-70 years4 who are the parents (the “G0 generation”) of a cohort of children (“G1 generation”) recruited in utero during the early 1990s. Detailed lifestyle and health data relating to these G0 parents are available stretching back 30 years, as well as detailed genetic data. We will collect high quality images of the retina and measurements of the eyes for these participants, to identify those with ARM or MM and we will use all the existing data to investigate the ways in which genetic, lifestyle and medical risk factors may have led to these diseases, over the last 30 years. A session for vision testing is already funded by a grant held by Prof Golding and Dr Northstone and we propose to take the retinal images in this session.

The costs of contacting the participants, bringing them to clinic and examining them, plus the collection of all the previous lifestyle and genetic data are already met and we have requested the costs of the retinal imaging, grading and analysis. There may be the chance to use old equipment to take some basic images showing existing ARM and MM assuming the clinic sweep starts before the grant we have submitted is decided upon. Thus, we will obtain results that will improve our understanding of the antecedents of ARM and MM and therefore potentially how to prevent them, by enhancing the vision data collection that is already planned.

References:
(1) Owen CG, et al; BJO 2012;96:752-756; (2)Emily Chew; Ophthalmology 2020. 127 S120-121 (3) .Baird PN al. Myopia. Nature Reviews Disease Primers. 2020; 6:99 (4) A Fraser et al; Int J Epidemiol 2012: 42 pp97-110:

Impact of research: 
We anticipate wide interest in these findings among patients with AMD and MM and potentially further research into trials if the data suggest behavioural modifications or advice may be useful. The data will also be of interest to the NHS as approximately a third of all spending on sight loss, is used in the treatment of maculopathy and thus it is a huge burden on the NHS, the government and the tax payer, as well as being potentially devastating for affected individuals.
Date proposal received: 
Thursday, 3 June, 2021
Date proposal approved: 
Monday, 7 June, 2021
Keywords: 
Epidemiology, Visual Impairment Blindness, Statistical methods, Ageing, Biological samples -e.g. blood, cell lines, saliva, etc., Mendelian randomisation, Mothers - maternal age, menopause, obstetrics, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc., Nutrition - breast feeding, diet, Sex differences, Statistical methods, Vision, Biomarkers - e.g. cotinine, fatty acids, haemoglobin, etc., Blood pressure, BMI, Cardiovascular, Cohort studies - attrition, bias, participant engagement, ethics, Fathers, Genetic epidemiology, Genetics

B3683 - Common maternal variants and the occurrence of Cleft in their children - 03/06/2021

B number: 
B3683
Principal applicant name: 
Garan Jones | Cleft Collective, Integrative Epidemiology Unit, University of Bristol (UK)
Co-applicants: 
Professor Sarah Lewis, Dr. Evangelia Stergiakouli , Dr Gemma C Sharp
Title of project: 
Common maternal variants and the occurrence of Cleft in their children.
Proposal summary: 

The Cleft Collective Cohort Studies investigates the biological and environmental causes of cleft, the best treatments for cleft and the psychological impact of cleft on those affected and their families. With the help of every cleft team in the UK, up to 3,500 children and their families will be recruited into the study.

After an extensive recruitment period we are now ready to start the investigation into the genetic contributions to Cleft. With the results of our analysis of both children with Cleft and their mothers we hope to increase our knowledge of the causes of cleft and inform the best treatments. We hope that by focusing on the mother's genetics we will be able to highlight areas that have not previously been investigated in depth.

Impact of research: 
We hope to find evidence for some of the underlying mechanisms and pathways that contribute to the development of cleft in children and the effects of maternal genetics on development of the foetus.
Date proposal received: 
Tuesday, 25 May, 2021
Date proposal approved: 
Thursday, 3 June, 2021
Keywords: 
Genetic epidemiology (including association studies and mendelian randomisation), Cleft, syndromic and non-syndromic, GWAS, Microarrays, Statistical methods, Development, Dental, Face - face shape, Genetic epidemiology, Genome wide association study, Methods - e.g. cross cohort analysis, data mining, mendelian randomisation, etc.

B3797 - Interrelations between sleep and ASD/ADHD symptoms and diagnoses in children - 01/06/2021

B number: 
B3797
Principal applicant name: 
sabine Plancoulaine | INSERM (France)
Co-applicants: 
to be recruited, Pr Carmen Schröder, Dr Stéphanie Bouliac
Title of project: 
Interrelations between sleep and ASD/ADHD symptoms and diagnoses in children
Proposal summary: 

Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD) are among the most prevalent neurodevelopmental disorders. ASD is characterized by persistent deficits in social communication and social interaction with restricted, repetitive patterns of behavior, interests, or activities; ADHD characterized by deficits in attention, organization, activity levels and impulse control.
Both disorders are commonly associated with sleep problems, especially short sleep duration, in adults and school-aged children. Less is known in preschoolers. In addition, it is not clear whether sleep troubles are risk factors, consequences or comorbidities of the neurodevelopmental disorder.

Impact of research: 
Very few studies with rather small sample sizes have previously examined the longitudinal association between sleep and ASD symptoms/diagnosis and ADHD symptoms/diagnosis. With combining the large amount of available data from five European birth cohorts in our analyses (with an individual meta-analysis using DataShield)), we are using an innovative approach to fill knowledge gaps and bring new insight into this research field.
Date proposal received: 
Wednesday, 26 May, 2021
Date proposal approved: 
Tuesday, 1 June, 2021
Keywords: 
Epidemiology, Developmental disorders - autism, Statistical methods, Sleep

B3798 - Does socioeconomic status moderate the relationship between adolescent drug use and mental health - 01/06/2021

B number: 
B3798
Principal applicant name: 
Lindsey Hines | University of Bristol
Co-applicants: 
Gemma Sawyer, Professor Laura Howe
Title of project: 
Does socioeconomic status moderate the relationship between adolescent drug use and mental health?
Proposal summary: 

Substance use represents a primary global burden of disease for young people (1) as it has been associated with a wide range of adverse outcomes. These include physical health outcomes, such as infectious diseases and chronic bronchitis, social outcomes, including lower educational attainment and criminal activity, as well as increased substance dependence, risk of overdose, and mental health issues (1). Mental health symptoms and disorders have previously been associated with increased cannabis use in adolescence, including depression, suicidality, anxiety (2), and psychosis (3) . However, substance use and mental health are both complex, multifaceted issues that are likely to be affected by a number of risk factors (3).

One possible risk factor that may influence the relationship between substance use and mental health issues is socioeconomic status (SES), resulting in a greater burden of substance use on individuals of low SES. Research has identified that cannabis use is greater amongst individuals from low SES groups and may potentially be increasing over time (4). Whilst increased use amongst low SES individuals may result in worse mental health outcomes, it is also possible that, either alternatively or additionally, the social environment associated with reduced SES may exacerbate the harms associated with substance use, thus resulting in worse mental health outcomes. Increased harm related to other substances, such as tobacco, amongst low SES individuals has been observed previously (5), and therefore it may be plausible that a similar pattern is true for cannabis. This indicates that SES may be an important moderator of the relationship between adolescent cannabis use and mental health issues, including depression, anxiety, and psychotic experiences.

However, much of the current literature focuses on either substances other than cannabis or the impact of adult substance use and therefore further investigation is needed to understand the impacts of adolescent cannabis use . In addition, many studies have limited ability to draw causal inferences as a result of the high plausibility of reverse causation owing to the utilisation of cross-sectional data. This project aims to investigate the moderating role of SES in the relationship between adolescent cannabis use and mental health using longitudinal data from the ALSPAC cohort.

Impact of research: 
Contirbute to the evidence base on the relatinship between adoelscent cannabis use and metnal health; potentially highlight health inequalities in drug use consequences
Date proposal received: 
Thursday, 27 May, 2021
Date proposal approved: 
Tuesday, 1 June, 2021
Keywords: 
Epidemiology, Addiction - e.g. alcohol, illicit drugs, smoking, gambling, etc., Mental health, Statistical methods, Mental health, adolesence, drug use

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